The Role of a CA Repeat Polymorphism in the Promoter Region of the Insulin like Growth Factor-I gene in Physiology and the Pathophysiology of Diabetes Mellitus

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• Statistical genetics > Genetic epidemiology
• Clinical/medical genetics > Patient related
• Clinical/medical genetics > Disease related (typology of disorder)
• Molecular genetics > Studies of DNA > Studies of DNA (as a sequence) > Disease-associated alterations (mutation/deletion/duplication/insertion)
• Molecular genetics > Studies of DNA > Studies of DNA (as a sequence)
• Molecular genetics > Techniques > Molecular techniques

Abstract

Thesis in English with a summary in English and Dutch Insulin like growth factor-1 (IGF-I) is a polypeptide which most important function is mediating physiological growth. It is also involved in fat, carbohydrate and protein metabolism and influences cell proliferation, differentiation and survival in many tissues. IGF-I is synthesized by most organs and may act as an endocrine, paracrine and/or autocrine growth factor. Its production is dependent on several factors. The most important regulators are growth hormone (GH), insulin, IGF-I binding proteins and the IGF-I gene. A CA repeat polymorphism in the promoter region of the IGF-I gene has been identified. This CAn polymorphism has a CA repeat range varying between 10 and 24 CA repeats. In the Caucasian population, the most common allele comprises 19 CA repeats (also called the 192-bp allele), suggesting that this is the wild type allele. Homozygous carriers of this allele have been found to have the highest total IGF-I serum levels, highest body height and an increased risk for diabetes mellitus compared to non-carriers of the 192-bp allele. In this thesis, we investigated the role of this CAn polymorphism on physiologic endpoints. We also examined the role of this polymorphism and beta cell function, diabetic retinopathy, micro-albuminuria and mortality. For all the investigations, we used the data of the Rotterdam Study, a population-based cohort study of diseases in the elderly. Baseline examination of the Rotterdam Study was conducted between 1990 and 1993 and a total of 7983 participants were examined. In the introduction part of this thesis, the functions and regulation of IGF-I and its role in the development of diabetes mellitus and development of micro- and macrovascular complications of diabetes are described. Serum IGF-I levels are known to decline with age as the influence of GH on IGF-I seems to become less important. Most of the IGF-I is bound in a trimeric complex with IGFBP3 and an acid lable subunit (ALS). The production of all of the components of this complex is under the influence of GH. In chapter 2 the role of the CAn promoter polymorphism in the age related decline of IGF-I and IGFBP-3 levels was studied in a subgroup of the Rotterdam Study. This group was partly selected on genotype, to maximize power to detect a relation between the IGF-I genotype and serum levels. In the total study group the well known inverse relation between age and total IGF-I levels was observed. After stratification according to the IGF-I genotypes, this relationship disappeared in heterozygous and non-carriers of the 192-bp allele and only remained highly significant in homozygous carriers of the 192-bp allele. Also IGFBP-3 levels decreased with age and stratification per genotype showed again only a significant correlation in homozygous carriers of the 192-bp allele. This suggests that the age related decline of IGF-I is more GH dependent in homozygous carriers of the 192-bp allele compared to heterozygous and non-carriers of the 192-bp allele. In heterozygous and non-carriers of the 192-bp alleles, IGF-I concentration is likely to become more dependent of other factors like nutrition, sex steroids and insulin levels. Our observation that homozygous carriers of the most frequent allele have the highest total serum IGF-I levels, was not consistently found by other investigators. Other study groups have found lower, equal and higher IGF-I levels in homozygous carriers of the wild type allele compared to non-carriers. IGF-I is not only a candidate for influencing body height, but determines also the response to famine in animals. Secular trends in body composition seem primarily related to lifestyle, environmental and socio-economic factors. Genetic factors might also play a role, but so far no major genes have been found to be related to secular trends in body composition. In chapter 3 we studied the relationship between the number of CA repeats in the IGF-I gene and total IGF-I serum levels and body height. We also studied the influence of this Can polymorphism on the secular trend in body height. We observed that total IGF-I serum levels of homozygous carriers of the 194-bp alleles were similar compared to the levels of homozygous carriers of the wild type allele. Homozygous carriers of 192-bp and 194-bp alleles had higher levels compared to homozygous carriers of alleles longer than 194-bp alleles and homozygous carriers of alleles shorter than 192 bp alleles. Also no difference was observed between homozygous carriers of the 192-bp alleles and 194-bp alleles when regarding body height. When we examined all genotypes, a clear optimum in IGF-I serum levels and body height was observed for the group comprising homozygous carriers of the 192-bp and 194- bp alleles, as well as the combination of the 192 and 194-bp alleles. In addition, no relation between the CAn polymorphism and the secular trend in body height was observed. Since the difference in body height between the IGF-I genotype groups didn’t increase over time, we believe that there is no specific effect of the IGF-I gene on the secular trend, nor in times of malnutrition. IGF-I is an important regulator of pancreatic beta cell growth and maturation. In a previous study an increased risk for diabetes mellitus was observed in non-carriers of the 192-bp allele. Insulin resistance and beta cell dysfunction are both prerequisites for the development of type 2 diabetes. The relation between beta cell function and insulin sensitivity in healthy individuals is hyperbolic. Changes in insulin sensitivity are compensated by inverse changes in beta cell responsiveness, such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. The disposition index indicates the metabolic status of an individual, i.e. the relative contributions of insulin sensitivity and beta cell function to their degree of glucose tolerance. A higher disposition index means a higher ability of the beta cells to compensate for the decrease in insulin sensitivity. In chapter 4 we investigated the relation between the IGF-I gene and beta cell function and insulin sensitivity in a casecontrol study, comprising persons with normal glucose tolerance, pre-diabetes and type 2 diabetes. Pre-diabetes was defined as subjects with impaired glucose tolerance and impaired fasting glucose. We used the genotypes based on the observation that carriers of 194-bp alleles had similar IGF-I serum levels as carriers of 192-bp alleles. Two groups were made: wild type and variant carriers. Wild type carriers are carriers homozygous for the 192-bp or for the 194-bp allele, and carriers heterozygote for these two alleles. Participants with all other combinations of alleles were considered variant carriers. In subjects with normal glucose tolerance, variant carriers had lower first and second phase insulin secretion than wild type carriers. We also performed a stratified analyses based on a BMI lower (<) or equal or higher (≥) 27 kg/m2, since it has been found that insulin sensitivity for glucose disposal is impaired in humans with normal glucose tolerance with a BMI ≥ 27 kg/m2. The parameters for beta cell function as well as the disposition index were significantly lower for variant carriers when looking in non-obese persons only. In obese subjects no differences in parameters of insulin sensitivity and beta cell function were observed between the IGF-I genotypes. Our study suggests that in individuals with a normal glucose tolerance, beta cells respond insufficiently to this glucose load in variant-carriers. This polymorphism in the IGF-I gene may thus contribute to diabetes susceptibility. The existing literature on the role of IGF-I in the development and progression of diabetic retinopathy is conflicting. Intravitreal levels have been found to be higher in diabetic patients compared to controls. On the other hand, GH deficient dwarfs with glucose intolerance rarely develop severe proliferative retinopathy. Proliferative retinopathy has been associated with low, normal and high total IGF-I serum levels. In chapter 5a, we studied the association of the IGF-I gene as a marker of IGF-I production and retinal vascular diameters as well as diabetic retinopathy. Vascular dilatation of the retinal vessels, especially the retinal venules, has been observed in the early stages of diabetic retinopathy. Furthermore, especially larger venular diameter has been associated with a 4-year incidence of proliferative retinopathy. At baseline, variant carriers with impaired glucose tolerance (IGT) or diabetes appeared to have a larger retinal arteriolar and venular diameter than wild type carriers with IGT/diabetes, but the differences were not statistically significant. Variant carriers with IGT/diabetes who developed retinopathy during follow-up already tended to have even larger retinal vascular diameter at baseline when compared with IGT/diabetes subjects who did not develop retinopathy. Finally, variant carriers with IGT/diabetes had a 1.8 increased risk of incident retinopathy compared with participants of the wild type. Our study suggests that the Can IGF-I promoter polymorphism may modulate the susceptibility and/or the progression of diabetic retinopathy. Micro-albuminuria (MA) is an early marker for renal disease in diabetics. It is also related to cardiovascular disease in diabetic and non-diabetic persons. IGF-I has been implicated in the development of diabetic nephropathy and cardiovascular disease. IGF-I enhances renal plasma flow and creatinine clearance and has been associated with renal hypertrophy and compensatory renal growth in amongst others diabetes. Raised renal concentrations are thought to protect diabetic kidney cells from ischemic damage and to accelerate tissue repair and recovery of renal function. In chapter 5b, we investigated if the promoter polymorphism in the IGF-I gene was related to the development of micro-albuminuria. In persons with an abnormal glucose tolerance (AGT), comprising persons with impaired glucose tolerance, impaired fasting glucose and diabetes, variant carriers had almost significantly more albuminuria and a higher albumin-to-creatinine ratio (ACR) than wild type carriers. Risk of development of MA was higher in AGT compared to normal glucose tolerance (NGT) and variant carriers had a higher risk compared to carriers of the wild type alleles in both glucose tolerance conditions. After stratification for glucose tolerance, variant carriers had a higher risk of development of MA in individuals with AGT, which was significant after adjustment for potential confounders. This suggests that the IGF-I gene polymorphism modifies the susceptibility and/or progression of MA as soon as a person develops MA. Susceptibility to MA probably results from an interaction of multiple genetic and environmental factors, meaning that MA only will develop in with a certain genetic background when other risk factors are also present. In chapter 6, the relation between the polymorphism and mortality was examined. In a population of 7983 elderly individuals, 345 of them developed a myocardial infarction during follow-up. The risk of mortality following myocardial infarction was 1.5 times higher in variant carriers compared to non-carriers, where as no relation between the polymorphism and mortality in the overall population was observed. IGF-I may be a determinant of survival because it promotes survival of cardiomyocytes that are affected by ischemia. In chapter 7 possible explanations for the differences in outcome between IGF-I genotype and circulating IGF-I levels are discussed as well as the clinical implications of our results. Furthermore, we outlined limitations of the candidate gene approach and the study design used in our study. Finally, perspectives for future research are described.

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I. Rietveld. The Role of a CA Repeat Polymorphism in the Promoter Region of the Insulin like Growth Factor-I gene in Physiology and the Pathophysiology of Diabetes Mellitus. EUROGENE portal. October 2010. online: http://eurogene.open.ac.uk/content/role-ca-repeat-polymorphism-promoter-region-insulin-growth-factor-i-gene-physiology-and-path

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