Osteoarthritis gene tic markers identified

By Lynda Williams

Scientists have used data from the Arthritis Research UK Osteoarthritis Genetics (arcOGEN) study to identify five gene loci significantly associated with the development of the disease.

The genome-wide association analysis (GWAS) - conducted in 7410 unrelated patients with severe osteoarthritis (OA), 80% of whom had undergone total joint replacement, and 11,009 unrelated healthy individuals - also identified three loci with near significant association with the disease.

The results were confirmed in an independent sample of 7473 OA patients and 42,938 controls from across Europe.

While acknowledging the increased risks for OA associated with the loci were small, and not necessarily causal, the researchers say: "These results provide a basis for functional studies to identify the underlying causative variants, biological networks, and molecular cause of [OA]."

The strongest loci association meeting the p=5·0×10^-8 criteria for GW significance with OA was on chromosome 3 with two single nucleotide polymorphisms (SNPs) in perfect linkage disequilibrium: rs6976 (odds ratio [OR]=1.12), which is in the 3' untranslated region of the GLT8D1 gene, and rs11177, which encodes a missense polymorphism in the nucleostemin-encoding gene GNL3.

Alterations to the GLT8D1 gene could disrupt cartilage protein glycosylation, suggest Eleftheria Zeggini (Wellcome Trust Sanger Institute, Cambridge, UK) and co-authors. They add that "levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies."

A further four GW significant signals were found in data associated with hip OA, including within the CHST11 gene, which regulates cartilage proteoglycan development and is expressed at higher levels in osteoarthritic than healthy cartilage.

Three associations that approached criteria for GW significance included a SNP within intron 1 of the fat mass and obesity-associated protein gene FTO.

"This signal was attenuated after adjustment for [body mass index], suggesting that the FTO gene exerts its effect on osteoarthritis through obesity," Zeggini et al comment in The Lancet.

Marc Hochberg and co-authors, from the University of Maryland in Baltimore, USA, note in an accompanying editorial that the small odds ratios of 1.11-1.21 for the associations are "sobering but completely in accord with the results of GWAS for other complex traits."

Expecting that new associations detected in the future will have "diminishing effect sizes," they conclude: "These associations are thus unlikely to be useful for disease prediction, but their real value might be to provide new biological insights and uncover new pathways."

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