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.
Rodríguez
Santiago
S
Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK.
Gaunt
Tom R
TR
Dennison
Elaine
E
Chen
Xiao-he
XH
Syddall
Holly E
HE
Phillips
David I W
DI
Cooper
Cyrus
C
Day
Ian N M
IN
D000368:Aged; D001724:Birth Weight / Q000235:genetics; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D005951:Glucose Tolerance Test; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics*; D007335:Insulin-Like Growth Factor II; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012044:Regression Analysis; D012737:Sex Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D044465:White People / Q000235:genetics
C035170:IGF2 protein, human; D007328:Insulin; D011506:Proteins; D007335:Insulin-Like Growth Factor II; D014446:Tyrosine 3-Monooxygenase