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

Abstract

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. Diabetes 52: [187][188][189][190][191][192][193] 2003

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

“…In fact, the positive association is derived solely from a single study showing a strong association [21], whereas the remaining studies do not show significant associations between the class III/III genotype of the INS-VNTR and Type 2 diabetes. Furthermore, other studies have also examined a potential association between Type 2 diabetes and the class III allele, and even though one did report an association between Type 2 diabetes and paternally inherited class III alleles [10], these studies reported a lack of overall association between the INS-VNTR class III allele and Type 2 diabetes [10,13]. The genotype distribution among the Type 2 diabetic patients in the six studies from the meta-analysis was very different.…”

“…Concerning Type 2 diabetes, it was reported from a study examining 155 parent-offspring trios that the association between Type 2 diabetes and the INS-VNTR is mediated exclusively through the paternally transmitted class III allele [10]. However, the impact of imprinting on the INS-VNTR in relation to Type 2 diabetes has not yet been clarified, as a study of Pima Indians, also using parentoffspring trios, failed to demonstrate a clear parentof-origin effect on risk of Type 2 diabetes [13].…”

“…Interestingly, the studies previously reporting associations between the class III allele and altered birthweight presented conflicting results. One study reported an association with increased birthweight (~250 g) when considering non-changers (subjects with a small change in weight standard deviation score from birth to one year of age) [12], whereas another study demonstrated an association with a decreased birthweight (~140 g) [13]. Moreover, a recent study also reported a lack of association between the class III allele and size at birth [3].…”

“…Thirdly, an association between the class III allele and impaired insulin secretion among healthy subjects has been reported [11]. Fourthly, variation of the INS-VNTR has been associated with increased and decreased birthweight [12,13]. And finally, it has been suggested, in a study of obese children [2], that variation of the INS-VNTR affects fasting serum insulin levels, while a recent study reported an effect of the class III allele on increased BMI and decreased insulin sensitivity in three Caucasian cohorts comprising a total of 1184 children and 1099 parents [3].…”

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

“…Other factors are likely to be involved. In particular, genetic factors are thought to influence fetal growth [12,[29][30][31][32].…”