rs58542926

This is a Turkish-language personalized nutrigenetics and epigenetics coaching report for individual Mehmet Efe Yildirim (Report No. 1332, dated 2023-11-21). The report analyzes the individual's genetic polymorphisms related to nutritional metabolism, food sensitivities, detoxification pathways, and other health-related traits, providing personalized dietary and lifestyle recommendations based on cited scientific literature. This is a direct-to-consumer genetic test report, not a peer-reviewed research study.

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 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.

This functional study demonstrates that TM6SF2 forms a protein complex with ERLINs (ERLIN1/ERLIN2) and APOB to stabilize apolipoprotein B and regulate lipid droplet metabolism. The E167K mutation in TM6SF2 attenuates these stabilizing effects. Using cell culture studies, tandem affinity purification, and Tm6sf2 knockout mice (with L23fs frameshift mutation), the authors show that deficiency of TM6SF2, ERLIN1, or ERLIN2 causes robust lipid droplet accumulation and impaired APOB secretion, establishing defective APOB stabilization as a mechanism underlying non-alcoholic fatty liver disease.

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).

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.

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.

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 the global burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), examining epidemiology, risk factors, and genetic predisposition across regions. The paper discusses genetic variants in PNPLA3 (I148M) and TM6SF2 (E167K, rs58542926) as major contributors to NAFLD severity, and identifies additional risk loci including MBOAT7 (rs641738) and TMC4 variants associated with disease 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.