The role of polymorphisms in the IGF-I gene in aging and age-related diseases

Abstract

The IGF-I gene is mapped on the long arm of chromosome 12 and has many polymorphisms in the 5' and 3' regions. About 1 Kb upstream of the promoter region the IGF-I gene there is a polymorphic region composed of multiple cytosine adenosine or CA-repeats. For other genes it has been found that the amount of protein that is formed from a gene is inversely related to the number of CA repeats. This IGF-I gene polymorphism may thus directly influence IGF-I production. In the Rotterdam Study, a population based study in a Caucasian population aged 55 years and over, 10 different alleles were observed in this polymorphic region near the promoter of the IGF-I gene. This IGF-I gene polymorphism has been associated with the age-related decline of serum IGF-I levels. In the Rotterdam Study we observed an optimum in IGF-I levels and final body height for the 192-bp and 194-bp allele of the IGF-I gene. Although the IGF-I genotype was not associated with known cardiovascular risk factors, both the risk of new type 2 diabetes and myocardial infarction were significantly related to this IGF-I gene polymorphism in an elderly population. This finding suggests that IGF-I genotype plays a role in the pathogenesis of both type 2 diabetes and myocardial infarction. Individuals with a variant form of this IGF-I gene polymorphism had a 215-gram lower birth weight than those homozygous for the wildtype allele. Other IGF-I gene polymorphisms have been associated with low IGF-I levels and with a reduction in birth weight, length and head circumference in children born small for gestational age. These IGF-I polymorphisms were also associated with persistent short stature and small head circumference in later life. All these data support the hypothesis that genetic variation in IGF-I activity affects fetal growth and provides a link for the association between low birth weight and susceptibility to diabetes and cardiovascular disease in later life. Recently we added some very exciting observations in the Rotterdam Study. We observed in an elderly population that IGF-I genotype was related to the risk of heart failure. Although we did not find differences in survival between IGF-I genotypes in the whole study population, in subjects with type 2 diabetes patients and prior myocardial infarction survival time was significantly lower in the variant carriers of this IGF-I gene polymorphism when compared to subjects with the wild type. In another study we observed that variant carriers of this IGF-I gene polymorphism had a decreased risk to develop prostate cancer suggesting that genetically determined chronic exposure to low IGF-I levels has a protective effect on the risk for prostate cancer in normal elderly men. In conclusion, all the studies reported above suggest that genetic variability in the genes responsible for IGF-I regulation plays a major role in IGF-I bioactivity and that this IGF-I bioactivity plays a role in the pathogenesis of cardiovascular disease, diabetes and cancer. Further study of IGF-I gene polymorphisms may help to define subpopulations for whom IGF-I decreasing and IGF-I increasing therapies are more or less likely to be effective. This process will help to optimize diagnosis and strategies for the use of (relatively) expensive drugs (such as GH) from a risk/benefit point of view.