Pathway-Based Genetic Risk Scores Are Associated with Blood Lipids Among Young Mexican Adults

Background/Objectives: Mexicans are disproportionately affected by dyslipidemia, specifically low high-density lipoprotein (HDL-C) and high triglyceride (TG) concentrations. Research on the genetic contributions to dyslipidemia, conducted primarily among European populations, has identified numerous single-nucleotide polymorphisms (SNPs) with small effect sizes and low replication rates. A genetic risk score (GRS) can examine the cumulative effects of multiple SNPs and potentially explain greater phenotypic variability than individual SNPs. GRS in Mexican populations and those without diagnosed dyslipidemia are limited. This study aims to construct a GRS from lipid metabolism-related SNPs and determine its associations with blood lipid concentrations in young Mexican college students. Methods: Adults (ages 18-25 years, n = 580) provided a fasting blood sample to determine TG and HDL-C concentrations. DNA was genotyped for 14 SNPs in lipid metabolism pathways (reverse cholesterol transport [RCT], cellular lipid uptake, and lipoprotein formation and transport). Additive (number of risk alleles) and weighted (regression-derived β coefficients) GRS were calculated for individual pathways, and their sum (total GRS) was explored. Associations among individual SNPs, GRS, and blood lipids were determined through general linear models in SAS. Results: The additive RCT and total GRS were associated with TG (both p < 0.05). The RCT pathway explained 3.4% of the variability in TG concentrations, and the total GRS explained 6.1%. The weighted RCT GRS was associated with HDL-C (p = 0.007). The ATP-binding cassette protein (ABCA1) rs9282541 variant was most strongly associated with HDL-C (p = 0.016). When this SNP was removed from the GRS, the association became non-significant. Conclusions: SNPs in lipoprotein metabolism pathways cumulatively associate with blood lipid concentrations in young Mexican adults. The ABCA1-rs9282541 variant, previously shown to be positively associated with low HDL-C concentrations in Amerindian populations, had the strongest association with HDL-C. Further work is needed to elucidate the roles of genetic admixture and lifestyle risk factors in dyslipidemia in this population.