Polymorphisms of the Scavenger Receptor Class B Member 1 Are Associated with Insulin Resistance with Evidence of Gene by Sex Interaction

Background: Genetic variation in diabetes-associated genes cumulatively explain little of the overall heritability of this trait. We sought to determine whether polymorphisms of the scavenger receptor class B, member I (SCARB1), an estrogen-regulated chromosome 12q24 positional candidate diabetes gene, were associated with type 2 diabetes or insulin resistance in a sex-specific fashion. Methods: We evaluated 34 haplotype-tagged single-nucleotide polymorphisms (SNPs) of SCARB1 for their association with type 2 diabetes and measures of insulin resistance in two populations: a clinic-based sample of 444 Mexican-American women from Proyecto SALSA and a community-based sample of 830 white women from the Rancho Bernardo Study. Results: We identified significant associations between a tagged SNP in intron 9, rs9919713, and fasting glucose in the SALSA population (P = 2.3 x 10(-4)). In the Rancho Bernardo Study, the same SNP also showed significant association with the related traits homeostasis model assessment for insulin resistance (P = 3.0 x 10(-4)), fasting glucose (P = 1.1 x 10(-3)), and type 2 diabetes (P = 9.0 x 10(-3)). In men from the Rancho Bernardo population, the opposite effect was found (genotype by sex interaction in the Rancho Bernardo population P < 10(-3) for insulin resistance). Conclusions: Our data support an association between SCARB1 variants and insulin resistance, especially in women, with evidence of significant gene by sex interaction. These findings warrant further investigation in additional populations and prompt exploration of a role for SR-BI in the development of insulin resistance. (J Clin Endocrinol Metab 94: 1789-1796, 2009)