A Putative Functional Polymorphism in the IGF-I Gene

Abstract

IGF-I has a critical role in growth and metabolism. A microsatellite polymorphism 1 kb upstream to the IGF-I gene has recently been associated with several adult phenotypes. In a large Dutch cohort, the absence of the commonest allele (Z) was associated with reduced serum IGF-I levels, reduced height, and an increased risk of type 2 diabetes and myocardial infarction. This result has not been replicated, and the role of this polymorphism in these traits in U.K. subjects is not known. We sought further evidence for the involvement of this variant in type 2 diabetes using a case-control study and IGF-I and diabetes-related traits in a population cohort of 640 U.K. individuals aged 25 years. Absence of the common allele was not associated with type 2 diabetes (odds ratio 0.70, 95% CI 0.47-1.04 for X/X versus Z/Z genotype, 2 test for trend across genotypes, P ‫؍‬ 0.018). In the population cohort, the common allele (Z) was associated with decreased IGF-I levels (P ‫؍‬ 0.01), contrary to the Dutch study, but not with adult height (P ‫؍‬ 0.23), glucose tolerance (P ‫؍‬ 0.84), oral glucose tolerance test-derived values of ␤-cell function (P ‫؍‬ 0.90), or insulin resistance (P ‫؍‬ 0.66). There was no association with measures of fetal growth, including birth weight (P ‫؍‬ 0.17). Our results do not support the previous associations and suggest that the promoter microsatellite is unlikely to be functionally important.

Absence of the common IGF1 19 CA-repeat allele is more common among BRCA1 mutation carriers than among non-carriers from BRCA1 families

“…It is therefore likely that other low penetrance genes that modify cancer risk, such as the IGF1 gene, also segregate at a high frequency in highrisk families. However, the allele frequencies found in this study were comparable to those reported in other Caucasian populations (Cleveland et al, 2006;Frayling et al, 2002). One strength of the present study is that many women belonged to the same family.…”

Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels

“…It could be argued that intrauterine growth restraint programs a lower beta cell mass resulting in persisting reduced insulin secretory capacity [31,32], and subsequent lower IGF-I generation and shorter stature. Alternatively, IGF-I activity may directly regulate not only childhood growth [15] but also the maintenance of beta cell mass and insulin secretory response to glucose, and this hypothesis may be supported by variable genetic associations between IGF-I gene variants with higher circulating IGF-I levels, taller stature and reduced risk of developing Type 2 diabetes [33,34].…”

An IGF-I gene polymorphism modifies the risk of developing persistent microalbuminuria in type 1 diabetes

“…Thus, this CA repeat polymorphism in the IGF-I gene has the potential to influence the IGF-I expression directly at the tissue level and, may therefore, serve as a better indicator of life-long IGF-I exposure than circulating IGF-I (15). Although others found no relationship or even reported lower circulating IGF-I levels in subjects, homozygous for the wild-type allele of this IGF-I gene polymorphism compared with those that were non-carriers or heterozygous for the wild-type allele (16)(17)(18)(19), we recently observed in a populationbased sample, like Missmer et al (20), that subjects homozygous for the wild-type alleles of this IGF-I gene polymorphism had higher serum IGF-I levels than subjects that were non-carriers of the wild-type alleles (21). Possible explanations for these discrepant observations might be due to chance, unknown confounders, variations in patterns of linkage disequilibrium between populations, different study designs and methods used to measure IGF-I across studies (22).…”