Objective: Recent studies have demonstrated an association between a 192 bp polymorphism of the IGF-I gene and total IGF-I serum levels, birth weight, body height and the risk of developing diabetes and cardiovascular diseases later on in life. This IGF-I gene polymorphism in the promoter region of the IGF-I gene may directly influence the expression of IGF-I. In the present study we evaluated the role of this polymorphism in the age-related decline in serum IGF-I levels. Subjects and methods: All subjects were participants of the Rotterdam Study, a population-based cohort study of diseases in the elderly. We studied a total group of 346 subjects, who comprised two subgroups: a randomly selected population-based sample of 196 subjects, and a group of 150 subjects selected on IGF-I genotype. In the total group of 346 individuals the relationship between this 192 bp polymorphism and the age-related decline in circulating total IGF-I levels was studied. Results: Homozygous carriers of the 192 bp allele demonstrated significant decline in serum IGF-I with age ðr ¼ 20:29; P ¼ 0:002Þ: This decline is similar to that seen in the general population. An agerelated decline in serum total IGF-I was not observed in heterozygotes ðr ¼ 20:06; P ¼ 0:48Þ and non-carriers (r = 20.12, P ¼ 0:32Þ: Interestingly, the relationship between age and serum IGF-binding protein-3 levels showed the same pattern. Conclusion: We observed only in homozygous carriers of the 192 bp alleles of the IGF-I gene an agerelated decline in circulating total IGF-I levels, but not in heterozygotes and non-carriers of the 192 bp allele. We hypothesize that this IGF-I gene polymorphism directly or indirectly influences GHmediated regulation of IGF-I secretion.

Objective: Microalbuminuria (MA) is related to cardiovascular disease both in diabetic patients and non-diabetic subjects. Design: We investigated whether a polymorphism near the promoter region of the IGF-I gene was related to the development of MA. Methods: For this study, 1069 participants of the Rotterdam study were selected (440 participants with an abnormal glucose tolerance (AGT), 220 participants with type 2 diabetes and 254 subjects with pre-diabetes, and 595 subjects with a normal glucose tolerance (NGT). Results: 787 subjects were carriers of the wild type IGF-I genotype (73.6%) and 282 subjects were variant carriers (26.4%) of this IGF-I gene polymorphism. Compared to subjects with NGT the risk for microalbuminuria was higher (Odds Ratio (OR): 3.1 (95% CI: 1.2-7.7); P ¼ 0.02) in variant carriers with AGT than in carriers of the wild type of this IGF-I gene polymorphism (OR: 2.2 (95% CI: 1.2 -4.0); P ¼ 0.009). Compared with wild type carriers with AGT, the relative risk for MA was unadjusted and non-significantly increased in variant carriers with AGT (1.6; 95% CI: 0.8 -2.9). However, after adjustment for possible confounding factors (age, gender, mean blood pressure, fasting insulin, fasting glucose and smoking) this risk became significant (OR: RR 2.1; 95% CI:1.1 -4.4; P ¼ 0.04). Conclusions: In subjects with AGT, a higher risk for MA was observed in variant carriers than in carriers of the wild type genotype of this IGF-I gene polymorphism. Since MA is primarily associated with cardiovascular disease in subjects with AGT, our study suggests that variant carriers have a higher risk for cardiovascular disease than carriers of the wild type when they develop an AGT. European Journal of Endocrinology 154 715-721

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