title: Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes.
abstract: A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10(-11)-1.4 × 10(-23)), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10(-7)). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 "mixed" heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10(-4), n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.
authors.affiliation: Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ 85004, USA. ymuller@mail.nih.gov
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Jamie
authors.initials: J
authors.lastname: Fleming
authors.forename: Jayita
authors.initials: J
authors.lastname: Goswami
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Traurig
authors.forename: Jeff
authors.initials: J
authors.lastname: Sutherland
authors.forename: Chris
authors.initials: C
authors.lastname: Wiedrich
authors.forename: Kim
authors.initials: K
authors.lastname: Wiedrich
authors.forename: Darin
authors.initials: D
authors.lastname: Mahkee
authors.forename: Vicky
authors.initials: V
authors.lastname: Ossowski
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014198:Trehalase / Q000097:blood* / Q000235:genetics
chemical_list: D014198:Trehalase