*3.2. ABCA1 Gene Variation Is Associated with HDL-C Levels*

*ABCA1* is a highly polymorphic gene located on human chromosome 9 (9q31.1) containing 50 exons [27]. According to the NCBI genetic variation database (https://www. ncbi.nlm.nih.gov/SNP), over 5000 polymorphisms have been reported in or near this gene. Several of these variants (intronic, missense and located in the promoter region) have important effects on the expression and function of the ABCA1 protein [28,29].

Both rare and common genetic variations in *ABCA1* contribute to circulating levels of HDL-cholesterol in population-based studies. Genome-wide association studies (GWAS) have consistently identified *ABCA1* as a locus associated with HDL-C levels in various ethnic groups [30,31]. Three nonsynonymous *ABCA1* polymorphisms have been extensively studied in terms of their associations with plasma lipid levels and CHD risk over the past two decades: rs2230806 (R219K) [32–37], rs2066714 (I883M) [33,35,38–40] and rs2230808 (R1587K) [33,38]. A recent meta-analysis confirmed the association of these three variants with plasma lipid levels [27]. Notably, a functional *ABCA1* missense variant (rs9282541; R230C) that was found to be private to the Americas was strongly associated

with low HDL-C levels in Mexican mestizos and Native American populations [41,42]. This variant is of particular interest because it decreases cholesterol efflux capacity of the protein, is relatively frequent in the Mexican mestizo population (minor allele frequency is approximately 10%) and the sole presence of the risk allele explains almost 4% of plasma HDL-C variation.

Few studies have reported interactions between *ABCA1* gene variants and dietary macronutrient proportions affecting plasma lipid levels. In the Mexican population, two independent studies observed that the inverse correlation between carbohydrate intake and HDL-C concentrations was of higher magnitude in premenopausal women bearing the *ABCA1*/R230C variant [43,44]. Jacobo-Albavera et al. also reported that premenopausal women carrying the *ABCA1*/R230C risk allele, and consuming lower fat and higher carbohydrate dietary proportions, showed an overall unfavorable metabolic pattern including lower HDL-C levels. This suggests that gene-diet interactions play a role in inter-individual lipid level variations and may provide information useful to design diet intervention studies. In this regard, a study in Mexican individuals with hyperlipidemia reported that those bearing the *ABCA1*/R230C variant showed lower HDL concentrations and were better responders to a dietary portfolio treatment designed to increase plasma HDL-C concentrations [45]. Altogether, these studies demonstrate the relevance of the *ABCA1*/R230C variant on the regulation of HDL-C levels in the Mexican population.
