Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam Study

Studies of the roles of variants of the IGF-I gene in the regulation of bone mineral density (BMD) have yielded conflicting results. We examined the role of a microsatellite repeat polymorphism in one of the promoter regions of the IGF-I gene in relation to femoral BMD in elderly women and men from the Rotterdam Study. We studied 5648 and 4134 individuals at baseline and follow-up ( approximately 2 yr later), respectively. Femoral BMD measurements were performed using dual energy x-ray absorptiometry. In women, baseline BMD levels were, on the average, 0.02 g/cm(2) [95% confidence interval (CI) for difference, -0.03, -0.00 g/cm(2)] lower in individuals without the 192-bp allele as compared with the homozygotes for the allele (P = 0.03). The mean rate of BMD change from baseline to follow-up was -6.9 mg/cm(2) (95% CI, -10.8, -3.0), -4.5 mg/cm(2) (95% CI, -6.4, -2.5), and -2.3 mg/cm(2) (95% CI, -4.2, 0.3) in noncarriers, heterozygotes, and homozygotes for the 192-bp allele, respectively (P trend = 0.03). Adjustment for age and body mass index did not essentially change this relation. No such effects were observed in men. Our findings suggest that this promoter polymorphism or another functional polymorphism in linkage disequilibrium may be a genetic determinant of BMD levels and rate of bone loss in postmenopausal women

A genome-wide search for linkage-disequilibrium with type 1 diabetes in a recent genetically isolated population from the Netherlands

Type 1 diabetes has a substantial genetic component, with consistent evidence for a susceptibility locus in the HLA-DR/DQ region (chromosome 6p) and the insulin gene region (chromosome 11p). Genome scans have identified >18 other genomic regions that may harbor putative type 1 diabetes genes. However, evidence for most regions varies in different data sets. Given the genetic heterogeneity of type 1 diabetes, studies in homogeneous genetically isolated populations may be more successful in mapping susceptibility loci than in complex outbred populations. We describe a genome-wide search in a recently Dutch isolated population. We identified 43 patients that could be traced back to a common ancestor within 15 generations and performed a genome-wide scan using a combined linkage- and association-based approach. In addition to the HLA locus, evidence for type 1 diabetes loci was observed on chromosome 8q24 (marker D8S1128) and on chromosome 17q24 (marker D17S2059). Both the 8q and 17q localization are supported by allele-sharing at adjacent markers in affected individuals. Statistical evidence for a conserved ancestral haplotype was found for chromosome 8q24

Insulin-like growth factor I gene promoter polymorphism, collagen type II alpha1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

OBJECTIVE: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. METHODS: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. RESULTS: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. CONCLUSIONS: SUBJECTS: with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested

The Genome of the Netherlands: Design, and project goals

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the fi

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug

The role of hemochromatosis C282Y and H63D gene mutations in type 2diabetes: findings from the Rotterdam Study and meta-analysis

Lette

Heritabilities of radiologic OA in peripheral joins and of disc degeneration of the spine

OBJECTIVE: To estimate the genetic influence on the occurrence of radiologic osteoarthritis (ROA) in the knees, hips, and hands and disc degeneration of the spine in the general population. METHODS: A random sample of 1,583 individuals was drawn to estimate the prevalence of ROA and disc degeneration in the general population. Of 118 probands with multiple affected joint sites who were derived from this sample, we were able to recruit 257 siblings. The variance of ROA and disc degeneration within sibling pairs was compared with the variance between sibling pairs. Heritability estimates for ROA in the knees, hips, and hands and for disc degeneration of the spine were calculated. OA was defined according to radiologic criteria, using the Kellgren/Lawrence grading system. RESULTS: We observed that hand ROA and disc degeneration of the spine were statistically significantly more frequent in siblings than in the random sample, whereas the prevalence of knee and of hip ROA was similar and lower, respectively. Heritability estimates for hand ROA and disc degeneration were statistically significant, P = 0.56 (95% confidence interval [95% CI] 0.34-0.76) and P = 0.75 (95% CI 0.30-1.00), respectively. For knee and hip ROA, no evidence of a genetic effect in the general population was found. Finally, the heritability estimate for a score that summed the number of joints affected in the knees, hips, hands, and spine was 0.78 (95% CI 0.52-0.98). All heritability estimates were adjusted for age, sex, body mass index, and bone mineral density. CONCLUSION: The present study shows that in the general population, there is a strong genetic effect for hand ROA and disc degeneration of the spine. The findings on the total number of joints affected at multiple sites suggest genetic susceptibility to generalized OA

Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the genetics, osteoarthritis and progression study

Objective. To assess whether genetic variation in the interleukin-1 (IL-1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL-1β or IL-1 receptor antagonist (IL-1Ra). Methods. Innate ex vivo IL-1β and IL-1Ra production upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radiographic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single-nucleotide polymorphisms (SNPs) encompassing the IL-1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analysis were performed to assess the relationship between the IL-1 gene cluster SNPs, innate ex vivo cytokine production, and OA. Results. Among subjects in the GARP Study, the haplotype variable-number tandem repeat in intron 2/T+8006C/T+11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL-1β upon LPS stimulation (P = 0.026) and with ROA at the highest number of joint locations. Conclusion. These results show that genetic variation at the IL-1 gene cluster is associated with lower IL-1β bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms