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. 2009 May;94(5):1789-96.
doi: 10.1210/jc.2008-2800. Epub 2009 Mar 10.

Polymorphisms of the scavenger receptor class B member 1 are associated with insulin resistance with evidence of gene by sex interaction

Jeanette J McCarthy  1 , Aleefia Somji, Lauren A Weiss, Brian Steffy, Raquel Vega, Elizabeth Barrett-Connor, Gregory Talavera, Richard Glynne
Affiliations

Polymorphisms of the scavenger receptor class B member 1 are associated with insulin resistance with evidence of gene by sex interaction

Jeanette J McCarthy et al. J Clin Endocrinol Metab. 2009 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Association between SCARB1 ht-SNPs and fasting glucose, HOMA, and type 2 diabetes (T2DM) in women from Proyecto SALSA (top) and the Rancho Bernardo Study (bottom). P values are for testing association between each SNP in an additive, age-adjusted model. Arrows indicate association with rs9919713 SNP in each population.
Figure 2
Figure 2
Mean (±se, bars) age-adjusted values of natural log (ln)-transformed fasting plasma glucose (A) and HOMA-IR (B) and proportion of subjects with type 2 diabetes mellitus (C) by SCARB1 rs9919713 minor allele status (0, 1, or 2 copies) in females from the Rancho Bernardo (RB) and SALSA studies.
Figure 3
Figure 3
Associated interval surrounding SNP rs9919713 in the SCARB1 gene. Top, Location of SCARB1 relative to other genes on chromosome 12q24.1; middle, intron-exon structure of SCARB1 gene; bottom, pairwise linkage disequilibrium (r2) between all SCARB1 SNPs and rs9919713 based on Caucasian HapMap subjects generated in Haploview software. Arrow points to SCARB1 SNP rs9919713.
Figure 4
Figure 4
Association between SCARB1 SNPs in the rs9919713 associated interval and fasting glucose, HOMA, and type 2 diabetes (T2DM) in the SALSA and Rancho Bernardo populations. Due to a low minor allele frequency, the SNP was analyzed in a dominant model (pooled homozygous variant and heterozygous genotypes) in the Rancho Bernardo population.
Figure 5
Figure 5
Mean (±se, bars) age-adjusted values of natural log (ln)-transformed fasting plasma glucose by SCARB1 rs9919713 minor allele carrier status in males and females from the Rancho Bernardo Study.
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