New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study.
Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (lambdas = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5.10(-5)) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0. 001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.
Cornélis
F
F
Pôle Génétique des Maladies Auto-immunes, Laboratoire de Radiologie Expérimentale et de Physiopathologie Articulaire, Centre Viggo-Petersen, Hôpital Lariboisière, 75010 Paris, France. francois.cornelis@lrb.ap-hop-paris.fr
Fauré
S
S
Martinez
M
M
Prud'homme
J F
JF
Fritz
P
P
Dib
C
C
Alves
H
H
Barrera
P
P
de Vries
N
N
Balsa
A
A
Pascual-Salcedo
D
D
Maenaut
K
K
Westhovens
R
R
Migliorini
P
P
Tran
T H
TH
Delaye
A
A
Prince
N
N
Lefevre
C
C
Thomas
G
G
Poirier
M
M
Soubigou
S
S
Alibert
O
O
Lasbleiz
S
S
Fouix
S
S
Bouchier
C
C
Lioté
F
F
Loste
M N
MN
Lepage
V
V
Charron
D
D
Gyapay
G
G
Lopes-Vaz
A
A
Kuntz
D
D
Bardin
T
T
Weissenbach
J
J
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans
D006680:HLA Antigens