rs641738

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 fine-mapping association study in 1926 European gastric cancer (GC) patients and 2012 controls confirmed associations at chromosome 5p13 (rs6872282, P=2.53×10⁻⁴, OR=1.22) and 8q24 (rs2585176, P=1.09×10⁻⁹, OR=1.34) and characterized them through eQTL analysis. The study found cis-eQTL effects for PTGER4 upregulation (5p13, P=9.27×10⁻¹¹) and PSCA upregulation (8q24, P=2.17×10⁻⁴⁷), plus trans-eQTL effects for MBOAT7 downregulation (8q24, P=1.99×10⁻⁹) in GC risk allele carriers.

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).

Retrospective cohort study of 1,195 patients with HCV-related hepatocellular carcinoma (HCC) comparing clinical presentation and outcomes between 390 Black and 805 non-Black patients. Black patients developed HCC at earlier stages of liver fibrosis (31% with FIB-4 < 3.25) with preserved liver function but presented with larger tumors (3.5 vs 3.1 cm), higher rates of multifocal disease, microvascular invasion (67.2% vs 56.5%), and poorly differentiated histology (30.3% vs 20.5%), resulting in significantly worse survival despite better hepatic reserve at diagnosis.

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.