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Genetic Predictors of Comorbid Course of COVID-19 and MAFLD: A Comprehensive Analysis

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06 July 2023

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07 July 2023

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Abstract
Metabolic-associated fatty liver disease (MAFLD) and its potential impact on the severity of COVID-19 have gained significant attention during the pandemic. This review aimed to explore the genetic determinants associated with MAFLD, previously recognized as non-alcoholic fatty liver disease (NAFLD), and their potential influence on COVID-19 outcomes. Various genetic polymorphisms, including PNPLA3 (rs738409), GCKR (rs780094), TM6SF2 (rs58542926), and LYPLAL1 (rs12137855), have been investigated in relation to MAFLD susceptibility and progression. Genome-wide association studies and meta-analyses have revealed associations between these genetic variants and MAFLD risk, as well as their effects on lipid metabolism, glucose regulation, and liver function. Furthermore, emerging evidence suggests a possible connection between these MAFLD-associated polymorphisms and the severity of COVID-19. Studies exploring the association between indicated genetic variants and COVID-19 outcomes have shown conflicting results. Some studies observed a potential protective effect of certain variants against severe COVID-19, while others reported no significant associations. This review highlights the importance of understanding the genetic determinants of MAFLD and its potential implications for COVID-19 outcomes. Further research is needed to elucidate the precise mechanisms linking these genetic variants to disease severity and to develop gene profiling tools for early prediction of COVID-19 outcomes. If confirmed as determinants of disease severity, these genetic polymorphisms could aid in identifying high-risk individuals and improving the management of COVID-19.
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Biology and Life Sciences  -   Immunology and Microbiology
Preprints on COVID-19 and SARS-CoV-2

1. Introduction

As of June 18, 2023, the global reported cases of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have exceeded 767 million, resulting in over 6.9 million fatalities [1].
The clinical manifestations of this infection range widely, encompassing mild or asymptomatic cases to severe acute respiratory syndrome.
However, it has become evident that the outcome of infection is heavily influenced by host-related factors, including advanced age [2,3,4,5], male gender [2,4,5], and the presence of various comorbidities such as hypertension [6,7], cardiovascular disease [5], obesity [2,3,8,9], and type 2 diabetes [5,10,11,12,13].
While the role of virally driven hyperinflammation, which leads to an excessive release of cytokines and triggers a phenomenon known as a "Cytokine storm," remains a topic of controversy [14], the involvement of inflammatory processes in the severity of COVID-19, particularly among patients with comorbidities, is widely acknowledged [15].
Since the initial phase of the pandemic, the observation of familial clustering of severe COVID-19 cases has suggested the potential contribution of a genetic predisposition [16].
Therefore, it is plausible to consider that the intricate nature of the host's genetic background, characterized by various polymorphisms, could significantly impact the pathogenesis and outcome of COVID-19.
While advanced age, male sex, obesity, diabetes mellitus (DM), and other comorbidities have been established as risk factors for severe forms of the disease, these factors alone do not adequately explain the wide-ranging inter-individual variations observed in the severity of COVID-19 [17,18].
Therefore, the influence of genetic variations on clinical outcomes must be considered [18,19]. In this regard, multiple studies have elucidated the involvement of genetic polymorphisms in susceptibility to and severity of COVID-19, with these polymorphisms being implicated in various biological pathways associated with the disease [18,19].
Interferons (IFN) serve as key mediators of antiviral signaling, stimulating the release of numerous vital components involved in the early host response to viral infection.
Consequently, polymorphisms occurring in IFN genes or their receptors have been linked to an increased susceptibility to COVID-19 or more severe clinical outcomes [19,20,21].
Another crucial genetic mechanism involved in combating viral infections involves a genomic locus that harbors three genes responsible for encoding antiviral 2',5'-oligoadenylate synthetase (OAS) enzymes (OAS1, OAS2, and OAS3). These enzymes are interferon-inducible antiviral proteins that activate the latent form of ribonuclease L (RNase L) [22,23]. Particularly, the RNase L pathway assumes specific significance in the immune response mounted against SARS-CoV-2, an RNA virus [19].
Regarding susceptibility to COVID-19, considerable attention has been directed toward investigating polymorphisms located in the Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2) genes, which are directly involved in viral binding and the subsequent entry of the virus into host cells [24,25].
Non-alcoholic fatty liver disease (NAFLD), currently recognized as metabolic-associated fatty liver disease (MAFLD), encompasses a spectrum of conditions that range from simple steatosis with or without mild inflammation to a necroinflammatory subtype characterized by hepatocellular injury, known as non-alcoholic steatohepatitis (NASH), and eventual progression to cirrhosis [26,27]. MAFLD represents the most prevalent cause of chronic liver disease globally, with an estimated impact on approximately one-fourth of the global population [28,29]. The adoption of a novel definition for MAFLD has been proposed as a more suitable characterization of the hepatic manifestation of metabolic syndrome compared to the conventional definition of NAFLD [30,31,32].
While the relationship remains contentious, initial reports during the COVID-19 pandemic suggested that patients with MAFLD may face an elevated risk of experiencing a more severe disease course [33,34,35,36]. However, it remains unclear whether MAFLD merely associates with adverse outcomes or whether it plays a causal role [37]. Furthermore, it is crucial not only to acknowledge the potential impact of MAFLD on the course of COVID-19 but also to recognize the effects of the COVID-19 pandemic itself on patients with MAFLD and the overall epidemiology of the disease [37].
The pathogenesis of fatty liver is influenced by genetic factors as well. Notably, a large-scale genome-wide association study (GWAS) identified specific DNA sequence variants, including Patatin-like phospholipase domain containing 3 (PNPLA3, rs738409-G), Glucokinase regulator (GCKR, rs780094-T), and Lysophospholipase-like 1 (LYPLAL1, rs12137855-C) that were associated with computed tomography-defined steatosis and biopsy-proven NAFLD characterized by lobular inflammation and fibrosis [38]. Moreover, other investigations have elucidated the functional significance of Transmembrane 6 superfamily member 2 (TM6SF2, rs58542926-T), a variant at the NCAN loci [39,40]. Among these genetic variants, PNPLA3 rs738409-G emerges as the most robust risk factor for NAFLD, exhibiting an odds ratio of 3.24 for histologic NAFLD [38]. Additionally, GCKR rs780094-T and TM6SF2 rs58542926-T have been recognized as significant determinants contributing to inter-individual variation in liver fat content [41,42,43]. Nevertheless, the functional implications of LYPLAL1 rs12137855-C remain relatively less explored.
Regarding the impact of these NAFLD-associated genetic polymorphisms on the course of COVID-19, the precise mechanisms remain incompletely understood (Figure 1). Nonetheless, several studies have already emerged, revealing unexpected associations between these genetic factors and COVID-19 outcomes [44,45,46,47].

2. Genetic Polymorphisms Associated with Susceptibility COVID-19

2.1. ACE2

ACE2 serves as a transmembrane protein and functions as the principal entry receptor for certain coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2, facilitating their entry into host cells [48]. The expression of ACE2 has been associated with an increased number of viral binding sites on cell membranes, rendering carriers susceptible to infection. In particular, the ACE2 single nucleotide polymorphism (SNP) rs2074192 has been identified as a risk factor for hypertension in adult males with obesity [49]. Moreover, rs2074192 has been implicated in the development of type 2 diabetes mellitus and cardiovascular disease [50].
The presence of the intronic variant rs2074192 has been associated with modifications in RNA secondary structure, which may disrupt the delicate equilibrium between ACE2 transcription and translation. This dysregulation has implications for the binding affinity of SARS-CoV-2 to angiotensin receptors [51]. Additionally, earlier studies have demonstrated that COVID-19 patients with coexisting hypertension experienced reduced mortality rates when treated with ACE inhibitors or angiotensin II receptor blockers (ARBs) compared to individuals who did not receive these medications [52].
ACE2 polymorphism (rs2074192) in obese, smoking males has been associated with greater variability in outcomes for COVID-19 disease, leading to more divergent outcomes [53].
Several investigations have highlighted a potential link between ACE2 gene polymorphisms and disease severity in individuals infected with SARS-CoV-2 (Table 1). Notably, a study conducted by Sienko et al. demonstrated a significant correlation between the ACE2 receptor gene rs2074192 polymorphism and the severity of COVID-19 in adult patients [54]. The authors observed a strong association between the ACE2 rs2074192 TT-genotype and adverse outcomes in patients with severe forms of COVID-19 (p = 0.0016). These findings align with a separate study conducted by Cafiero et al., which reported a higher prevalence of the T-allele of ACE2 rs2074192 in symptomatic individuals compared to asymptomatic Italian patients [55].
Ma et al. investigated the association between rs2074192 and COVID-19 in the Chinese population, revealing a significant relationship (p < 0.05)[56]. Additionally, Molina et al. found that heterozygosity of rs2074192 SNPs in ACE2 was associated with disease severity caused by SARS-CoV-2, acting as a protective factor specifically in women.
Several studies have also reported conflicting results regarding the association between this ACE2 variant and disease outcomes [57,58,59]. These discrepancies in findings may be attributed to variations in sample sizes and the genetic backgrounds of the populations under investigation.

2.2. IFNAR2

Interferons (IFNs) encompass a diverse group of cytokines that elicit various biological activities through the induction of thousands of interferon-stimulated genes (ISGs). These ISGs exhibit antiviral, antiproliferative, antiangiogenic, and immunomodulatory functions [60]. The antiviral response is amplified and disseminated by innate IFN types I and III (IFN-α/β and IFN-γ, respectively). While IFN-λ mainly acts on mucosal epithelium due to receptor expression constraints, IFN-α/β exerts its effects on all nucleated cells, making it indispensable in the antiviral defense mechanism [61,62,63].
The genetic association studies conducted during the coronavirus disease 2019 (COVID-19) outbreak has highlighted the notable involvement of IFNAR2 (Table 1). Pairo-Castineira et al., in collaboration with a group of researchers, carried out an extensive genome-wide association study known as GenOMICC (genetics of mortality in critical care). This study encompassed a cohort of 2,244 critically ill COVID-19 patients admitted to 208 intensive care units across the United Kingdom. The findings of this study demonstrated a significant association between the IFNAR2 rs2236757 gene variant and increased severity of the disease [19].
Likewise, various studies employing diverse methodologies have corroborated the significance of IFNAR2 as a crucial gene implicated in the severity of COVID-19 [64,65,66,67,68].
In their research, Fricke-Galindo et al. (2022) discovered a notable association between genetic polymorphisms of IFNAR2 (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) and an increased mortality risk in individuals afflicted with COVID-19 [20]. Intriguingly, the non-surviving group exhibited significantly lower levels of soluble receptors in comparison to the surviving group. These findings are consistent with previous studies that have elucidated the suppression of the IFN-I activation pathway by SARS-CoV-2, resulting in reduced levels of IFN-α and -β among COVID-19 patients [69,70,71]. Furthermore, the group of survivors displayed higher levels of sIFNAR2 in comparison to the non-survivors, indicating an augmented antiviral activity of IFN facilitated by the stability conferred by sIFNAR2 [20].
The findings from the investigation conducted by Dieter K. et al. (2022) [21] further support the existing body of research [19,20] by confirming the association between the rs2236757 genotype of IFNAR2 and an elevated risk of hospitalization in intensive care units and mortality among patients with COVID-19.
These results suggest that the rs2236757 polymorphism may contribute to reduced expression of IFNAR2, consequently predisposing individuals to more severe manifestations of COVID-19.

2.3. OAS

Following viral infection, the immune system initiates the production of antiviral cytokines, with interferons (IFNs) being particularly prominent. Among the IFN-stimulated genes, the 2´, 5´- oligoadenylate synthetases (OAS) family plays a crucial role in the innate immune response. OAS proteins exhibit antiviral functions by serving as nucleotidyltransferases, facilitating the oligomerization of ATP into 2´, 5- linked oligoadenylates (2-5A). This process leads to the activation of latent RNase L, which provides antiviral protection through the degradation of viral RNA [72,73,74,75]. The human OAS gene family comprises four genes, namely OAS1, OAS2, OAS3, and OAS-like (OASL), which are located on chromosome 12. Alternative splicing of these genes gives rise to 10 isoforms [76,77,78].
Several genome-wide association studies (GWASs) have identified various genetic variants at specific loci that are associated with susceptibility to COVID-19 (Table 1), either in general or in severe cases, when compared to controls from the general population [19,79].
One of the prominent variants identified within these loci is rs10774671 located at 12q24.13, which encompasses three genes responsible for encoding OAS enzymes, namely OAS1, OAS2, and OAS3 [19,79].
The investigation carried out by Banday et al. (2022) provided compelling evidence of the substantial influence of rs10774671 on the expression of OAS1, a crucial antiviral protein involved in the eradication of SARS-CoV-2, and its overall impact on the hospitalization outcomes of individuals with COVID-19 [80]. They propose that the functional impact of rs10774671 contributes to the association with COVID-19 severity by modulating the abundance of the OAS1 protein [80].
In a separate study, Pairo-Castineira et al. identified an association between the polymorphism OAS3 rs10735079 and the development of critical illness in individuals with COVID-19 [19].
Table 1. Summary of commonly reported single nucleotide polymorphisms associated with susceptibility to COVID-19.
Table 1. Summary of commonly reported single nucleotide polymorphisms associated with susceptibility to COVID-19.
Gene SNP Patient # SNP Effects Significans Features Population References
IFNAR2 rs 2236757 G/A 694 Associated with severe forms of COVID-19 and increased mortality p = 0,031 In patients of non-white ethnicity, the presence of the A allele was linked to an increased risk of both intensive care unit (ICU*) admission and mortality Brazil population [21]
2244 Associated with severe forms of COVID-19 p < 0,005 The A allele demonstrated an association with an elevated risk of developing severe COVID-19. Additionally, lower expression of IFNAR2 was observed in individuals with life-threatening cases of COVID-19 UK population [19]
1202 Associated with mortality risk among patients with severe COVID-19 p = 0,023 N/A Mexico population [20]
ACE2 rs 2074192 G/A 318 Associated with the disease severity caused by SARS-CoV-2 p = 0,016 Heterozygosity of rs2074192 was identified as a protective factor against COVID-19 infection in women Spain population [81]
rs 2074192 C/T 104 Correlated with more severe outcomes of SARS-CoV-2 infection p = 0,0088 (for female)
p < 0,0001 (for male)		 The T allele exhibited a higher prevalence in symptomatic patients compared to asymptomatic individuals Italian population [55]
293 Was not associated with COVID-19 p > 0,005 The ACE2 rs2074192 variant does not confer a predisposition to the development of long-COVID symptoms in individuals who were previously hospitalized due to COVID-19 Spain population [59]
191 Was not associated with COVID-19 p > 0,005 N/A China population [58]
481 Was not associated with COVID-19 Severe: p = 0,49
Critical: p = 0,6		 N/A Mexico population [57]
456 Associated with COVID-19 p  <  0,001 Rs2074192 may potentially correlate with susceptibility to COVID-19-related cardiovascular complications and acute inflammatory infections China population [56]
188 Associated with an increased risk of a more severe disease course of SARS-CoV-2 infection p = 0,002 A strong correlation was observed between the TT-genotype of ACE2 rs2074192 and unfavorable outcomes in individuals with severe forms of COVID-19 [54]
OAS1 rs10774671 A allele 3084 Associated with susceptibility to COVID-19 Europeans: p < 0,005;
Africans: p = 0,079		 The presence of the A allele in rs10774671 may lead to decreased expression of OAS1, thereby increasing the specific human risk of developing severe COVID-19 Europeans, Asians, Africans, African American, Hispanic [80]
OAS3 rs10735079 A/G 2244 Associated with severe forms of COVID-19 p < 0,001 N/A UK population [19]
* ICU - intensive care unit;.

3. Genetic Polymorphisms Associated with Susceptibility to MAFLD

3.1. PNPLA3

An integral aspect of MAFLD pathogenesis involves the perturbation of lipid metabolism, resulting in the aberrant accumulation of lipids within the liver, specifically steatosis. The principal source of hepatic triglycerides (TG) arises from adipocytes-released free fatty acids (FFAs), which are facilitated by lipase enzymes [82,83]. Adipose triglyceride lipase (ATGL), encoded by the Patatin-like phospholipase domain containing 2 (PNPLA2) gene, represents a significant enzyme involved in this cascade. In 2008, a pioneering genome-wide association study (GWAS) investigating NAFLD patients, encompassing diverse cohorts of Hispanics, African Americans, and European Americans, revealed noteworthy findings [84]. Specifically, the presence of a genetic variant in Patatin-like phospholipase domain-containing 3 (PNPLA3), known as rs738409 or I148M, was linked to heightened lipid accumulation, even after adjusting for crucial factors such as ethnicity, body mass index (BMI), diabetes status, and alcohol consumption [84]. Furthermore, a range of studies conducted across distinct populations has further elucidated the impact of the I148M variant and other variants associated with NAFLD (Table 2).
Within the PNPLA3 gene, the production of adiponutrin, a triacylglycerol lipase, takes place, enabling the hydrolysis of triacylglycerols. However, the presence of the I148M variant has been shown to impede the enzymatic activity of this lipase, thereby fostering the onset of hepatic steatosis [85]. A recent meta-analysis investigating the impact of the I148M variant on NAFLD risk revealed that individuals carrying the minor G-allele had a 19% increased risk of developing NAFLD. Notably, the risk escalated to 105% among individuals harboring both GG alleles [86].
The I148M variant of PNPLA3 exhibits a comparable effect to more advanced stages of NAFLD. A meta-analysis encompassing 16 studies demonstrated that individuals carrying homozygous GG alleles have a 3.5-fold increased risk of developing NASH and a 3.2-fold elevated risk of experiencing fibrosis [87]. Furthermore, another meta-analysis revealed a significant association between the I148M variant and a 2.54-fold increased risk of NASH development [88]. Notably, a significant dose-dependent relationship of the G allele was observed concerning this risk [86,88]. Similarly, an association between the I148M variant and cirrhosis progression was also noted. Specifically, the presence of a single G allele conferred a 2-fold increased risk of developing cirrhosis, while individuals with homozygous GG alleles had a 3-fold higher risk compared to those with CC genotypes [89].

3.2. TM6SF2

The rs58542926 (E167K) variant, derived from the Transmembrane 6 superfamily, member 2 (TM6SF2) gene, represents another significant single nucleotide polymorphism (SNP) associated with NAFLD (Table 2). TM6SF2 is an endoplasmic reticulum (ER) transmembrane protein primarily expressed in hepatocytes, renal cells, and intestinal cells, playing a crucial role in the regulation of lipoprotein secretion [90]. The presence of the E167K variant disrupts the protein's functionality, leading to a loss of its normal function and subsequently reducing the secretion of very low-density lipoprotein (VLDL) [91]. This variant has been linked to an increased susceptibility to NAFLD, hepatic steatosis, and advanced fibrosis (Table 2), while its association with inflammation remains inconclusive [92,93,94]. Although the impact of the E167K variant is relatively modest when compared to the PNPLA3 I148M variant, individuals harboring both the I148M and E167K variants exhibit a synergistic or additive effect, resulting in a twofold or cumulative risk of developing NAFLD [95]. These findings suggest the existence of gene-gene interactions contributing to the pathogenesis of the disease.
The E167K variant is present in lean individuals with NAFLD, in addition to those who are obese or overweight [96]. This observation underscores the specific involvement of the E167K variant in the development of NAFLD. Notably, the majority of studies examining "lean" NAFLD cases have predominantly focused on Asian populations [97], which aligns with the higher prevalence of the E167K variant in East Asians. The minor T allele frequency of this variant is more prevalent in East Asian populations (~34%) compared to Europeans (~26%), Hispanics (~10%), and Africans (~6%) [98].
A study conducted by Liu et al. [99] demonstrated the potential impact of the TM6SF2 rs58542926 variant on fibrosis progression in NAFLD participants of European Caucasian descent. However, in contrast, Wong et al. [100] reported that the TM6SF2 rs58542926 variant did not contribute to the development of liver fibrosis or cirrhosis in Chinese individuals with NAFLD. These findings highlight the potential influence of genetic and ethnic variations on the association between the TM6SF2 variant and fibrosis progression in different populations.
In a recent exome-wide association study focusing on liver fat content, the TM6SF2 rs58542926 variant demonstrated a significant association with alanine aminotransferase (ALT) levels in both the Dallas Biobank and the Copenhagen Study. However, this variant did not show a statistically significant relationship with aspartate aminotransferase (AST) levels [39]. Nevertheless, these findings were not replicated in genome-wide association studies (GWASs) [101]. Conversely, certain GWASs have suggested a close association between the TM6SF2 rs58542926 variant and serum lipid levels [102,103].
In a meta-analysis conducted by Li et al., the TM6SF2 rs58542926 T allele was confirmed as a risk factor for the susceptibility and development of NAFLD and its associated metabolic phenotypes in both adults and children [93]. Interestingly, the rs58542926 T allele was found to be a protective factor for serum lipid levels. Notably, in this study, the risk of NAFLD associated with carrying the T allele was higher in children compared to adults. The effect size of the rs58542926 T allele was more pronounced in pediatric NAFLD than in adult NAFLD. Furthermore, their findings revealed that the rs58542926 variant was associated with the progression of steatosis, severe steatosis, fibrosis stages, and fibrosis progression in adults. However, there was no statistically significant difference observed in the fibrosis stages [93].

3.3. GCKR

The GCKR gene is responsible for encoding a glucokinase regulator that forms a complex with glucokinase and influences hepatic glucose storage and metabolism by directing its localization to the nucleus [104]. Any genetic variant that affects the functionality of the GCKR protein may contribute to the risk of NAFLD. In previous genome-wide association studies (GWAS) focusing on NAFLD, a common single nucleotide polymorphism (SNP) in the GCKR gene, namely rs780094, was identified and found to be associated with NAFLD [38]. This GWAS included 592 NAFLD patients with biopsy-proven cases from the NASH Clinical Research Network [38] and was the first to report the role of rs780094 in NAFLD. Furthermore, this study revealed a significant and robust association between rs780094 and lipid and glycemic traits. Subsequently, several genetic association studies have replicated and supported this association [43,105,106,107] (Table 2).
A meta-analysis conducted by Zain et al. examined the association of the GCKR rs780094 SNP with NAFLD, revealing a pooled effect of a 1.25-fold increased risk when comparing individuals carrying the T-allele with those carrying the C-allele [108]. This meta-analysis further demonstrated a significant association between rs780094 and NAFLD across different genetic models, including the dominant, recessive, and homozygote models [108].
The potential risk effect of the T-allele in NAFLD susceptibility has been observed in the initial studies, which reported a significant association between the rs780094-T-allele and an increased risk of NAFLD. While two studies conducted by Yang et al. [107] and Gorden et al. [43] did not find a statistically significant association between the T-allele and the risk of NAFLD, the direction of the effect and the effect size demonstrated similar trends to the findings of the GOLD's consortium [38]. It is worth noting that the pooled effective allele frequency exceeded 40% in each study population, emphasizing the substantial impact it can have on the risk of NAFLD.
In a comprehensive meta-analysis conducted by Li et al., which encompassed 25 studies with a total of 6,598 cases and 19,954 controls, the objective was to precisely evaluate the association between GCKR polymorphisms and the risk of NAFLD [109]. The pooled estimates from the analysis revealed a significant predisposition to NAFLD in individuals carrying the T allele of the GCKR rs780094 polymorphism [109].

3.4. LYPLAL1

The LYPLAL1 gene encodes a 26 kDa cytosolic protein known as lysophospholipase-like protein 1, which belongs to a subclass of the lysophospholipase family [110]. Several single nucleotide polymorphisms (SNPs) located near the LYPLAL1 gene have been found to exhibit a significant association with fat distribution, displaying a relatively sex-specific pattern [111]. In a large-scale genome-wide association study (GWAS) conducted by The Genetics of Obesity-Related Liver Disease Consortium, LYPLAL1 rs12137855 was identified as being associated with NAFLD in a cohort of 7,177 adults of European ancestry [38]. This variant was found to be linked to steatosis as defined by computed tomography, as well as biopsy-proven NAFLD characterized by lobular inflammation and fibrosis [38].
In a study conducted by Sliz et al., the influence of genetic polymorphisms on the risk of NAFLD was investigated. It was observed that the metabolic effects associated with LYPLAL1 rs12137855-C were similar, albeit statistically less robust, to those observed with GCKR rs1260326-T. These findings suggest that LYPLAL1 may contribute to the regulation of circulating and hepatic triglyceride levels by influencing hepatic glucose metabolism, similar to the role played by GCKR. This hypothesis is supported by the findings of Ahn et al., who demonstrated that inhibiting LYPLAL1 leads to an increase in glucose production in the hepatocytes of humans, rats, and mice [112].
Nevertheless, conflicting results have been reported regarding the impact of LYPLAL1 rs12137855 on NAFLD steatosis. Several studies [105,112,113,114,115] do not provide evidence supporting the association between LYPLAL1 rs12137855 and NAFLD steatosis. As such, among all the genetic polymorphisms discussed, the influence of LYPLAL1 rs12137855 on the development of NAFLD remains the most contentious and subject to debate.
Table 2. Summary of Commonly Reported Single Nucleotide Polymorphisms Associated with Susceptibility to MAFLD.
Table 2. Summary of Commonly Reported Single Nucleotide Polymorphisms Associated with Susceptibility to MAFLD.
Gene SNP The number of patients SNP Effects Significance Features NAFLD diagnosed by Population Reference(s)
PNPLA3 rs738409 C > G (I148M) 9515 Associated with NAFLD risk, steatosis and NASH p > 0,001 Hepatic fat content exhibited a more than twofold increase in PNPLA3-148M homozygotes compared to individuals without this genetic variant H-MRS African American; European American; Hispanic; [84]
1117 Associated with steatosis and histological severity of NAFLD p = 0,039 steatosis); p < 0,001 (portal inflammation);, p = 0.004 (NAS); p < 0.001 (fibrosis The presence of the G allele in rs738409 was associated with the development of steatosis and greater histological severity of NAFLD. In pediatric patients, the high-risk G allele in rs738409 was linked to an earlier onset of the disease Histologically Americans (894 adults/223 children) [116]
1092 Associated with steatosis and hepatocyte ballooning p > 0,001 (steatosis); p=0,006 (ballooning); PNPLA3 rs738409 G allele was correlated with liver steatosis and an elevated risk of progression from simple steatosis to NASH Histologically Americans [43]
126 Increased the risk for NAFLD p < 0,001 The risk of NAFLD increased by 3,7-fold in subjects carrying the PNPLA3 GG genotype Ultrasonography Hispanic children [117]
1709 Associated with NAFLD steatosis p < 0,001 The G allele was associated with elevated levels ALT, HOMA-IR*, and insulin Magnetic resonance imaging (MRI) African Americans; Japanese Americans;
Latinos; Native Hawaiians; European Americans		 [118]
7176 Associated with NAFLD risk and steatosis p < 0,001 (both) N/A CT, Histologically European population [38]
417 Associated with steatosis p < 0,0001 Individuals with the PNPLA3 GG genotype at rs738409 exhibited 2,7-fold higher liver fat content compared to those with the CC genotype proton NMR (Proton nuclear magnetic resonance) Finnish population [119]
405 Associated with the ultrasonography-determined steatosis p < 0,001 The 148M allele was linked to reduced levels of LDL-C* in patients with NAFLD Ultrasonography Chinese population [120]
1027 Associated with NAFLD and moderate-to-severe steatosis p = 0,006 (NAFLD); p = 0,001 (steatosis). The G-allele of PNPLA3 rs738409 exhibited an association with NAFLD and a 1,09 IU/L increase in ALT levels Ultrasonography Chinese children [121]
768 Associated with NAFLD p = 0.00087 PNPLA3 GC and GG genotypes were significantly linked to an elevated risk of the disease Ultrasonography Chinese population. [113]
4300 Associated with hepatic steatosis, and developed NAFLD and liver fibrosis p <0,001 (NAFLD)
 Compared to CC homozygotes, GG homozygotes presented higher liver fat and liver fibrosis scores, despite having a better metabolic status (P < 0,05) Ultrasonography Chinese population [122]
879 Associated with NAFLD and insulin resistance p = 0,004 The prevailing paradigm surrounding the PNPLA3 I148M (GG+GC) polymorphism indicates a positive correlation with elevated waist circumference, fasting insulin levels, HOMA-IR* scores, as well as higher concentrations of ALT and ferritin Ultrasonography Normoglycaemic population [123]
270 Associated with NAFLD risk, steatosis, and fibrosis p < 0,001 (NAFLD);
p = 0,0003 (steatosis);
p = 0,0445 (fibrosis)		 Characterized by a pattern of steatosis, inflammation, and fibrosis, which are interconnected factors Histologically German population (70 adolescents; 200 adult control cohort) [124]
515 Associated with liver steatosis, and fibrosis p < 0,001 (steatosis);
p < 0,001 (fibrosis)		 The presence of the PNPLA3 risk allele exhibited heightened serum AST and ALT activities, with statistical significance observed at a p-value less than 0,05 Histologically (320 biopsied patients) German population [125]
1326 Associated with steatosis, NAS* and fibrosis p < 0,001 (NAFLD);
p = 0,0016 (steatosis);
p < 0,001 (NAS*)		 The PNPLA3 risk allele was found to be linked with elevated levels of AST and ALT in individuals diagnosed with NAFLD Histologically and CT Japanese population [126]
445 Associated with NAFLD risk, steatosis, fibrosis, and cirrhosis p < 0,001 (NAFLD)
 The ability to export VLDLs* from the liver is influenced by certain factors. Ultrasonography Italian population [127]
574 Associated with the severity of steatosis and fibrosis and the presence of NASH 95% CI = 1,04-1,76 (steatosis);
CI = 1,12-2,04 (NASH)		 The G allele was observed to be disproportionately transmitted to children affected by the condition Histologically Italian (253) and United Kingdom (321) population [128]
246 Associated with the risk of cirrhotic evolution р < 0,001 In the NAFLD population, each copy of the G allele was found to be associated with nearly a twofold increase in the risk of cirrhosis. Furthermore, individuals who were GG homozygous exhibited a tripled risk compared to those who were CC homozygous Histologically Italian population [89]
1380 Associated with NAFLD risk, steatosis, NASH, fibrosis, cirrhosis and HCC* p < 0,0001 (steatosis, NASH, fibrosis);
p = 0,0007 (cirrhosis)		 Such results are caused by the co-presence of the 3 at-risk variants: rs738409 C>G (PNPLA3 I148M), rs58542926 C>T (TM6SF2 E167K), and rs641738 C>T MBOAT7 Histologically European population [129]
470 Associated with NAFLD risk, steatosis and NASH p < 0.001 (steatosis); p < 0,001 (lobular inflammation); p = 0,002 (ballooning) The presence of specific features of steatohepatitis was found to be linked to the identified factor, but no significant associations were observed with liver fibrosis, anthropometry (body measurements), or insulin resistance Histologically Belgian population [130]
285 Associated with NAFLD risk and NASH p = 0,002 (NAFLD);
p <0,001 (NASH)		 While the PNPLA3 genotype did not exhibit an association with the grade of steatosis, individuals with GG homozygosity had an increased likelihood of significant NASH activity and fibrosis Ultrasonography Brazilian population [131]
342 Associated with NAFLD risk, NASH severity and fibrosis p < 0,0001 (NAFLD);
p < 0,0001 (NASH);
p = 0,013 (fibrosis)		 No associations were identified between the PNPLA3 genotype and simple steatosis or other histological parameters Histologically Chinese, Indian and Malay [132]
365 Associated with the development of NAFLD and the severity of liver histology p = 0,002 (NAFLD development);
p < 0,005 (NAFLD severity)		 Patients who possessed the PNPLA3 GG genotype exhibited higher levels of NAS* compared to those with the PNPLA3 CC genotype Histologically Turkish population [133]
225 Associated with NAFLD and NASH risk, and fibrosis p = 0,04 (NASH);
p = 0,016 (fibrosis)		 The GG genotype demonstrated an association with decreased platelet counts Histologically Turkish population [134]
232 Associated with NAFLD, fibrosis but not steatosis 95% [CI] = 1,98-6,71 (NAFLD)
 No significant associations were found between the GG genotype and body mass index, triglyceride levels, high- and low-density lipoprotein levels, or diabetes, as well as the steatosis grade (with a p-value greater than 0,05) Histologically Chinese population [135]
904 Associated with NAFLD in lean individuals p = 0,003 (NAFLD)
 Among individuals diagnosed with (NAFLD, a higher frequency of lean subjects (30.3%) carried the PNPLA3 rs738409 GG genotype compared to overweight (17.9%) and obese subjects (17.4%) Proton-magnetic resonance spectroscopy Chinese population [136]
831 Associated with NAFLD and fibrosis, but not steatosis p < 0,0001 (NAFLD);
p = 0,011 (fibrosis)		 The GG genotype was associated with elevated levels of AST (p = 0,00013), ALT (p < 0,0001), and ferritin (p = 0,014) Histologically Japanese population [137]
1461 Associated with NAFLD and NASH p < 0,0001 (NAFLD, NASH) Was also linked to hyaluronic acid levels, HbA1c* levels, and iron deposition in the liver Histologically Japanese population [138]
339 Associated with NAFLD and fibrosis p = 0,028 (NAFLD);
p = 0,01 (fibrosis)		 Within the NAFLD patient population, the frequency of CG+GG genotypes was significantly higher in individuals with advanced fibrosis Ultrasonography Korean population [139]
1363 Associated with NAFLD p < 0,0001 (NAFLD) Carriers of the rs738409-G allele had a 1,19-fold increased risk for NAFLD and exhibited significantly lower levels of visceral and subcutaneous adiposity, body mass index, triglycerides, and insulin resistance compared to CC carriers Ultrasonography and CT Korean population [140]
244 Associated with NAFLD, NASH risk. p < 0,0005 (NAFLD); p < 0,05 (NASH) N/A Proton magnetic resonance spectroscopy Indian population [141]
335 Associated with NAFLD risk p = 0,04 (NAFLD) The presence of the G allele exhibited a significant association with higher levels of fasting insulin, HOMA-IR*, ALT, and AST values specifically among affected cases, while no such association was observed in the control group Ultrasonography Asian Indians [142]
200 Associated with NAFLD risk and steatosis p < 0,05 (steatosis) Patients carrying the G allele demonstrated elevated levels of ALT, dyslipidemia, and insulin resistance Ultrasonography Indian population [143]
306 Associated with NAFLD risk p = 0,001 (NAFLD) PNPLA3 gene polymorphism was found to be linked to higher levels of ALT Ultrasonography Indian population [144]
207 Associated with NAFLD risk p < 0,001 (NAFLD) The PNPLA3 rs738409 gene polymorphism significantly increases the risk of NAFLD by up to four-fold in individuals with elevated triglyceride levels Ultrasonography Indian population [145]
224 Associated with NAFLD, NASH, fibrosis, and cirrhosis. p < 0,05 The GG genotype exhibited a 20,25-fold higher odds of developing NAFLD, as well as a 6,53-fold higher odds of experiencing non-alcoholic steatohepatitis (NASH) Ultrasonography Indian population [146]
144 Associated with MAFLD p = 0,017 In a multivariable analysis, hypertriglyceridemia, BMI, and the PNPLA3 GG genotype were identified as factors associated with MAFLD CT, MRT Chinese population. [147]
143 Associated with NAFLD p = 0,002 The presence of PNPLA3 risk alleles impairs the response to dietary interventions in individuals diagnosed with NAFLD Ultrasonography German population [148]
525 Associated with NASH and fibrosis p = 0,008 (NASH);
p = 0,020 (fibrosis)		 The PNPLA3 genotype showed an association with the HOMA-IR* and insulin resistance in adipose tissue Histologically Korean population [149]
211 Associated with NAS* (NAFLD Activity Score) NAS: ≤2 vs ≥3,
p = 0,667;
≤4 vs ≥5,
p = 0,034)		 The PNPLA3 genotype was found to have a partial impact on the NAFLD activity score
 Histologically Japanese population [150]
4804 Associated with steatosis p = 0,01 The presence of PNPLA3 variants was found to be associated with elevated levels of ALT Ultrasonography Non-Hispanic white, non-Hispanic black, and Mexican American participants in the US population [151]
797 Associated with NAFLD p = 0,008 PNPLA3 variants may contribute to the susceptibility of NAFLD in obese individuals across various ethnic groups Ultrasonography Chinese children [105]
307 Associated with NAFLD p < 0,01 No significant effect modification was observed with BMI FibroScan Mexican population [114]
382 Associated with NAFLD, and fibrosis p = 0,0044 (NAFLD);
p = 0,0272 (fibrosis)		 Individuals with the PNPLA3 GG genotype had a significantly increased risk (3,29-fold) of developing NAFLD compared to those with the CC genotype Histologically Brazilian population [152]
349 Increased the risk of NAFLD p = 0,29 Although the presence of the GG genotype showed a 1.39 times increased risk of NAFLD, this association did not reach statistical significance Histologically and Ultrasonography Turkey population [153]
GCKR rs780094 C > T 1092 Was not associated with NAFLD p > 0,05 The GCKR SNP rs780094 exhibited a significant association with elevated serum triglyceride levels (p = 0,04) Histologically American [43]
270 Associated with NAFLD risk, steatosis, and especially fibrosis p = 0,0281 (NAFLD);
p = 0,0275 (fibrosis)		 In individuals with the rs738409 G/G genotype, proteome profiling analysis revealed a reduction in the levels of GCKR protein and a downregulation of the retinol pathway Histologically German population (70 adolescents; 200 adult control cohort) [124]
7176 Associated with NAFLD risk and steatosis p < 0,001 (NAFLD risk);
p = 0,01 (steatosis)
 N/A CT; Histologically European population [38]
4804 Associated with steatosis p = 0,03 Was associated with a high level of ALT Ultrasonography Non-Hispanic white, non-Hispanic black, and Mexican American participants in the US population [151]
366 Associated with the severity of liver fibrosis p < 0,001 Associated with higher serum triglyceride levels (p = 0,02) Histologically Italian population [154]
797 Associated with NAFLD p = 0,008 Associated with higher mean serum ALT concentration Ultrasonography Chinese children [105]
620 Associated with NAFLD 95% CI: 1,14-1,28 (NAFLD) Demonstrated an association with specific dietary habits, such as the consumption of soda, eggs, and soybean. Ultrasonography Uyghur population [115]
342 Associated with NAFLD, NASH, and fibrosis p = 0,013 (NAFLD); р = 0,012 ( NASH);
p = 0,038 ( fibrosis)		 The combined effect of GCKR and adiponutrin rs738409 indicated a substantially increased risk of NAFLD (p = 0,010) Histologically Malaysians (Malays, Chinese, and Indians) [106]
903 Associated with NAFLD p = 0,0072 The T-allele of GCKR rs780094 showed a significant association with an elevation in fasting triglyceride levels Ultrasonography Chinese population [107]
TM6SF2 rs58542926 C>T 768 Associated with NAFLD p = 0,0016 The T allele of TM6SF2 rs58542926 showed a higher prevalence among subjects diagnosed with NAFLD Ultrasonography Chinese population [113]
515 Associated with NAFLD risk and steatosis but not fibrosis p = 0,003 (steatosis) Associated with significantly increased AST but not ALT Histologically (320 biopsied patients) German population [125]
445 Associated with NAFLD risk p = 0,008 (NAFLD) Affects the liver's ability to export very low-density lipoproteins (VLDLs) Ultrasonography Italian population [127]
1380 Associated with NAFLD risk, steatosis, NASH, fibrosis, cirrhosis and HCC* p < 0,0001 (steatosis, NASH, fibrosis);
p = 0,0007 (cirrhosis)		 Such results are caused by the co-presence of the 3 at-risk variants: rs738409 C > G (PNPLA3 I148M), rs58542926 C>T (TM6SF2 E167K), and rs641738 C > T MBOAT7 Histologically European population [129]
3260 Associated with NAFLD p = 0,02 No significant effect on inflammation was observed for the rs58542926 T allele Histologically International [155]
361 Associated with NAFLD, steatosis and disease severity p = 0,038 (NAFLD) rs58542926 was not associated with levels of liver enzymes, lobular inflammation and fibrosis Ultrasonography and Histologically Argentina population [101]
300 Associated with liver fat p < 0,05 Individuals with this variant exhibit preserved insulin sensitivity in relation to processes such as lipolysis and hepatic glucose production, and they do not typically experience hypertriglyceridemia H-MRS Finnish population [156]
143 Associated with NAFLD p = 0,041 The presence of TM6SF2 risk alleles hinders the response to dietary interventions in individuals diagnosed with NAFLD Ultrasonography German population [148]
1010 Associated with steatosis p < 0,0001 (steatosis) It is associated with higher levels of ALT and lower levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and non-high-density lipoprotein cholesterol Ultrasonography Italian children [157]
878 Associated with steatosis p = 0,002 Carriers of the TM6SF2 167K variant have a threefold increased risk of developing hepatic steatosis, which often manifests early in life Ultrasonography Italian children [158]
957 Associated with NAFLD risk, steatosis and fibrosis p = 0,05 (NAFLD);
p < 0,05 (steatosis)

 Associated with high HFF% in Caucasians and African Americans, with high ALT levels in Hispanics and with a more favorable lipoprotein profile in Caucasians and Hispanics Magnetic resonance imaging (MRI) and Histologically Caucasians, African, Americans, and Hispanics children and adolescents [42]
1074 Associated with NAFLD risk, steatosis, NASH, advanced hepatic fibrosis p = 0,0008 (NAFLD);
P < 0,001 (steatosis);
p = 0,039 (NASH); p = 0,0074 (fibrosis)		 Carriage of the TM6SF2 variant does not appear to further increase HCC* risk independent of its effect on fibrosis stage Histologically Caucasians and Europeans [99]
316 Associated with NAFLD risk and steatosis p = 0,003 (NAFLD);
p = 0.023 (steatosis)		 Associated with increased ALT but no other clinical parameters, such as AST, ALP* and lipids FibroScan Chinese population [95]
768 Associated with NAFLD risk p = 0,0007 TM6SF2 167K allele was associated with NAFLD after adjustment for age, sex, body
mass index and status of diabetes		 Ultrasonography Chinese population [159]
1201 Associated with NASH and fibrosis p < 0,05 Associated with more-severe steatosis, necroinflammation, ballooning, and fibrosis Histologically Italian, Finnish, and Swedish [160]
525 Associated with NASH and fibrosis p = 0.008 (NASH);
p = 0.020 (fibrosis)		 Even after adjustment for metabolic risk factors rs58542926 increased the risk of NASH and significant fibrosis Histologically Korean population [149]
503 Associated with NAFLD risk p = 0,0004 The presence of rs58542926 variant in the TM6SF2 gene exhibited a significant association with NAFLD, indicating a 2,7-fold higher risk of developing the condition Ultrasonography South Indians and North-East Indians [161]
285 Was not associated with NAFLD risk p = 0,78 The presence of the T allele was not found to be associated with NAFLD or NASH, and it did not show any association with histological features related to these conditions Ultrasonography Brazilian population [131]
144 Was not associated with NAFLD risk p > 0,05 There was no association between rs58542926 and liver steatosis (p = 0.62), ballooning (p = 0.14), lobular inflammation (p = 0.99) and fibrosis (p = 0.89) CT, MRT Chinese population [147]
211 Was not associated with NAS p > 0,05 The TM6SF2 genotype did not affect the NAFLD activity score ( ≤ 2 vs ≥ 3, p = 0.867; ≤ 4 vs ≥ 5, p = 0,936) Histologically Japanese population [150]
LYPLAL1 rs12137855 C > T 7176 Associated with NAFLD risk and steatosis p < 0,001; (NAFLD risk) C-allele was associated with CT defined steatosis and biopsy-proven NAFLD CT; Histologically European [38]
797 Was not associated with NAFLD p > 0,05 N/A Ultrasonography Chinese children [105]
307 Was not associated with NAFLD p > 0,05 N/A FibroScan Mexican population [114]
620 Was not associated with NAFLD p > 0,05 N/A Ultrasonography Uyghur population [115]
* LDL-C - low-density lipoprotein cholesterol; HOMA-IR - Homeostasis Model Assessment of Insulin Resistance; NAS - NAFLD activity score; VLDLs - very low-density lipoproteins; HCC - hepatocellular carcinoma; HbA1c - hemoglobin A1C; ALP - Alkaline Phosphatase; CT - computerized tomography.

4. The Influence of MAFLD-Associated Polymorphisms on the Severity of COVID-19

The COVID-19 pandemic has brought to light the association between NAFLD and increased susceptibility to severe SARS-CoV-2 infection [33,34,35,162].
Consequently, it has been hypothesized that genetic variants associated with NAFLD may indirectly influence the severity of COVID-19 infection. This intriguing hypothesis has motivated investigations into candidate genes through association studies. One such study utilized the UK Biobank dataset to develop a genetic risk score for NAFLD, considering the combined effects of variants involved in hepatic fat accumulation (PNPLA3-TM6SF2-MBOAT7-GCKR) [45]. Building upon this knowledge, Valenti et al. examined the impact of this NAFLD-genetic risk score on the susceptibility to COVID-19 and observed a trend suggesting that the rs738409 variant conferred protection against COVID-19 [45].
Grimaudo et al. conducted a study that revealed a significant association between the rs738409 G-allele and severe COVID-19 outcomes in patients aged 65 years or younger [44].
In contrast, Innes et al. reported a striking inverse association between rs738409 and the severity of COVID-19 outcomes in a cohort of 1585 participants from the UK Biobank [46]. Their findings indicated that the rs738409-G allele was independently associated with a reduced risk of COVID-19 hospitalization and mortality. Importantly, this protective effect persisted even after adjusting for major demographic factors and underlying metabolic and liver co-morbidities [46].
From a functional perspective, the observed association between lipid metabolism and the immune response to COVID-19 could be attributed to various factors. For instance, retinoids are stored as retinyl esters in hepatic mesenchymal cells and adipose tissue, where the PNPLA3 gene is expressed. When the need arises, retinoids are mobilized to extrahepatic tissues, where they play a crucial role in stimulating the production of interferon type 1, a potent cytokine response to viral infections [163]. Conversely, certain risk factors associated with severe COVID-19, such as obesity and liver disease [164], are known to be linked to decreased retinoid levels and impaired retinoid signaling. This impairment could potentially limit the availability of retinoids during infection. Moreover, individuals with the rs738409 G allele may exhibit a lower ratio of omega-6 to omega-3 polyunsaturated fatty acids, which has been implicated in modulating inflammation and providing protection against cytokine storm syndrome [165].
Furthermore, Innes et al. [46] conducted a comprehensive meta-analysis encompassing three distinct data sources to explore the potential relationship between the rs738409 variant and COVID-19. The study incorporated data from the FinnGen study, which consisted of 83 individuals with COVID-19 hospital admissions and 274 SARS-CoV-2-positive patients without hospital admission. Additionally, the Geisinger Health System dataset included 854 subjects of European Ancestry, with 165 individuals experiencing COVID-19 hospitalization and 689 SARS-CoV-2-positive patients without hospital admission. Lastly, the study by Grimaudo et al. contributed data from a total of 383 COVID-19 patients [44]. The pooled analysis of these aforementioned data sources revealed that the presumed protective effect of the G "NASH-risk allele" on COVID-19 morbidity and mortality could not be definitively confirmed. Nevertheless, there was a discernible trend suggesting an association with a reduced risk of COVID-19 hospitalization and severe disease, although this trend did not reach statistical significance [46].
Similarly, Bianco et al. conducted a study examining the potential impact of the rs738409 G allele on COVID-19 outcomes. Their findings indicated that this allele exhibited a tendency not only to be associated with protection against COVID-19 but also with lower levels of C-reactive protein, despite higher ALT and lower albumin levels in severe COVID-19 patients of European ancestry [47].
Currently, the body of research investigating the influence of genetic polymorphisms associated with NAFLD on the progression and severity of coronavirus disease remains limited (Table 3). However, these studies shed light on the potential interplay between NAFLD-related genetic variants and the course of COVID-19. Further investigations are warranted to elucidate the underlying mechanisms and determine the clinical implications of these associations.

5. How do MAFLD-Associated Polymorphisms Affect Gene Expression in Different Tissues?

Understanding the causality between genotypes and phenotypes provides valuable insights into the genes and their interactions that contribute to the expression of specific traits in organisms. This is particularly relevant for comprehending complex traits that result from the combined effects of multiple genes and environmental factors.
Currently, the investigation of expression quantitative trait loci (eQTLs) represents a prominent and extensively explored avenue for understanding the functional consequences of genetic variation [166]. Numerous genetic studies focusing on gene expression have successfully identified thousands of eQTLs across diverse tissue types, encompassing a large proportion of human genes.
The comprehensive collection of eQTLs serves as a valuable tool for exploring the underlying molecular mechanisms of prevalent genetic disorders [167,168].
Our current knowledge of gene expression genetics heavily relies on the identification of eQTLs, which represent the associations between gene expression levels and specific genotypes at particular genomic loci. Genome-wide investigations of eQTLs have revealed that these loci contribute significantly to the variation in gene expression, with certain genes exhibiting up to 90% of their expression variation attributable to nucleotide variants.
By utilizing the eQTL database available at http://www.mulinlab.org/qtlbase/index.html, we can examine whether the four aforementioned SNPs exhibit eQTL effects in various tissue types. Selected findings are presented in Table 4 for reference. Notably, these data shed light on the potential impact of single nucleotide polymorphisms within the GCKR (rs780094), PNPLA3 (rs738409), TM6SF2 (rs58542926), and LYPLAL1 (rs12137855) genes on gene expression patterns in immune cells and blood (Figure 2). This implies that these genetic variants could potentially influence the immune response against infectious diseases, including COVID-19.
In light of these findings, it is evident that these genetic polymorphisms hold promise as prospective targets for future research endeavors. Their potential influence on gene expression, particularly in immune cells and blood, suggests their potential involvement in modulating the immune response to infectious diseases, including COVID-19. As such, investigating the functional implications of these genetic variants could provide valuable insights into disease susceptibility, pathogenesis, and therapeutic strategies. Therefore, further exploration of these genetic polymorphisms is warranted to deepen our understanding of their role and potentially identify novel avenues for therapeutic interventions.

6. Conclusions

The available genetic data thus far do not provide strong evidence for a significant predisposition conferred by MAFLD to the development of severe COVID-19. However, the COVID-19 pandemic has underscored the importance of obtaining a comprehensive understanding of not only the associations attributed to the PNPLA3 gene with liver-related traits but also the intricate protein interactions, active protein ligands, and, crucially, the accurate and comprehensive assessment of the variant pleiotropic effects.
Considering these factors, we advocate for a comprehensive approach to evaluating polymorphisms of the host's genetic determinants, particularly those associated with susceptibility to MAFLD. This approach should aim to develop gene profiling tools that can support early prediction at the individual level during the course of COVID-19. If confirmed as determinants of disease severity, these host polymorphisms could enable the identification of vulnerable populations or patients at higher risk for severe outcomes, thereby facilitating improved diagnosis, treatment, and prognosis of COVID-19.

Author Contributions

Conceptualization, and writing—original draft preparation, M.B. and A.K.; writing—review and editing, M.B., V.O., I.K., and S.G.V.; supervision, A.K., V.O. and S.G.V; project administration, V.O. and A.K.; visualization, I.K.; funding acquisition, M.B. and V.O. All authors have read and agreed to the published version of the manuscript.

Funding

RECOOP Grant #36 – CSMC Senior Scientists (RCSS) "Comprehensive Analysis of Genetic Predictors for MAFLD Development in patients with COVID-19".

Data Availability Statement

Data is contained within the article or supplementary material.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Genetic polymorphisms contributing to the risk of NAFLD and COVID-19.
Figure 1. Genetic polymorphisms contributing to the risk of NAFLD and COVID-19.
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Figure 2. The heatmap plot illustrates the distribution of molecular traits associated with various tissue/cell types and compares them to eQTL-associated traits (genes). Each row corresponds to a unique tissue or cell type, and each column represents a distinct eQTL-associated trait (gene). The color of each grid cell indicates the median P-value of the eQTLs associated with the specific tissue and trait combination. Overview of eQTL for: TM6SF2 rs58542926 (a) 47 tissues and 25 traits; PNPLA3rs738409 (b) 13 tissues and 22 traits; GCKR rs780094 (c) 44 tissues and 50 traits; GCKR rs780094 (d) 11 tissues and 5 traits.
Figure 2. The heatmap plot illustrates the distribution of molecular traits associated with various tissue/cell types and compares them to eQTL-associated traits (genes). Each row corresponds to a unique tissue or cell type, and each column represents a distinct eQTL-associated trait (gene). The color of each grid cell indicates the median P-value of the eQTLs associated with the specific tissue and trait combination. Overview of eQTL for: TM6SF2 rs58542926 (a) 47 tissues and 25 traits; PNPLA3rs738409 (b) 13 tissues and 22 traits; GCKR rs780094 (c) 44 tissues and 50 traits; GCKR rs780094 (d) 11 tissues and 5 traits.
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Table 3. The impact of MAFLD-associated polymorphisms on the severity course of COVID-19.
Table 3. The impact of MAFLD-associated polymorphisms on the severity course of COVID-19.
Gene SNP The number of patients SNP ’s effect Significance Features Patient cohorts References
PNPLA3 rs738409 (C > G) (I148M) 383 Associated with an increased risk of severe COVID-19 outcomes p = 0,035 (GG genotype) Individuals harboring a GG genotype in the PNPLA3 gene may exhibit inherent upregulation of the NLRP3 inflammasome, rendering them more susceptible to tissue damage upon infection with SARS-CoV-2 Italian populations [44]
1460 Was not associated with the risk of severe COVID-19 p > 0,1 There appears to be an inclination towards protection against COVID-19 when considering the aforementioned genotype. These findings imply that the genetic inclination towards hepatic fat accumulation does not independently heighten the susceptibility to severe COVID-19. Moreover, this indicates that MAFLD does not assume a causal role in this particular condition UK populations [45]
1585 Associated with a lower risk of COVID-19 hospitalization and death p = 0,027 (hospitalization); p = 0,037 (death) On average, the presence of each additional G allele was associated with a notable decrease of 21% in the likelihood of COVID-19 hospitalization and a further decrease of 25% in the likelihood of COVID-19-related mortality UK populations [46]
1397 Was not associated with the risk of severe COVID-19 in hospitalized
patients		 p = 0,46 Intriguingly, a genetic predisposition to accumulate fat in the liver may paradoxically confer protection during the course of COVID-19
 Hospital-based Fondazione IRCCS Ca' Granda cohort [47]
Table 4. EQTL data for SNPs association in tissues.
Table 4. EQTL data for SNPs association in tissues.
Trait CHR Effective Allele Tissue Effect Size p-value Population Sample Size
GCKR rs780094
AC074117.1 2 C Fibroblast -0,206732 3,23E-09 MIX 483
ATRAID 2 T Blood -0,20743 2,2E-13 MIX 2765
ATRAID 2 C Blood-T cell CD8+ activated 0,130598 0,00000114 EAS 416
ATRAID 2 C Lymphocyte 0,163788 0,0000466 EUR 368
EIF2B4 2 C Blood -0,00922729 0,0000631 MIX 5257
EMILIN1 2 T Adipose-Subcutaneous 0,24 0,00000333 EUR 770
GPN1 2 C Blood-T cell CD4+ activated 0,188994 0,00000277 EAS 416
KRTCAP3 2 T Blood -0,237548 6,3E-17 MIX 2765
KRTCAP3 2 C Blood-T cell CD4+ activated 0,234009 0,0000181 EAS 416
NRBP1 2 C Lymphocyte -0,141265 0,00000365 EUR 368
NRBP1 2 C Blood -0,013931 2,04E-12 MIX 5257
NRBP1 2 T Blood 0,153229 0,000000044 MIX 2765
NRBP1 2 NA Blood-Monocyte 5,524902 6,21E-08 EUR 432
PPM1G 2 C Adipose -0,331022 0,0000007 EUR 434
SLC5A6 2 T Blood 0,165322 4,7E-09 MIX 2765
SLC5A6 2 NA Blood-Monocyte 0,233295 0,00000113 MIX 696
SNX17 2 C Blood-Monocytes CD14+ -0,03898 0,00000409 MIX 197
SNX17 2 T Blood 0,141788 0,00000034 MIX 2765
SNX17 2 NA Blood-Monocyte 4,2447721 0,0000286 EUR 432
ZNF512 2 C Blood 0,0147365 7,47E-08 MIX 5257
AC074117.1 2 C Fibroblast -0,206732 3,23E-09 MIX 483
ATRAID 2 T Blood -0,20743 2,2E-13 MIX 2765
ATRAID 2 C Blood-T cell CD8+ activated 0,130598 0,00000114 EAS 416
ATRAID 2 C Lymphocyte 0,163788 0,0000466 EUR 368
PNPLA3 rs738409
SAMM50 22 G Blood-T cell CD8+ -3,90455 9,44E-05 EUR 283
PNPLA3 22 G Skin -0,13586 1,54E-06 MIX 605
SAMM50 22 C Blood -0,07719 5,67E-106 MIX 5257
SAMM50 22 G Adipose-Subcutaneous 0,188769 9,6E-07 EUR 385
AL031595.2 22 G Blood-Monocyte 0,220815 0,00188 EAS 416
TM6SF2 rs58542926
ATP13A1 19 G Blood 0,442548 3,13E-08 EUR 121
ATP13A1 19 T Blood-T cell CD4+ 5,639089 1,71E-08 EUR 293
ATP13A1 19 T Blood-T cell CD8+ 5,943743 2,79E-09 EUR 283
BORCS8 19 T Breast -0,27489 4,48E-06 MIX 396
GATAD2A 19 C Blood -0,03402 5,07E-15 MIX 5257
GATAD2A 19 T Blood 0,163165 3,74E-06 MIX 670
MAU2 19 T Blood-T cell CD4+ -4,67124 2,99E-06 EUR 293
MAU2 19 T Blood -0,19358 6,75E-14 MIX 670
MAU2 19 T Blood -0,18721 2,07E-07 EUR 369
TM6SF2 19 T Adipose-Subcutaneous 0,32323 7,09E-05 MIX 581
YJEFN3 19 T Large Intestine-Colon 0,200617 7,71E-05 MIX 318
LYPLAL1 rs12137855
LYPLAL1 1 C Lymphocyte -0,122143 0,00085 EUR 368
LYPLAL1 1 NA Blood -0,220481 0,000305 EUR 240
SLC30A10 1 NA Stem cell-iPSC -0,143156 0,0313 EUR 215
LYPLAL1 1 T Blood-B cell -2,04427 0,0409 EUR 45
RPS15AP12 1 T Adipose 0,146055 0,0723 EUR 434
AC096642.1 1 T Artery-Tibial -0,14702 1,58E-05 MIX 584
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