http://repub.eur.nl/res/aut/8027/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/8506/ 2004-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/5966/ 2003-09-01T00:00:00Z For quantitative traits with a genetic component, random effects approaches are used to test for linkage at observed marker loci. We propose to use these approaches also for binary outcomes observed in sib pairs derived from a population-based cohort study. In addition to a random effect modelling correlation due to polygenic effect, a random effect is included to model the correlation between siblings due to sharing alleles identical by descent (IBD) at the observed marker locus. A two-step analysis is proposed. Firstly, score statistics are computed to test whether correlation is present in the data. Secondly, random effects models are fitted, yielding heritability estimates. To illustrate the methods, data on the contribution of the COL2A1 gene to various binary and quantitative outcomes including the presence of Heberden's nodes and bone mineral density (BMD) are analysed. For most of the traits studied, the score statistics were significant, indicating the presence of genetic effects. For BMD and for Heberden's nodes, the variance explained by the marker locus was 44% (P = 0.0008) and 15% (P = 0.38) respectively. We conclude that the score statistics can be used as a preliminary data analysis. In more sophisticated analysis, heritabilities can be estimated by fitting random effects models. http://repub.eur.nl/res/pub/19737/ 1999-03-03T00:00:00Z O steoalthritis eO A) is the most common rheumatic disease and an i.mportant cause of disability in the elderly (l,2). It is characterized by a progressive degeneration of articular cartilage of diarthrodial joint::; without synovial inflammation or bone erosions. Il leads in a minority of subjects to clinical OA, Le. joint pain, limited range of motion of the affected jOint, joint effusion, local inflanul1atory reaction or crepitus. The dinical diagnosis of OA is confirmed by radiographic evidence, reflecting deterioration of cal1ilage with narrowing of joint space, formation of osteophytes at the joint margins, development of sclerosis of subchondral bone and development of pseudocystic areas in subchondral bone. OA is a chronic disease with a multifactorial etiology that includes genetic factors (e.g. skeletal disorders, heritable forms of obesity\\ other systemic factors (e.g. age, sex, race, bone mineral density), biomechanical factors (e.g. trauma, joint deformity, muscle weakness) and environmental factors (e.g. nutrition, spons, estrogen replacement therapy). The genetic influence on the etiology of OA has long been recognized for women with Heberden's nodes and for patients with generalized OA 0,4). There is growing evidence from POFulationbased studies, that comnlOn forms of OA, such as hand and knee OA, are also heritable (5-7). Various mutations in several genes have been detected in families with severe early-onset OA associated with heritable disorders as osteochondrodysplasia, Stickler syndrome, chondrocalcinosis or epiphyseal dysplasia (8,9). It remains largely unclear which genes are involved in causing common forms of OA that occur in an elderly population. Finally, genetic susceptibility to OA could also result from genetic influences on risk factors for OA, like obesity and increased bone mineral density. This thesis first describes some issues of consideration when studying the genetic epidemiology of a complex disease as osteoarthritis (Chapter 2.1). Next, the methods of the studies presented in this thesis are described. http://repub.eur.nl/res/pub/5945/ 1999-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/5946/ 1999-01-01T00:00:00Z It was investigated whether radiographic osteoarthritis (ROA) is associated with specific haplotypes of the COL2A1 gene. Radiographs of knees, hips, hands, and spine were scored for the presence of ROA in subjects of 55-70 years from a population-based cohort study, the Rotterdam study. Cases had ROA in 3 or more joint groups; controls, from the same population, had ROA in less than 3 joint groups. Allele frequencies of 3 dimorphisms (HaeIII, HindIII, MaeII) and a VNTR polymorphism of the COL2A1 gene were determined. The VNTR allele 14R2 and the HindIII polymorphism showed a significant association. Haplotype analysis of the HaeIII, HindIII and VNTR polymorphisms showed that a specific haplotype (1-2-14R2) is strongly associated with ROA in 3 or more joint groups (OR = 5.3, 95% CI 2.3-12.7). Our results suggest that a specific haplotype of the COL2A1 locus may predispose to generalised ROA. http://repub.eur.nl/res/pub/8513/ 1998-01-01T00:00:00Z OBJECTIVE: A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene. METHODS: Subjects aged 55-65 years were selected from a population-based study of which ROA at the knee, hip, spine, and hand was assessed. Genotypes were determined of a polymorphism in the promoter region of the IGF-1 gene. RESULTS: The IGF-1 locus was significantly associated with the presence of ROA (over-all adjusted OR for heterozygous subjects = 1.9, 95% CI 1.2, 3.1 and for homozygous subjects 3.6, 95% CI 0.8, 16.2). CONCLUSION: These results suggest that variation at the IGF-1 locus is associated with ROA development and may play a part in ROA pathogenesis. To confirm these findings replication in another population-based sample is needed.