rs738409

A two-stage genome-wide association study (GWAS) of lean nonalcoholic fatty liver disease (NAFLD) in Japanese patients identified HLA as a novel candidate locus, with rs2076529 (OR 1.19, P=2.10E-06) showing significant association with whole NAFLD. HLA-B*54:01 allele carriers demonstrated altered gut microbiota composition, with reduced Verrucomicrobia and Akkermansia, suggesting HLA may influence NAFLD susceptibility through microbiome regulation.

This association study of 6039 European subjects (1020 HCC cases, 5019 controls including prospective cohorts) identified PNPLA3 rs738409 (OR=3.91, p=1.14E-09) and TM6SF2 rs58542926 (OR=1.79, p=0.001) as significant risk variants for hepatocellular carcinoma in alcoholic liver disease patients, with a dose-dependent additive effect. PNPLA3 rs738409 was also associated with HCC developed on non-fibrotic liver (OR=2.19, p=0.007), suggesting a direct carcinogenic role independent of cirrhosis.

This cross-sectional study of 142 children with biopsy-proven NAFLD found that the PNPLA3 rs738409 G allele (encoding I148Met) was independently associated with significantly decreased estimated glomerular filtration rate (eGFR, β = -23.6, p < 0.001) and increased 24-hour urinary proteinuria (β = 15.3, p = 0.046), independent of NAFLD severity, obesity, and other renal risk factors. The G/G genotype conferred a ~4-fold increased risk of stage 2 chronic kidney disease.

This exploratory study examined the prevalence of the PNPLA3 rs738409 [G] allele in a small Hmong community sample (n=26) and found a high frequency of 0.46 (12/26 heterozygotes, 2 homozygotes), ranking third highest globally. The high frequency of this nonsynonymous variant (C>G, I148M), previously associated with nonalcoholic fatty liver disease (NAFLD) susceptibility in other populations, suggests a potential genetic component to the elevated rates of chronic liver disease in Hmong Americans.

This meta-analysis of 6 studies (5 cohort, 1 case-control) examined the association between PNPLA3 rs738409 (I148M, C>G) and liver complications in HBV-infected patients. The GG genotype showed strong association with liver steatosis across multiple genetic models (OR=2.85-3.74, p=4.57×10⁻⁶ to 6.18×10⁻⁸), but no significant association with cirrhosis development (all p>0.05).

This study examined the PNPLA3 rs738409 C>G variant (I148M) in 270 patients undergoing coronary angiography. The G allele was associated with nonalcoholic fatty liver disease and liver fibrosis, and with increased diabetes prevalence (22% vs 28% vs 58% for CC/CG/GG genotype, P=0.02). Interestingly, the G allele was inversely associated with total cholesterol and LDL levels (P=0.003 and P=0.02), suggesting a relatively benign cardiovascular risk profile despite metabolic complications.

DEPDC5 rs1012068 is associated with liver fibrosis progression in Europeans with chronic HCV infection, with a 40% increased risk of cirrhosis (OR 1.40, 95% CI 1.08-1.81, P=0.011) and 50% increased risk of moderate/severe fibrosis (OR 1.52, 95% CI 1.09-2.12, P=0.015). Nonsynonymous DEPDC5 variants increased fibrosis risk by 54% (OR 1.54, P=0.040). MICA rs2596542 showed no association with HCC or cirrhosis in this European cohort. In vitro studies demonstrated DEPDC5 downregulation increases β-catenin expression and MMP2 production in hepatic stellate cells.

This doctoral thesis comprises three studies on metabolic syndrome-related traits. Study III is a GWAS identifying seven novel loci associating with circulating inflammatory markers (cytokines and adhesion molecules) in 5,284 Finnish individuals from NFBC1966, with meta-analysis including three additional Finnish populations totaling 13,577 participants. Studies I and II use Mendelian randomization and association analysis to examine metabolic effects of lipid-lowering therapies and NAFLD risk alleles (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, GCKR rs780094-T/rs1260326-T, LYPLAL1 rs12137855-C, and NCAN rs2228603-T).

A functional study using Pnpla3 I148M knockin mice demonstrates that the rs738409 variant (I148M), which is strongly associated with nonalcoholic fatty liver disease (NAFLD) in humans, directly causes hepatic steatosis through accumulation of catalytically inactive PNPLA3 protein on lipid droplets. Knockin mice developed 2-3 fold increased liver fat on high-sucrose diet despite normal mRNA levels, with a 40-fold increase in PNPLA3 on hepatic lipid droplets.

This Hepatology correspondence includes commentary on PNPLA3 rs738409 (C>G, p.I148M) and hepatocellular carcinoma risk in cirrhotic patients, with discussion of oxidative stress mechanisms. The final section presents three case reports of chronic hepatitis E virus infection in immunosuppressed patients without prior transplantation or HIV infection.

Meta-analysis examining the association between the PNPLA3 rs738409 C>G variant and hepatocellular carcinoma risk, providing evidence from individual participant data pooling to assess this genetic risk factor across multiple studies.

This case-control study of 257 Caucasian HCC patients and 494 healthy controls found that the PNPLA3 rs738409 GG genotype confers a threefold increased risk of hepatocellular carcinoma (adjusted OR = 3.21, 95% CI 1.68-6.41), with notably strong risk modification in diabetic patients (OR = 19.11). The GG genotype was also independently associated with underlying cirrhosis in HCC patients (OR = 2.48) and poor prognosis, with an adjusted hazard ratio of 2.11 for death.

A comprehensive review of the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in children and adolescents, examining the evolution from the 'two-hit theory' to the 'multiple-hit model'. The paper discusses genetic factors including PNPLA3 rs738409 and GCKR rs1260326 polymorphisms, which together account for up to one-third of variability in liver fat content in obese children, along with contributions from MBOAT7, SAMM50, PARVB, TM6SF2, and other genes involved in lipid metabolism.

In the HALT-C cohort of 1,319 patients with advanced chronic hepatitis C, elevated baseline gamma-glutamyl transferase (GGT) activity was strongly associated with diminished virological response to interferon-based treatment and with adverse clinical outcomes including hepatic decompensation, death, and fibrosis progression. Notably, IL28B rs12979860 T allele carriers with high GGT had markedly poor treatment response, with only 1 of 56 TT homozygotes in the highest GGT quintile achieving sustained virological response, whereas CC homozygotes showed favorable response rates relatively unaffected by GGT levels.

This comprehensive review examines the genetic background of nonalcoholic fatty liver disease (NAFLD), focusing on variants identified by genome-wide association studies (GWAS) and candidate gene studies. The most significant GWAS-identified variants are PNPLA3 rs738409 (I148M), which strongly associates with increased liver steatosis, fibrosis severity, and HCC risk (12-fold increased risk for homozygous carriers), and TM6SF2 rs58542926 (E167K), which increases NASH progression but reduces cardiovascular risk. The review also discusses numerous candidate genes involved in lipid and glucose metabolism and liver injury mechanisms.

Genome-wide association study in Japanese population identified nine SNPs in PNPLA3 (rs738409, rs2896019, rs3810622), SAMM50 (rs738491, rs3761472, rs2143571, rs6006473), and PARVB (rs5764455, rs6006611) genes strongly associated with nonalcoholic fatty liver disease (NAFLD) development and progression. rs738409 showed the strongest association (P = 6.8×10⁻¹⁴, OR = 2.05); other SNPs had P < 2.0×10⁻¹⁰ and ORs of 1.84–2.02. These variants were associated with decreased serum triglycerides, increased liver enzymes (AST/ALT), and histological features including steatosis grade and fibrosis.

This study compared adipose tissue inflammation in two forms of NAFLD: obesity-related versus genetic (PNPLA3-I148M, rs738409). In 82 volunteers, obesity-related NAFLD showed increased liver fat (9.5% vs 5.1% in controls), hyperinsulinemia, and adipose tissue inflammation marked by upregulation of MCP-1 and CD68 with downregulation of Twist1 and ADIPOQ. PNPLA3-148MM NAFLD showed similarly elevated liver fat (11.4% vs 5.3%) but lacked insulin resistance and adipose tissue inflammation, suggesting that liver fat itself may not be inherently pathogenic without accompanying adipose tissue inflammation.

A cross-sectional study of 470 obese patients found that PNPLA3 variant rs738409 (I148M) was significantly associated with non-alcoholic steatohepatitis (NASH) and severity of necroinflammatory changes (steatosis, lobular inflammation, ballooning) independently of metabolic factors and BMI. Conversely, the APOC3 variant rs2854117 showed no significant associations with liver histology or metabolic parameters of NAFLD.

This study investigated the interaction of PNPLA3 rs738409 (C→G) genetic variation with metabolic and histologic characteristics in 144 patients with medically complicated obesity undergoing bariatric surgery. The PNPLA3 G allele was associated with increased risk of nonalcoholic steatohepatitis (NASH), insulin resistance, and elevated liver enzymes. In multivariate analysis, PNPLA3 G allele (OR 2.43) remained an independent risk factor for NASH alongside elevated glucose, CK-18, and C-reactive protein; the probability of NASH increased from 9% with no risk factors to 82% with all four risk factors present.

PNPLA3 rs738409 G allele (C>G) is significantly associated with hepatocellular carcinoma (HCC) risk in patients with alcoholic cirrhosis. In a combined analysis of Belgian (n=325) and French (n=246) Caucasian cohorts, the GG genotype conferred a 4.70-fold increased HCC risk (OR=4.70, 95% CI 2.63-8.42, p=1.83×10⁻⁷) compared to CC genotype under a recessive inheritance model, independent of age, sex, BMI, and diabetes.

This multi-ethnic association study examined PNPLA3 rs738409 (C>G, encoding I148M) in 144 biopsy-proven NAFLD patients and 198 controls from Malaysian populations (Chinese, Indian, Malay). The G allele was significantly associated with NAFLD susceptibility in pooled subjects (OR 2.34, 95% CI 1.69-3.24, p < 0.0001) and each ethnic group. The G allele was associated with NASH severity (OR 1.85, p = 0.035) and fibrosis presence (OR 1.95, 95% CI 1.17-3.26, p = 0.013), but not simple steatosis or other histological features.

This association study examined 455 obese children and adolescents (181 Caucasians, 139 African Americans, 135 Hispanics) and found that rs1260326 in GCKR is associated with hepatic fat accumulation and elevated triglycerides/large VLDL levels across all ethnic groups (p=0.034-0.00002). The PNPLA3 rs738409 variant also associated with hepatic fat content. Jointly, these variants explained 32% of hepatic fat variance in Caucasians, 39% in African Americans, and 15% in Hispanics.

This patent describes genetic polymorphisms associated with liver fibrosis and bridging fibrosis/cirrhosis in HCV-infected patients, with a focus on the PNPLA3 I148M variant (rs738409 C>G) and other SNPs identified through case-control studies. Multiple SNPs including hCV11935588, hCV7450990 (DDX5 A480S), and hCV15851335 (CPT1A) showed significant associations with severe fibrosis progression in HCV patients across multiple clinic sites (UCSF, Stanford, VCU, UIC) with odds ratios <1 for protective variants.

This review examines the role of Myeloid-Epithelial-Reproductive Tyrosine Kinase (MerTK) and macrophage polarization in atherosclerotic lesion progression associated with nonalcoholic fatty liver disease (NAFLD). The paper discusses genetic variants including PNPLA3 rs738409 (I148M), TM6SF2 rs58542926 (E167K), and MERTK rs4374383, which are associated with NAFLD susceptibility and severity, and highlights nuclear receptor-mediated regulation of macrophage lipid metabolism as a therapeutic target.

This patent describes a genome-wide association study identifying SNPs associated with liver fibrosis progression in HCV-infected patients across multiple sample sets (UCSF, VCU, Stanford, UIC). The study genotyped ~21,470 SNPs in discovery and tested ~175 SNPs in replication, identifying 67 replicated markers significantly associated with severe fibrosis (bridging fibrosis/cirrhosis). Key protective markers include hCV7450990 (missense SNP in DDX5 with OR <1.0) and hCV11935588 in a chromosome 16 region. Additional findings include hCV15851335 (CPT1A missense mutation) and hCV11638783.

Comprehensive review of genetic background in nonalcoholic fatty liver disease (NAFLD). The PNPLA3 I148M variant (rs738409 C>G) is identified as a major genetic player strongly associated with increased liver fat content, NASH development, fibrosis severity, and HCC risk. The TM6SF2 E167K variant (rs58542926) emerges as another key contributor to NAFLD pathogenesis and disease progression. Multiple additional GWAS-identified variants and candidate genes are reviewed for their roles in NAFLD susceptibility and progression.

This is a comprehensive review of genetic associations with pediatric nonalcoholic fatty liver disease (NAFLD). The PNPLA3 I148M variant (rs738409) is the most well-established genetic determinant, associated with higher serum ALT levels across multiple pediatric populations (mean difference ~9 U/L for GG vs. CC genotype) and imaging evidence of hepatic steatosis. Additional genes including TM6SF2, MBOAT7, HIF3A, PPARGC1A, UGT1A1, HO-1, CB2, and LPIN1 show associations with various NAFLD phenotypes, though with fewer supporting studies.

A case-control study examining genetic variants associated with liver function tests and steatosis and their relationship to histologically-defined nonalcoholic fatty liver disease (NAFLD). The rs738409 PNPLA3 variant showed the strongest association with NAFLD (OR = 3.26, 95% CI 2.11-7.21, p = 3.60E-43), and displayed significant associations with severe histologic features including fibrosis, ballooning, and inflammation within the NAFLD cohort. Other genetic variants at CPN1, ABO, GPLD1, JMJD1C, GGT1, and HNF1A loci did not show significant associations with NAFLD, suggesting PNPLA3 genetic variation specifically confers increased risk for histologic NAFLD without strong effects on metabolic traits.

In a cohort of 894 adults with histologically-confirmed NAFLD, the rs738409 minor allele in PNPLA3 (I148M) was associated with increased steatosis (p=0.03, OR 1.46), portal inflammation (p=2.5×10⁻⁴, OR 1.57), lobular inflammation (p=0.005, OR 1.84), Mallory-Denk bodies (p=0.015, OR 1.55), and fibrosis (p=7.7×10⁻⁶, OR 1.50 per G allele). Three SNPs on chromosome 10 (rs11591741, rs11597086, rs11597390) in the CPN1-ERLIN1-CHUK region were independently associated with fibrosis severity (p=0.010). In pediatric patients, rs738409 G allele was associated with younger age at biopsy (p=0.045).

This functional study examined PNPLA3 deficiency in mice to investigate the role of rs738409(G), a nonsynonymous variant associated with nonalcoholic and alcoholic fatty liver disease in humans. Loss of Pnpla3 did not affect body weight, adiposity, liver triglyceride content, serum ALT/AST levels, or glucose tolerance/insulin sensitivity under regular chow, high-fat, high-sucrose, or methionine-choline-deficient diets, or in Lep ob/ob obese mice, suggesting that PNPLA3 loss of function may not directly mediate hepatic steatosis.

A common variant (rs738409, I148M) in the PNPLA3 gene is associated with fatty liver disease in obese children and adolescents. The study of 85 obese youths found that the G allele (risk allele) was significantly associated with higher hepatic fat content in Caucasians (P=3.6×10⁻⁴) and African Americans (P=0.012), independent of BMI and insulin resistance. Carriers of the G allele showed smaller adipocytes and lower leptin expression (P=0.03), suggesting PNPLA3 affects hepatic steatosis through adipocyte size regulation rather than insulin resistance pathways.

This study replicates the association between rs738409 G allele in PNPLA3 (encoding adiponutrin) and increased liver fat content in 291 Finnish individuals, with an adjusted p-value of 0.002. The rs738409 G allele is also associated with increased serum aspartate aminotransferase (AST) concentrations (p=0.002) independently of age, sex, and BMI. PNPLA3 mRNA expression in liver was positively correlated with obesity and liver fat content in non-morbidly obese participants.