Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.
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.
Cassell
Paul G
PG
Department of Diabetes and Metabolic Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, University of London, London.
Jackson
Alan E
AE
North
Bernard V
BV
Evans
Julie C
JC
Syndercombe-Court
Denise
D
Phillips
Chris
C
Ramachandran
Ambady
A
Snehalatha
Chamukuttan
C
Gelding
Susan V
SV
Vijayaravaghan
Shanti
S
Curtis
David
D
Hitman
Graham A
GA
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
D002154:Calpain; C415197:calpain 10