title: Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.
abstract: Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT (P = 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P = 0.025, urban survey P = 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes. However, the relative infrequency of the "at-risk" combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes.
authors.affiliation: Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, University of London, London.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Cassell
authors.forename: Alan E
authors.initials: AE
authors.lastname: Jackson
authors.forename: Bernard V
authors.initials: BV
authors.lastname: North
authors.forename: Julie C
authors.initials: JC
authors.lastname: Evans
authors.forename: Denise
authors.initials: D
authors.lastname: Syndercombe-Court
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
authors.forename: Ambady
authors.initials: A
authors.lastname: Ramachandran
authors.forename: Chamukuttan
authors.initials: C
authors.lastname: Snehalatha
authors.forename: Susan V
authors.initials: SV
authors.lastname: Gelding
authors.forename: Shanti
authors.initials: S
authors.lastname: Vijayaravaghan
authors.forename: David
authors.initials: D
authors.lastname: Curtis
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
mesh_terms: D000328:Adult; D000368:Aged; D002154:Calpain / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D014505:Urban Population
chemical_list: D002154:Calpain; C415197:calpain 10