Positive associations between single nucleotide polymorphisms in the IGF2 gene region and body mass index in adult males.
We previously demonstrated an association between the insulin-like growth factor 2 (IGF2) gene 3'-untranslated region (3'-UTR) ApaI polymorphism and body mass index (BMI) in over 2500 middle-aged Caucasoid males. In the same cohort, we have now tested association with 11 more markers, including seven novel single nucleotide polymorphisms (SNPs), spanning >30 kb across the IGF2 gene. Three SNPs showed significant positive associations with BMI: 6815 A/T in the IGF2 P1 promoter (P = 0.00012, n = 2394) and the newly identified SNPs 1156 C/T in intron 2 (P = 0.017, n = 1567) and 1926 C/G in the 3'-UTR (P = 0.0062, n = 1872). There was strong pairwise linkage disequilibrium (LD) between the ApaI and 1926 C/G sites, whereas LD between ApaI and 6815 A/T, and between ApaI and 1156 T/C, was minimal. Univariately 6815 A/T, 1156 T/C and ApaI explained 1.03, 1.02 and 0.67% of the variation in BMI. Multi-way analysis of variance (ANOVA) models showed that 6815 A/T and 1156 T/C explained a further 0.4 and 0.8% of the variation beyond that accounted for by ApaI and the association of 1926 C/G with BMI disappeared after adjustment. The 6815 A/T, 1156 T/C and ApaI markers in effect constitute independent affirmations of our original hypothesized candidate gene region. In a stepwise multi-way ANOVA model, all three terms were significantly independently associated with BMI. The total proportion of BMI variance explained by this model was 2.25%, strongly suggesting that IGF2 genetic variation is a significant determinant of body weight in middle-aged males.
Gaunt
T R
TR
Human Genetics Research Division, University of Southampton School of Medicine, Duthie Building (MP 808), Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK.
Cooper
J A
JA
Miller
G J
GJ
Day
I N
IN
O'Dell
S D
SD
D020413:3' Untranslated Regions / Q000235:genetics; D015415:Biomarkers / Q000032:analysis*; D015992:Body Mass Index; D015331:Cohort Studies; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D005784:Gene Amplification; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment
D020413:3' Untranslated Regions; D015415:Biomarkers; D007328:Insulin; D007335:Insulin-Like Growth Factor II; D015252:Deoxyribonucleases, Type II Site-Specific