title: 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.
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.forename: Michael
authors.initials: M
authors.lastname: Traurig
authors.forename: Clint C
authors.initials: CC
authors.lastname: Mason
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Jessica
authors.initials: J
authors.lastname: Perez
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000328:Adult; D001130:Arizona; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007198:Indians, North American; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012727:Sex Characteristics; D012737:Sex Factors; D056564:Sirtuin 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D007328:Insulin; C447939:SIRT1 protein, human; D056564:Sirtuin 1