RESEARCH - Susceptibility variants for RA in the TRAF-1-C5 and 6q23 loci: a meta-analysis

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Ann Rheum Dis. Published Online First: 27 April 2009.

doi:10.1136/ard.2009.109447

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Extended Report

Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and

6q23 loci: a meta-analysis

Nikolaos A Patsopoulos 1 and P A Ioannidis 1*

1 Clinical and Molecular Epidemiology Unit, Department of Hygiene and

Epidemiology, Univ of Ioannina, Greece

Abstract

Objectives: Genome-wide association studies have proposed

susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus

and 6q23 region. Furthermore, additional independent studies have

investigated the same or highly linked polymorphisms in the same

regions. We meta-analyzed the available evidence on these proposed

associations.

Methods: Data were synthesized for four polymorphisms: rs3761847 (n=12

datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and

rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23

region. We also performed meta-analyses for subgroups defined by

anti-CCP and RF status.

Results: The polymorphism rs6920220 reached genome-wide statistically

significance with p=7.9x10-17 and an allelic odds ratio of 1.24 (95%

CI: 1.18-1.30) and no between-study heterogeneity (I2 =0%). The risk

was significantly stronger in patients with anti-CCP antibodies and in

patients with rheumatoid factor (RF). The other three variants showed

large between-study heterogeneity across datasets (I2 range 74-82%);

rs10499194 was nominally statistically significant after exclusion of

the discovery data. Two variants had genome-wide statistical

significance in subgroups defined by the presence of RF (rs3761847 and

rs6920220) or anti-CCP (rs6920220).

Conclusions: Genetic markers in the 6q23 region and TRAF1-C5 are

associated with rheumatoid arthritis, in particular with positive

anti-CCP and rheumatoid factor profile. With the exception of

rs6920220 that shows highly consistent results, other proposed markers

have high between-study heterogeneity that may reflect unrecognized

phenotypic or genetic variability (e.g. gene environment interactions)

within rheumatoid arthritis. Furthermore, these markers may not be the

true causative loci but rather be in linkage disequilibrium with the

true ones.

http://ard.bmj.com/cgi/content/abstract/ard.2009.109447v1?papetoc

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