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Claessen K.M.J.A.,Leiden University | Kloppenburg M.,Leiden University | Kroon H.M.,Leiden University | Bijsterbosch J.,Leiden University | And 13 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background: Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. Objective: To study associations between the d3-GHR polymorphism and symptomatic OA. Methods: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r2=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. Results: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. Conclusions: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site. Source


Kerkhof H.J.M.,Erasmus Medical Center | Bierma-Zeinstra S.M.A.,Erasmus Medical Center | Castano-Betancourt M.C.,Erasmus Medical Center | De Maat M.P.,Erasmus Medical Center | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objective: To study the relationship between serum C reactive protein (CRP) levels, genetic variation in the CRP gene and the prevalence, incidence and progression of radiographic osteoarthritis (ROA) in the Rotterdam Study-I (RS-I). A systematic review of studies assessing the relationship between osteoarthritis (OA) and CRP levels was also performed. Methods: The association between CRP levels and genetic variation in the CRP gene and ROA was examined in 861 patients with hand OA, 718 with knee OA, 349 with hip OA and 2806 controls in the RS-I using one-way analysis of covariance and logistic regression, respectively. PubMed was searched for articles published between January 1992 and August 2009 assessing the relationship between CRP levels and OA. Results: In RS-I the prevalence of knee OA, but not hip OA or hand OA, was associated with 14% higher serum CRP levels compared with controls (p=0.001). This association disappeared after adjustment for age and especially body mass index (BMI) (p=0.33). Genetic variation of the CRP gene was not consistently associated with the prevalence, incidence or progression of OA within RS-I. The systematic review included 18 studies (including RS-I) on serum CRP levels and the prevalence, incidence or progression of OA. Consistently higher crude CRP levels were found in cases of prevalent knee OA compared with controls. No association was observed between serum CRP levels and the prevalence of knee OA following adjustment for BMI (n=3 studies, meta-analysis p value=0.61). Conclusion: There is no evidence of association between serum CRP levels or genetic variation in the CRP gene with the prevalence, incidence or progression of OA independent of BMI. Source


Smith C.E.,Tufts University | Ngwa J.,Boston University | Tanaka T.,U.S. National Institute on Aging | Qi Q.,Harvard University | And 50 more authors.
International Journal of Obesity | Year: 2013

Objective:Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.Design and methods:We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).Results:After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m -2 greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m -2 greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.Conclusion:Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits. © 2013 Macmillan Publishers Limited. Source


Kerkhof H.J.M.,Erasmus Medical Center | Doherty M.,Academic Rheumatology | Arden N.K.,University of Southampton | Arden N.K.,University of Oxford | And 34 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objective: To clarify the role of common genetic variation in the Interleukin-1β (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. Methods: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. Results: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I2=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). Conclusion: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA. © 2010 Osteoarthritis Research Society International. Source


Kerkhof H.J.M.,Erasmus Medical Center | Meulenbelt I.,Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging NGI NCHA | Meulenbelt I.,Leiden University | Akune T.,Tokyo Medical University | And 55 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. Methods: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. Results: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as " at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as " at least one definite osteophyte" was significantly associated with gender (P=3×10-9). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. Conclusion: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies. © 2010 Osteoarthritis Research Society International. Source

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