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/m2, 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.

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