SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians

Abstract

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5' region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P=0.01, OR=1.25 95%CI 1.05-1.48, and P=0.02, OR=1.17 95%CI 1.02-1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N=243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P=0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P=0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.

Figure 1

Linkage disequilibrium pattern (D' is indicated by shading and r² is shown as numbers) for SNPs spanning SIRT1 and the adjacent 5′ (21 kb) region in Pima Indians. Genotypic data from 15 SNPs, identified by sequencing SIRT1 or present on the Affymetrix Genome-Wide Human SNP Array 6.0, were used to determine that all variants could be captured by 4 representative SNPs (denoted by open rectangles). Sequence information for the 3 novel SNPs: SIRT1-1, TGCAATGGCG[C/G]GATCTCGGCT; SIRT1-2, CTCAGCCTCC[C/G]C AGCAGCTGG; SIRT1-3, AATAAAGGCA[G/A] AGCTGGAACC.

Figure 2

Correlation of SIRT1 gene expression levels in adipose tissue isolated from 135 Pima Indian subjects with (A) BMI and (B) percent body fat after adjusting both axes for age and sex.