Assessment of Osteoarthritis Candidate Genes in a Meta‐Analysis of Nine Genome‐Wide Association Studies

Abstract

ObjectiveTo assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.MethodsA total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.ResultsSNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.ConclusionTwo candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.

Mesenchymal Stem Cell Alterations in Bone Marrow Lesions in Patients With Hip Osteoarthritis

“…Other selected genes included those previously described as being associated with OA 3, 22 (see also Supplementary Table 4, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39622/abstract). MSCs derived from trabecular bone from age‐matched controls as well as MSCs derived from the femoral heads of patients with OP were included as controls.…”

A family history of knee joint replacement increases the progression of knee radiographic osteoarthritis and medial tibial cartilage volume loss over 10 years

“…A recent meta-analysis of nine genome-wide association studies including 5636 knee OA patients and 16,972 controls, found that only 2 out of 199 published candidate OA genes had any significant association with OA 7 . The inconsistency may be due to different study designs 7 , inherent measurement error associated with diagnosis of ROA, short followup periods and varying levels of genetic susceptibility of different phenotypic components of knee OA 8,9 . Magnetic resonance imaging (MRI) is being increasingly used to study OA as it allows visualisation of the whole joint 10 . It is possible that different structures comprising the knee joint are under separate genetic influences.…”

DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism

“…As a result, there is the potential for development of new therapeutic approaches to target factors involved in inflammation, oxidative stress, and autophagy, to name a few (9). In addition to altered cellular and molecular pathways, a number of gene polymorphisms have been reported in human OA (e.g., GDF5 and SMAD3) (10,11) and there are now several, robustly replicated, significant OA loci that have been identified by large-scale genome wide association studies (GWAS) (12)(13)(14). However, many candidate gene studies for OA have identified false associations due to relatively small sample sizes.…”