Variation in the gene for insulin-like growth factor II and its relationship with anthropometric traits

Obesity is a complex disorder caused by a combination of genetic and environmental factors. One candidate is the 30kb IGF2 gene coding for insulin-like growth factor II (IGF-II) on chromosome 11p15.5. Previous work identified an association between the IGF2 gene 3' untranslated region (3'-UTR) Apal polymorphism and body mass index (BMI) in over 2500 middle-aged Caucasoid males from the Northwick Park Heart Study (NPHSII). A further single nucleotide polymorphism (SNP) in the P1 promoter of IGF2 was also found to be significantly associated with BMI. This study identified a further eleven novel polymorphisms and confirmed four published polymorphisms in the IGF2 gene by use of single-strand conformation polymorphism analysis (SSCP) and denaturing high performance liquid chromatography (DHPLC). Nine of the eleven novel polymorphisms were single nucleotide polymorphisms (SNPs) and two were homopolymeric tract length polymorphisms. Eight SNPs were genotyped in 2743 samples from the same cohort as the Apal and P1 promoter polymorphisms and, combined with these data, yield four SNPs significantly associated with BMI in middle-aged men. Regression analysis indicated that three of these associations are significantly independently associated with BMI. Haplotype analysis of NPHSII results identified significant differences in haplotype frequencies between BMI quartiles. The data indicated an association between a haplotype containing 'light' alleles for each of the four significantly associated SNPs and BMI in middle-aged men, supporting the individual association data. Genotyping these SNPs in a second cohort (containing 626 men and 428 women) did not identify significant associations in men, although BMI trends for two of the SNPs were similar to those observed in the NPHSII cohort. Several associations were found in women suggesting a role for IGF2 in weight determination. No evidence was found to support the hypothesis that IGF2 influences foetal and early life development as well as adult weight.