IGF-I Genotype Research Articles

Effect of the <i>IGF-I</i> gene polymorphism on growth, body size, carcass and meat quality traits in Coloured Polish Merino sheep

Abstract. Insulin-like growth factor I, encoded by the IGF-I gene, plays a role in cell growth and differentiation, embryogenesis, metabolism regulation, skeletal growth, and protein synthesis. The aims of this study were to investigate the polymorphism in the 5′ flanking region of the IGF-I gene and evaluate associations between the single-nucleotide polymorphism (SNP) in this gene and growth, body size, carcass and meat quality traits in Coloured Polish Merino sheep. In total 78 live and post mortem traits were investigated. Polymorphism in the IGF-I gene was identified with the use of the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method in 305 Coloured Polish Merino sheep. In association studies, traits of interest were analysed with the use of the MIXED and GENMOD procedures of the SAS statistical package. Two alleles named A and B, and two IGF-I genotypes – AA and AB – were detected. The A allele and the AA genotype were predominant, with the frequencies of 91.6 and 83.3 %, respectively. The IGF-I genotype was found to have a highly significant effect on fore shank weight (P = 0.006), kidney fat class (P = 0.002) and EUROP fat class (P = 0.005). Furthermore, the IGF-I genotype significantly affected external fatness of carcass class (P = 0.038), drip loss (P = 0.049), and subjective assessment of meat colour (P = 0.043), and it tended to be associated with longissimus dorsi (LD) muscle width (P = 0.063) and flavour (0.067). Concluding, the IGF-I gene could be considered as a candidate gene of selected carcass and meat quality traits in sheep.

Effects of polymorphism in the 5′-flanking region of the IGF-I gene on milk-production traits in Chinese Holstein cattle

Milk and milk products are major components of human dietary intake and have a potential influence on health. In our experiment, associations between insulin-like growth factor 1 (IGF-I) gene polymorphism and milk-production traits were analysed in Chinese Holstein cattle. A polymorphism, transition at position g.1407 T > C, was identified in the 5′-flanking region of the IGF-I gene by pooled DNA sequencing. The identified single-nucleotide polymorphism (SNP) was genotyped by matrix-assisted laser desorption–ionisation time-of-flight mass spectrometry (MALDI–TOF MS) methods from 752 individuals. Significant associations between IGF-I genotypes and 305-day milk yield, fat yield and protein yield were found. Homozygous cows with TT genotype showed the highest milk, fat and protein yields, with increases of 532.75 kg, 23.57 kg and 14.69 kg, respectively, as compared with homozygous CC cows. Heterozygous CT cows had intermediate yields. Allele substitution showed that the C allele decreased milk yield (255.23 kg), fat yield (11.37 kg) and protein yield (7.05 kg), whereas it increased protein percentage (0.01%). The results suggest that IGF-I is a candidate gene that influences milk-production traits, and provides useful information to be implemented in breeding programs to improve the performance of the Chinese Holstein.

Postnatal growth and cardiometabolic profile in young adults born large for gestational age

The association between large for gestational age (LGA) phenotype, postnatal growth and cardiometabolic risk (CMR) in adult life remains unclear. The role of IGF1 genotype on LGA-related outcomes in adult life is unknown. To assess the postnatal growth, IGF-I levels, CMR and the influence of the 737.738 IGF1 in adults born LGA. Case-control study (n = 515) nested in a population-based prospective cohort (n = 2063); 117 LGA and 398 gender-matched controls appropriate for gestational age (AGA) subjects. Anthropometry was evaluated at birth, at 9-10 and at 23-25 years old. At the age of 23-25 years, blood pressure (BP), glycaemia, insulinaemia, homeostasis model assessment - insulin resistance, lipids, fibrinogen, and plasma IGF-I and 737.738 IGF1 polymorphism were assessed. Large for gestational age subjects remained heavier and taller than AGA at 9-10 and 23-25 years (P < 0·05); at 23-25 years, LGA had greater waist circumference (WC; P < 0·05) and higher BP (P < 0·05) than controls. Body proportionality at birth did not predict metabolic outcome. LGA subjects presenting catch-down of weight in childhood had lower body mass index (BMI; P = 0·001), lower WC (P < 0·05) and lower BP (P < 0·05) at 23-25 years. 737.738 IGF-I genotype differed between groups (P < 0·001). Homozygosis for polymorphic alleles was associated with increased odds of LGA (OR: 3·2; 95% CI: 1·5-6·9), higher IGF-I (56·9 ± 16·4 vs 37·7 ± 16·0 nm; P < 0·01) and lower BP (114/68 vs 121/73 mmHg; P < 0·05). Young adults born LGA presented higher BMI, WC and BP and appear to be at higher CMR risk than AGA subjects. The 737.738 IGF1 polymorphism appears to play a role on birth size and LGA-related metabolic outcomes.

Metabolic and endocrine profiles and reproductive parameters in dairy cows under grazing conditions: effect of polymorphisms in somatotropic axis genes

BackgroundThe present study hypothesized that GH-AluI and IGF-I-SnabI polymorphisms do change the metabolic/endocrine profiles in Holstein cows during the transition period, which in turn are associated with productive and reproductive parameters.MethodsHolstein cows (Farm 1, primiparous cows, n = 110, and Farm 2, multiparous cows, n = 76) under grazing conditions were selected and GH and IGF-I genotypes were determined. Blood samples for metabolic/endocrine determinations were taken during the transition period and early lactation in both farms. Data was analyzed by farm using a repeated measures analyses including GH and IGF-I genotypes, days and interactions as fixed effects, sire and cow as random effects and calving date as covariate.Results and DiscussionFrequencies of GH and IGF-I alleles were L:0.84, V:0.16 and A:0.60, B:0.40, respectively. The GH genotype was not associated with productive or reproductive variables, but interaction with days affected FCM yield in multiparous (farm 2) cows (LL yielded more than LV cows) in early lactation. The GH genotype affected NEFA and IGF-I concentrations in farm 1 (LV had higher NEFA and lower IGF-I than LL cows) suggesting a better energy status of LL cows.There was no effect of IGF-I genotype on productive variables, but a trend was found for FCM in farm 2 (AB cows yielded more than AA cows). IGF-I genotype affected calving first service interval in farm 1, and the interaction with days tended to affect FCM yield (AB cows had a shorter interval and yielded more FCM than BB cows). IGF-I genotype affected BHB, NEFA, and insulin concentrations in farm 1: primiparous BB cows had lower NEFA and BHB and higher insulin concentrations. In farm 2, there was no effect of IGF-I genotype, but there was an interaction with days on IGF-I concentration, suggesting a greater uncoupling somatropic axis in AB and BB than AA cows, being in accordance with greater FCM yield in AB cows.ConclusionThe GH and IGF-I genotypes had no substantial effect on productive parameters, although IGF-I genotype affected calving-first service interval in primiparous cows. Besides, these genotypes may modify the endocrine/metabolic profiles of the transition dairy cow under grazing conditions.

Genotypes and phenotypes of IGF-I and IGFBP-3 in breast tumors among Chinese women

The relationship between IGF genotypes and phenotypes in breast tumors and their associations with breast cancer risk remain to be elucidated. Such information is especially scarce in Chinese women. To evaluate IGF-I and IGFBP-3 genotypes in relation to their phenotypes in local breast tissues and in association with breast cancer risk, we conducted a case-control study among Chinese women. The study recruited 403 breast cancer patients and 403 age-matched controls. Four single nucleotide polymorphisms (SNP) in the IGF-I gene (rs1520220, rs2946834, rs2195239, and rs7965399) and two SNPs of the IGFBP-3 gene (rs2854746 and rs2960436) with known correlations with their phenotypes in the circulation were genotyped using TaqMan assays. Fresh tumor samples from the same patients were analyzed with immunoassays for protein concentrations of IGF-I and IGFBP-3. Associations of breast cancer with these SNPs were examined using unconditional logistic regression. Correlations between IGF genotypes and phenotypes were determined with Wilcoxon rank-sum test. Of the six selected SNPs, only one IGF-I SNP (rs7965399) was associated with breast cancer risk in a recessive model (OR = 1.86; 95% CI: 1.04-3.32), and the association was more evident in patients who had menopause under age 50 or ER negative tumors. No associations were found between breast cancer and other three IGF-I and two IGFBP-3 SNPs. Patients with variant IGF-I or wild IGFBP-3 genotypes had higher peptide levels of IGF-I compared to those with wild IGF-I or variant IGFBP-3 genotypes. The selected IGF-I and IGFBP-3 SNPs did not show any strong evidence for being associated with breast cancer risk, but the genotypes were correlated with IGF-I phenotypes in tumor samples, suggesting possible influences of these SNPs on IGF-I activity in local tissues.

Age- and Sex-Related Interactions between Insulin-Like Growth Factor-I Promoter Polymorphisms and IGF-I Levels

The present study explored sex-and age-related interactions of IGF-I polymorphisms with IGF-I serum levels. In 2000 data on IGF-I promoter polymorphism and IGF-I level were available of 344 (mean age 36; 162 men) and 6 years later in 287 subjects (133 men). As the sample sizes of groups of subjects with IGF-I genotypes 192/192, 190/192, 192/194 and 192/196 were large enough to be analyzed, the relationship between these specific genotypes and IGF-I-level was determined. The results indicated that in women aged 36 IGF-I levels for genotype 190/192 (mean 29.24 nmol/l) were higher than those for genotypes 192/192 (mean 24.29), 192/194 (mean 24.61) and 192/196 (mean 23.93). Male IGFI levels were decreased in 2006 compared to 2000 for genotypes 192/192 (mean decline - 3.67), 192/194 (mean decline - 1.61), 192/196 (mean decline - 4.18), but not for 190/192. Female IGF-I levels were decreased for genotypes 192/192 (mean decline - 1.85) and 190/192 (mean decline - 4.64), but not for 192/194 and 192/196. Thus females with genotype 190/192 have higher IGF-I levels, while females with genotypes 192/194 or 192/196 and males with genotype 190/192 do not show a decline of IGF-I level. © van Turenhout et al.

Biological markers of neonatal calf performance: The relationship of insulin-like growth factor-I, zinc, and copper to poor neonatal growth1

Raising a heifer calf to reproductive age represents an enormous cost to the producer. Poor neonatal growth exacerbates the costs incurred for rearing, and use of blood variables that may be associated with poorly growing calves may offer predictive value for growth and performance. Thus, the principal objective of the present study was to describe changes in serum IGF-I, zinc, and copper from birth to 90 d in Holstein calves, while accounting for sex and twin status, in poorly growing calves and calves growing well. A second objective was to test the hypothesis that an association exists between these serum variables and morphometric indicators of growth. Measurements of BW, length, and height were recorded at birth and at 30, 60, and 90 d of age. Jugular blood (12 mL) was collected from each calf on d 1 to determine serum total protein, serum IgG, packed cell volume, serum zinc, serum copper, serum IGF-I, and CD18 genotype for bovine leukocyte adhesion deficiency; serum zinc, serum copper, and serum IGF-I (predictor variables) were also determined for each calf on d 2 through 10 and on d 30, 60, and 90. Stepwise multiple regression and logistic regression analyses were used to examine the relationships between the predictor variables and the dependent variables (BW, height, and length at d 30, 60, and 90 of life). Birth weight, sex, serum IGF-I (at all ages), serum copper, and the serum copper-to-zinc ratio were associated, to varying degrees, with the dependent growth variables. Birth weight was consistently the dominant predictor. In conclusion, these results suggest that lighter birth weight, reduced serum IGF-I, and inflammation may be important causes of poor growth in neonatal Holstein dairy calves.

Analysis of cytosine adenine repeat polymorphism of the IGF-I promoter gene in children with idiopathic short stature

Purpose : A polymorphism in the IGF-I gene promoter region is known to be associated with serum IGF-I levels, birth weight, and body length, suggesting that IGF-I gene polymorphism might influence postnatal growth. The present study aimed to investigate the role of this polymorphic cytosine-adenine (CA) repeat of the IGF-I gene in children with idiopathic short stature. Methods : The study involved 131 children (72 boys and 59 girls) diagnosed with idiopathic short stature, aged 715 years. Genomic DNA was extracted from anticoagulated peripheral whole blood. The primers were designed to cover the promoter region containing the polymorphic CA repeat. Data were analyzed using GeneMapper software. The correlations between age and serum IGF-I levels were analyzed using Spearmans correlation coefficient. Results : The CA repeat sequences ranged from 15 to 22, with 19 CA repeats the most common with an allele frequency of 40.6%. Homozygous for 19 CA repeat was 13.0%, heterozygous for 19 CA repeat was 56.5%, and 19 CA non-carrier was 30.5%. The three different genotype groups showed no significant differences in height, body weight and body mass index, and serum IGF-I levels. The serum IGF-I level and age according to the IGF-I genotypes were significantly correlated in the entire group, 19 CA repeat carrier group, and the non-carrier group. The three groups also showed no significant differences in the first year responsiveness to GH treatment. Conclusion : There were no significant different correlations between 19 CA repeat polymorphism and serum IGF-I levels according to genotype. Our results suggest that the IGF-I 19 CA repeat gene polymorphism is not functional in children with idiopathic short stature.

Absence of the Wild-type Allele (192 Base Pairs) of a Polymorphism in the Promoter Region of the IGF-I Gene but Not a Polymorphism in the Insulin Gene Variable Number of Tandem Repeat Locus Is Associated With Accelerated Weight Gain in Infancy

Our goal was to investigate whether a polymorphism in the insulin-like growth factor I promoter gene (IGF-I, wild-type, 192 base pairs) and in the insulin gene (INS) variable number of tandem repeat locus influence birth weight and weight gain in infancy. We obtained genomic DNA from 768 children. Exclusion criteria were multiple births, gestational diabetes, maternal diabetes, gestational age <37 weeks, >42 weeks, or unclear, and any condition potentially influencing weight gain. SD scores were calculated and adjusted for gestational age and gender. A gain in SD scores for weight between birth and 1 year >0.67 SD scores was defined as accelerated weight gain. Genotyping was performed by fragment length analysis (IGF-I) and by fragment length analysis after using a restriction enzyme-based assay (INS variable number tandem repeat). Accelerated weight gain was present in 205 of 768 children. IGF-I and INS variable number tandem repeat genotype were not associated with birth weight. The IGF-I 192-base pair allele was less frequent in children with accelerated weight gain and was shown to reduce the risk for accelerated weight gain in a logistic regression model. The IGF-I 192-base pair allele may reduce the risk for rapid weight gain in early infancy.

IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes

Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes. We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older. The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers. During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7-1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2-4.8, P = 0.01). Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.

An insulin-like growth factor-I gene polymorphism modifies the risk of microalbuminuria in subjects with an abnormal glucose tolerance

Microalbuminuria (MA) is related to cardiovascular disease both in diabetic patients and non-diabetic subjects. We investigated whether a polymorphism near the promoter region of the IGF-I gene was related to the development of MA. 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). 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 = 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 = 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 = 0.04). 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.

Analysis of cytosine adenine(CA) repeat polymorphism of the IGF-I gene and influence on serum IGF-I levels in healthy children and adolescents

Purpose:The aim of the present study was to investigate the role of polymorphic cytosine adenine (CA) repeat of the IGF-I gene in the age-related alterations of serum IGF-I levels in healthy children. Methods:Two hundred and forty three normal healthy children (136 boys; 107 girls) aged between 7 and 15 years were enrolled in the present study. The primers were designed to cover the promoter regions containing the polymorphic CA repeat. Data were analyzed using GeneMapper software, version 3.7. All analyses were performed using MEDCALC software packages. Results:Deletion of 2 bp (G, A) following 3' of CA repeat were observed in all Korean children. The CA repeat sequences ranged from 17 to 23, and 19 CA repeat were the most common with an alleles frequency of 39.3 percent. Considering genotypes, 63.8 percent of subjects were homozygote or heterozygote for 19 CA repeat (192 bp allele), suggesting that this is wild type allele from which all other alleles originated in Korean children. Homozygote for 19 CA repeat were 14.7 percent, heterozygote for 19 CA repeat was 49.1 percent and 19 CA noncarriers totalled 36.2 percent. In 19 CA repeat noncarriers, the mean height, weight and serum IGF-I level were lower compared with those of 19 CA homozygous carriers, but statistically not significant. Correlations between serum IGF-I level and age according to the IGF-I genotypes revealed statistically significant relationships in the all groups, in the 19 CA repeat carrier group and, even in the noncarrier group. Conclusions:There were no significant differences of the mean height, weight and serum IGF-I levels among three different genotype groups. Also, there were no significantly different correlations between 19 CA repeat polymorphisms and serum IGF-I levels, according to genotype. Our results suggest that the IGF-I 19 CA repeat gene polymorphism is not associated with circulating IGF-I levels in healthy children

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

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.

Relationship Between Egg Productivity and Insulin-Like Growth Factor-I Genotypes in Korean Native Ogol Chickens

Endocrine factors, such as steroid hormones and growth factors, regulate egg productivity in terms of the quantity of egg production, egg weight, sexual maturity, and the number of small yellow follicles (SYF). Insulin-like growth factors (IGF) are involved in the regulation of ovulation rate and ovarian follicular development in chickens, and a relationship between IGF-I genotype and egg weight has been reported. However, the effect of IGF on egg productivity in Korean Native Ogol chickens (KNOC) has been little studied. Therefore, this study was conducted to identify the relationship among endocrine factors (IGF-I, IGF-II, estradiol, and progesterone), IGF-I genotypes, and egg productivity. Frequencies of IGF-I genotypes (AA, AB, BB) were 17.3, 26.9, and 55.8%, respectively, within a population. When compared with the IGF-I genotypes, the AB genotype had the highest serum levels of estradiol and progesterone at 40 and 30 wk of age, respectively; the highest IGF-II concentration in F1 follicles at 60 wk; and was positively associated with the number of SYF at 60 wk. The results showed that the A allele was associated with a higher IGF-II expression in the follicles and stimulated the development of follicles, indicating a positive association of the A allele with egg production and the number of SYF. Therefore, these results suggest that there is a possibility of IGF-I genotypes acting as a genetic marker for egg productivity of KNOC.

Genetic Factors and Insulin Secretion

IGFs are important regulators of pancreatic beta-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI.

Insulin-like growth factor-I governs submucosal growth and thickness in the newborn mouse ileum.

Spontaneous intestinal perforations in extremely premature infants are associated with glucocorticoid-induced thinning of the ileal bowel wall. We have previously demonstrated that insulin-like growth factor-1 (IGF-1) is abundant within the submucosa of the newborn mouse ileum but is diminished by glucocorticoid exposure, concomitant with bowel wall thinning. These findings prompted us to hypothesize that IGF-I governs submucosal growth during neonatal gut development and that diminished IGF-I abundance results in submucosal thinning. Heterozygous IGF-I knockout, wild type and homozygous IGF-I over-expresser newborn mice were euthanized at 3 d of life. Additionally, wild type newborn mice received daily dexamethasone (DEX) (1microg/gm/d) or vehicle control on days of life 1 and 2 and were also euthanized at 3 d of life. Their ileums were harvested, fixed and the resulting sections were processed in parallel for IGF-I immunohistochemistry and morphometric measurements of submucosal thickness and bowel diameter. Immunolocalization of IGF-I in each genotype was also compared with that seen in DEX-treated and control mice euthanized at the same time of life. IGF-I heterozygous knockouts had diminished submucosal IGF-I immunolocalization (similar to that seen in DEX-treated newborn mice) whereas homozygous IGF-I over-expressers exceeded that seen within wild type mice. IGF-I genotype and submucosal abundance was positively correlated with ileal submucosal thickness. DEX treatment of newborn mice diminished IGF-I and caused significant thinning of the submucosa compared with controls. Submucosal growth and thickness in the neonatal mouse ileum is governed by IGF-I and is diminished by dexamethasone treatment.

A polymorphism in the IGF-I gene influences the age-related decline in circulating total IGF-I levels.

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. 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. Homozygous carriers of the 192 bp allele demonstrated significant decline in serum IGF-I with age (r=-0.29, P=0.002). This decline is similar to that seen in the general population. An age-related decline in serum total IGF-I was not observed in heterozygotes (r=-0.06, P=0.48) and non-carriers (r = -0.12, P=0.32). Interestingly, the relationship between age and serum IGF-binding protein-3 levels showed the same pattern. We observed only in homozygous carriers of the 192 bp alleles of the IGF-I gene an age-related 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 GH-mediated regulation of IGF-I secretion.

Polymorphic CA repeats in the IGF-I gene and breast cancer.

Insulin-like growth factor (IGF)-I is a potent mitogen for breast cancer cells and may play a role in the disease. Although the involvement of IGF-I phenotype in breast cancer has been studied extensively, little is known about IGF-I genotype in relation to the disease. The IGF-I gene contains a polymorphic region composed of multiple cytosine-adenine dinucleotides (CA repeats). Studies of other genes indicate that the CA-repeat region in the promoter of a gene may affect transcription activity and that the length of the repeat is inversely correlated with transactivation. To examine if the IGF-I polymorphism is associated with breast cancer, we compared the length of CA repeats in the IGF-I gene between 53 breast cancer patients and 53 controls. Genomic DNA extracted from peripheral blood was used to determine the number of CA repeats through PCR amplification and DNA sequencing. Associations between CA repeats and breast cancer were assessed using unconditional logistic regression analysis. The results showed that the median number of CA repeats was 19, ranging from 15 to 23, and that compared to women without 19 CA repeats, women with 19 CA repeats were more likely to be breast cancer patients (OR = 2.87, 95%CI: 1.16-7.06) after adjusting for age, race, menopausal status, age at menopause, and alcohol use. The study also suggested possible synergistic interplay between IGF-I genotype and phenotype as women with 19 CA repeats and high plasma IGF-I had a much higher odds ratio for breast cancer (OR = 5.12, 95%CI: 1.42-18.5) than those with only one of the conditions. If our observations can be confirmed in larger studies, the findings will provide further evidence to support the role of IGF-I in breast cancer and the link between genetic polymorphism and cancer susceptibility.