Investigation of susceptibility loci identified in the UK RA whole-genome scan in a further series of 217 UK affected sibling pairs

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Arthritis Rheum. 2004 Mar;50(3):729-35.

Investigation of susceptibility loci identified in the UK rheumatoid

arthritis whole-genome scan in a further series of 217 UK affected

sibling pairs.

Eyre S, Barton A, Shephard N, Hinks A, Brintnell W, MacKay K, Silman A,

Ollier W, Wordsworth P, S, Worthington J.

Arthritis Research Campaign Epidemiology Unit, University of Manchester,

Manchester, UK.

OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid

arthritis (RA) affected sibling pair (ASP) families suggested linkage to

HLA and 11 other chromosome regions. Replication of such findings in an

independent cohort can help to distinguish true linkages from

false-positive linkages. Since RA is a heterogeneous disease, some loci

may be linked only in subsets of patients. Thus, the aim of this study

was to investigate in an additional set of RA ASP families linkage to

regions showing deviation in expected allele-sharing ratios in the UK

WGS and to perform subset analysis on the combined cohort. METHODS:

Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs.

Stratification analysis was performed on the combined cohort of 377 RA

ASP families to account for sex, RA severity, and the shared epitope

(SE). RESULTS: None of the regions of linkage identified in the initial

WGS achieved statistical significance in the second cohort. In contrast,

after stratification analysis, 14 regions showed nominal evidence of

linkage (logarithm of odds score >0.8) in one or more subgroups. In

particular, the strength of evidence for linkage to chromosome 16p was

increased in subsets of ASPs with younger age at disease onset (LOD

score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD

score 2.31) and in ASPs in which both siblings had 2 copies of the SE

(LOD score 3.03).

CONCLUSION: These results support the evidence for heterogeneity of RA.

This information will inform the future design of association-based

investigations as the search for disease genes in the linked regions

begins.

PMID: 15022312

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