*4.3. ABCA1 Gene Variation and T2D*

There are few studies analyzing β-cell function and insulin sensitivity in human heterozygotes for loss-of-function *ABCA1* mutations, most likely because these mutations are extremely scarce. In consistency with the mouse model, a small study (15 individuals with loss-of function *ABCA1* mutations vs 14 family controls) reported that heterozygosity for these mutations was associated with impaired insulin secretion, mild hyperglycemia and reduced first-phase insulin response to hyperglycemia. However, hyperglycemic clamp studies showed that mutation carriers had normal insulin secretion in response to an oral glucose challenge and had normal insulin sensitivity [64]. Notably, none of the *ABCA1* mutation carriers had diabetes, suggesting that heterozygosity alone confers a relatively mild susceptibility for diabetes. In contrast, a large study including 94 *ABCA1* heterozygotes from the Copenhagen City Heart and the Copenhagen General Population Studies did not find an association with increased T2D risk [121].

Similarly, associations of *ABCA1* polymorphisms with T2D are not always consistent. ABCA1 has not been reported to be significantly associated with T2D in genome-wide association studies [122–124]. However, candidate-gene studies have reported associations of *ABCA1* polymorphisms with T2D mostly in Asian and Latin American populations. Notably, several of these studies are small, including only hundreds of cases and controls. Daimon et al. (2005) were the first to report an association of *ABCA1* gene polymorphisms (a 34-SNP haplotype of the promoter region) with T2D in a small sample of the Japanese population [125]. A few years later, a functional variant (R230C), which decreases ABCA1 cholesterol efflux capability, was associated with early-onset T2D in two independent small cohorts of the Mexican population [126]. Interestingly, R230C was only marginally associated with T2D in Pimas [41], but significantly associated with T2D in Mayan individuals [127], and was not found to be associated with T2D in a case-control study of the Colombian population [128]. Moreover, the missense rs2230806 (R219K), frequently associated with higher HDL-C levels, was found to be associated with decreased T2D risk in a recent meta-analysis including Korean, Chinese and Indian individuals [129]. Several small studies have sought to associate rs1800997, a 5′UTR variant known as the C69T polymorphism, with T2D, with inconsistent results. The minor *ABCA1*/C69T allele was associated with decreased T2D risk in Turkish [130], Saudi [131], and Chinese Han [132] individuals, while the intronic rs4149313 variant was associated with increased T2D risk in a study including 8842 Koreans [133].

In addition to small sample sizes, which may limit statistical power, other factors could explain inconsistencies in studies seeking associations of *ABCA1* gene variation with T2D. According to observations in global and β-cell specific *Abca1* KO models, differences in serum lipid levels may be a determinant factor. Dyslipidemia is highly prevalent in the Mexicans [134], which is consistent with the association of the *ABCA1*/R230C variant with T2D in this population. Likewise, the association of this variant with lower total cholesterol and TG levels found in Pimas could be a factor explaining why it was only marginally associated with T2D in this group [41]. In addition, *Abca1* adipocyte and hepatocytespecific KO models have shown that a high fat high cholesterol diet may influence the effect of ABCA1 impairment on certain traits [119,120]. In this regard, dietary macronutrient proportions have been found to modulate the effect of the *ABCA1*/R230C not only on lipid levels, but on other metabolic parameters such as homeostasis assessment model for insulin resistance (HOMA-IR), serum adiponectin levels and visceral to subcutaneous abdominal fat ratio [43]. In this study, lower proportions of dietary carbohydrate and higher proportions of dietary fat were associated with a more favorable metabolic profile in premenopausal women bearing the R230C variant. Because these gene-diet interactions were observed only in premenopausal women, gender effects on the associations with T2D are also likely.
