Replication of IGF2-INS-TH*5 Haplotype Effect on Obesity in Older Men and Study of Related Phenotypes

Eur J Hum Genet. 2006 Jan;14(1):109-16. doi: 10.1038/sj.ejhg.5201505.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Birth Weight / genetics
  • Body Mass Index
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Female
  • Glucose Tolerance Test
  • Haplotypes / genetics*
  • Humans
  • Infant, Newborn
  • Insulin / genetics*
  • Insulin-Like Growth Factor II
  • Male
  • Middle Aged
  • Multigene Family
  • Obesity / genetics*
  • Phenotype
  • Proteins / genetics*
  • Regression Analysis
  • Sex Factors
  • Tyrosine 3-Monooxygenase / genetics*


  • IGF2 protein, human
  • Insulin
  • Proteins
  • Insulin-Like Growth Factor II
  • Tyrosine 3-Monooxygenase