The Insulin Gene Variable Number Tandem Repeat Class I/III Polymorphism Is in Linkage Disequilibrium With Birth Weight but Not Type 2 Diabetes in the Pima Population
- Robert S. Lindsay,
- Robert L. Hanson,
- Chris Wiedrich,
- William C. Knowler,
- Peter H. Bennett and
- Leslie J. Baier
- From the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (−23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring “trio” design was used to assess parent-of-origin effects and population stratification. The presence of the −23Hph1 T-allele was associated with lower birth weight (n = 192; −140 g per copy of the T-allele; P = 0.04), even after adjustment for effects of population stratification (P = 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: −250 g, P = 0.05; maternally transmitted: −111 g, P = 0.43), but this difference was not statistically significant (P = 0.50). The −23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P = 0.009), which family-based association analysis suggested was attributable to population structure (P = 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P = 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between −23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight.
Address correspondence to Dr. Robert L. Hanson, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Rd., Phoenix, AZ 85014. E-mail:.
Received for publication 11 June 2002 and accepted in revised form 23 September 2002.
LD, linkage disequilibrium; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism; VNTR, variable number tandem repeat; WHO, World Health Organization.