Assessment of age-related changes in heritability and IGF-1 gene effect on circulating IGF-1 levels.

It is well established that insulin-like growth factor 1 (IGF-1) circulating levels correlate with age and that heritability and influence of IGF-1 gene variation on IGF-1 levels also well-known. However, the influence of age on the genetic factors determining IGF-1 levels is not clear. In this study, we compared heritability estimates between younger (<52 years) and older (>52 years) twins and tested: (a) whether single nucleotide polymorphisms (SNPs) lying within 100 kbp of the IGF-1 gene are also associated with IGF-1 variation and (b) whether associated SNPs show interaction with age on IGF-1 levels. To achieve these aims, we measured plasma levels of IGF-1 and genotyped 18 SNPs with minor allele frequency >0.1 in a large sample, 4,471 UK female twins. Heritability explained 42 % of IGF-1 variation adjusted for age and in unadjusted sample was independent of age. Ten SNPs in four haploblocks showed significant association with IGF-1 levels, with p = 0.01-0.0005. The most distal SNP was located up to 90 kbp from the IGF-1 gene. When their age-dependent effects were examined, one SNP, rs855203, showed significant (p = 0.0009) age-dependent interaction effect on IGF-1 levels variation. This is the first study to test the age × genotype interaction in IGF-1 levels. The genomic region marked by rs855203 may consequently be of significance for further molecular and pharmacogenetic research, in particular in advanced age.