Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom.
OBJECTIVE
To undertake a systematic whole-genome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA).


METHODS
Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis.


RESULTS
Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 x 10(-4)) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis.


CONCLUSIONS
Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 x 10(-5)). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.
MacKay
Kirsten
K
Wellcome Trust Centre for Human Genetics, Oxford, UK. Jane@fs1.ser.man.ac.uk
Eyre
Stephen
S
Myerscough
Anne
A
Milicic
Anita
A
Barton
Anne
A
Laval
Steven
S
Barrett
Jenny
J
Lee
Dorothea
D
White
Sarah
S
John
Sally
S
Brown
Matthew A
MA
Bell
John
J
Silman
Alan
A
Ollier
William
W
Wordsworth
Paul
P
Worthington
Jane
J
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002874:Chromosome Mapping; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D018895:Microsatellite Repeats; D009679:Nuclear Family; D015588:Observer Variation; D006113:United Kingdom