RESEARCH - Genome-wide pathway identifies MSRA gene as RA susceptibility locus

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Arthritis Rheum. 2010 Jul 8. [Epub ahead of print]

Genome-wide pathway analysis identifies oxidative stress related gene

MSRA as rheumatoid arthritis susceptibility locus.

Martín JE, Alizadeh BZ, González-Gay MA, Balsa A, Pascual-Salcedo D,

Fernández-Gutiérrez B, Raya E, e L, Van't Slot R, Coenen MJ, van

Riel P, Radstake TR, Koeleman BP, Martín J.

Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.

Abstract

OBJECTIVE:: Genome-wide association studies (GWASs) carried out in

rheumatoid arthritis (RA) have led to the discovery of several genetic

associations with this disease. Still, the current associated genetic

variations can explain only part of the genetic risk involved in RA,

and it is well recognised that these GWASs are likely underpowered to

detect all common disease variants. Therefore, we explored the genomic

regions showing low-significance associations in previous GWASs of RA.

METHODS:: To reduce the false-positive signal fraction, we exploited

pathway analysis to prioritise regions containing genes most likely to

be implicated in RA. We hypothesised that true disease genes would be

in a similar pathway. Therefore, genes from similar pathways but

located in different regions were prioritised for replication using

Prioritizer software. 384 genetic variants selected from previous RA

GWASs were tested in a Spanish case/control discovery cohort

comprising 376 RA patients and 478 healthy controls for replication.

Statistically significant associations were further validated in

replication cohorts from Spain and Netherlands, up to a total of 1,818

RA patients and 2,498 controls.

RESULTS:: We detected a novel genetic association between RA and the

MSRA gene (rs10903323, P = 2.91x10(-5), OR = 1.51) in the Spanish

combined population. This association was further tested in our

independent Dutch replication cohort. Combined analysis showed an

overall association of MSRA with RA (P = 2.19x10(-4), OR = 1.28).

CONCLUSION:: Novel association in the MSRA gene related to oxidative

stress is described herein and support a major role for this process

in RA.

PMID: 20617525

http://www.ncbi.nlm.nih.gov/pubmed/20617525

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