Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity

Body mass index (BMI) is an established epidemiological predictor of corona ry disease, diabetes and hypertension. In a previous study of 2560 healthy British Caucasoid males aged 50-61 years (Northwick Park Heart Study II; NP HSII), we showed that IGF2 ApaI AA homozygotes display a mean body weight 3 .3 kg lower than GG homozygotes (P = 0.0002) independent of height, Two RFL Ps in the insulin (INS) gene, + 1127/PstI shown previously and -23/HphI in this study, both of which are in strong linkage disequilibrium,vith class U m alleles of the INS 5' variable number tandem repeat (VNTR), are not assoc iated with weight or BMI, The IGF2 ApaI polymorphism therefore appears to m ark an effect independent of INS VNTR class I vs class III, We now show by regression that there is a positive correlation of BMI with I;INS VNTR clas s I allele size, with an average 0.33% (95% CI = 0.13%, 0.50%) increase in BMI per extra tandem repeat (P < 0.0001) representing variation of 4.8% ove r the allele size range, However, an alternative interpretation is of 'step ' rather than 'slope', the small class I subclass allele group (mode 669 bp ) being lighter than the large subclass group (mode 814 bp), This small eff ect would not be evident as an association between INS VNTR class I/III gen otype and BMI, The IGF2 ApaI association and INS VNTR class I subclass regr ession association account for at least 1.1% of population BMI variance, Ne ither, both, or a third site may be aetiological.