Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs.
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).


CONCLUSIONS
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.
Eyre
Stephen
S
Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK.
Barton
Anne
A
Shephard
Neil
N
Hinks
Anne
A
Brintnell
William
W
MacKay
Kirsten
K
Silman
Alan
A
Ollier
William
W
Wordsworth
Paul
P
John
Sally
S
Worthington
Jane
J
D017668:Age of Onset; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008126:Lod Score; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D012727:Sex Characteristics; D035781:Siblings; D006113:United Kingdom
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains