rs1044498

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.

A hospital-based case-control study in rural and urban India (1,204 cases; 1,212 controls) examined genetic and lifestyle risk factors for breast cancer. Four SNPs in FGFR2 (rs1219648, rs2420946, rs2981575, rs2981582) showed positive associations with breast cancer (ORs 1.32-1.47). Additional SNPs in obesity and metabolic genes (rs374748 in FBN2, rs2922763 in HNF4G, rs2116830 in KCNMA1, rs11121832 in MTHFR, rs16886165 in MAP3K1, rs11594610 in TCF7L2, rs2274459 in MLN) were associated with increased breast cancer risk. Waist-to-hip ratio ≥0.95 showed strong association (OR 3.78; 95% CI 2.92-4.89), and women living first 20 years in rural areas showed protective effect (OR 0.77).

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.

In a study of 1,563 European ancestry participants at increased type 2 diabetes risk, the ENPP1 K121Q polymorphism (rs1044498) did not show cross-sectional association with insulin sensitivity. However, during a 9-month lifestyle intervention in 342 participants, minor allele (Q) carriers showed significantly impaired improvement in insulin sensitivity (p=0.0067 additive, p=0.0027 dominant), suggesting K121Q determines individual susceptibility to the insulin-sensitizing effects of lifestyle intervention.

This prospective study of 16,143 individuals from the Malmö Preventive Project (mean follow-up 23 years) investigated whether genetic variants in 26 genes previously associated with type 2 diabetes or metabolic syndrome components could predict future development of metabolic syndrome. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, p=0.00097), FTO (rs9939609, OR 1.08, p=0.0065), WFS1 (rs10010131, OR 1.07, p=0.0078), and IGF2BP2 (rs4402960, OR 1.07, p=0.021) predicted metabolic syndrome development, with TCF7L2, WFS1, and IGF2BP2 acting through hyperglycemia and FTO through obesity. A composite genotype score of 17 polymorphisms predicted metabolic syndrome risk (OR 1.04, p<0.00001), with carriers of ≥19 risk alleles having 51% increased risk compared to carriers of ≤12 alleles.

Prospective study of 5,153 French participants (DESIR cohort) investigating ENPP1 variants for associations with obesity and type 2 diabetes. The K121Q polymorphism (rs1044498) showed limited associations: class II obesity at baseline (OR 1.65, p=0.02), and type 2 diabetes restricted to participants with family history (OR 1.61, p=0.01). The IVS20delT-11 and A/G+1044TGA variants and QdelTG haplotype showed no significant associations.

This study examined the ENPP1 K121Q polymorphism (rs1044498) in 7,333 Danish subjects and found no significant associations with type 2 diabetes or insulin resistance in their cohort. However, a meta-analysis of published and present case-control studies revealed association of the Q allele with type 2 diabetes (OR 1.17 per Q allele, 95% CI 1.10–1.25, p=1×10^-6). A putative recessive association with overweight (BMI≥25) was observed for the QQ genotype (OR 1.63, p=0.015), though the authors cannot exclude multiple testing artifacts.