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

Abstract

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 (À1.81 kg/m 2 , P ¼ 0.009), lower waist circumference (À6.3 cm, P ¼ 0.001) and lower waist -hip ratio (À5%, Po0.001). This haplotype also marks nearly two-fold lower 120 min insulin (P ¼ 0.004) as well as low baseline insulin (À11.02 pmol/l, P ¼ 0.043) and low 30 min insulin (À64.44 pmol/l, P ¼ 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.

IGF2 Gene Polymorphisms and IGF-II Concentration are Determinants of Longitudinal Weight Trends in Type 2 Diabetes

“…A haplotype including the minor (A) alleles of the IGF2 ApaI (rs680) polymorphism and microsatellites in the INS and TH01 genes was associated with a reduction in body mass index in Caucasian males [ 23 ] . A replication study suggested that this association was specifi c to male subjects and that reduction in BMI was related to a decrease in visceral obesity [ 24 ] . The ApaI AA genotype has also previously been associated with a decrease in circulating IGF-II and higher body weight in Caucasian males [ 25 ] .…”

Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease

“…*5 was also associated with related subphenotypes (plasma insulin and glucose levels at baseline and after a GTT), supporting that the weight-lowering eVect found for *5 has a biological basis Rodríguez et al (2006a) Other species…”

“…There is evidence in the literature suggesting that there may be diVerences between men and women in the genetic factors that inXuence variation in metabolic syndrome risk traits (Poulsen et al 2001;Schousboe et al 2003). Interestingly, most metabolic eVects that our group has seen in the growth hormone and growth factor pathways are sex-speciWc (Rodríguez et al 2004(Rodríguez et al , 2006aDay et al 2004a). Indeed, there are considerable diVerences between men and women in the diurnal proWles of GH pulsatility from the brain (van den et al 1996;Roelfsema et al 2002;Day et al 2004a).…”

“…Since then, we have shown (with replication of signiWcant associations both in diVerent cohorts and using several statistical approaches) that one haplotype (IGF2-INS-TH*5) spanning this gene cluster may have a pleiotropic eVect on diVerent cardiovascular risk traits including BMI, fat mass, visceral obesity, plasma insulin levels, plasma glucose levels and age of Wrst regular smoking in current adult smokers (Rodríguez et al 2004(Rodríguez et al , 2006a. We have also demonstrated for the Wrst time that at least one causal site for weight is located in the IGF2-INS-TH region in human 11p15 (Zhang et al 2006).…”

Co-Expression and Purification of Recombinant Human Insulin-Like Growth Factor II and Insulin-Like Growth Factor Binding Protein-6 in Pichia pastoris Yeast

“…There are six well-characterized mammalian IGF binding proteins, designated IGFBP-1 to IGFBP-6 [2][3][4][5][6]. They are proteins of 216-289 residues and consist of three distinct domains of approximately equal size [7].…”