rs2228603

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.

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.