Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.
OBJECTIVE
A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings.


METHODS
We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL.


RESULTS
Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates.


CONCLUSIONS
These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q.
Jawaheer
Damini
D
Center for Genomics and Human Genetics, Manhasset, New York 11030, USA.
Seldin
Michael F
MF
Amos
Christopher I
CI
Chen
Wei V
WV
Shigeta
Russell
R
Etzel
Carol
C
Damle
Aarti
A
Xiao
Xiangli
X
Chen
Dong
D
Lum
Raymond F
RF
Monteiro
Joanita
J
Kern
Marlene
M
Criswell
Lindsey A
LA
Albani
Salvatore
S
Nelson
J Lee
JL
Clegg
Daniel O
DO
Pope
Richard
R
Schroeder
Harry W
HW
Bridges
S Louis
SL
Pisetsky
David S
DS
Ward
Ryk
R
Kastner
Daniel L
DL
Wilder
Ronald L
RL
Pincus
Theodore
T
Callahan
Leigh F
LF
Flemming
Donald
D
Wener
Mark H
MH
Gregersen
Peter K
PK
D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D009679:Nuclear Family; D014481:United States / Q000453:epidemiology