Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes.

Interindividual variation of the IGF2-INS-TH region influences risk of a variety of diseases and complex traits. Previous studies identified a haplotype (designated IGF2-INS-TH()5 and tagged by allele A of IGF2 ApaI, allele 9 of TH01 and class I alleles of INS VNTR) associated with low body mass index (BMI) in a cohort of UK men. We aimed here both to study whether previous findings relating ()5 with weight are replicated in a different cohort of men (East Hertfordshire) characterised in more phenotypic detail and to test the effect of this haplotype on related subphenotypes. The PHASE program was used to identify ()5 and not()5 haplotypes. A total of 490 haplotypes were derived from 131 men and 114 women, the frequency of ()5 being around 9%. Specific tests of ()5 haplotype (vs not()5 haplotypes) conducted included Student's t-test and multiple regression analyses. We observed replication of weight effect for the ()5 haplotype in men: significant associations with lower BMI (-1.81 kg/m(2), P=0.009), lower waist circumference (-6.3 cm, P=0.001) and lower waist-hip ratio (-5%, P<0.001). This haplotype also marks nearly two-fold lower 120 min insulin (P=0.004) as well as low baseline insulin (-11.02 pmol/l, P=0.043) and low 30 min insulin (-64.44 pmol/l, P=0.072) in a glucose tolerance test. No association between ()5 and these traits was found in women. Our results, taken together with other data on IGFII levels and TH activity, point to the importance of ()5 as an integrated polygenic haplotype relevant to obesity and insulin response to glucose in men.