RESEARCH - STAT4 and the risk of RA and SLE

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NEJM

Volume 357:977-986 September 6, 2007 Number 10

STAT4 and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus

Elaine F. Remmers, Ph.D., M. Plenge, M.D., Ph.D., Annette T. Lee,

Ph.D., R. Graham, Ph.D., Geoffrey Hom, Ph.D., W. Behrens,

M.D., I.W. de Bakker, Ph.D., M. Le, B.S., Hye-Soon Lee, M.D.,

Ph.D., Franak Batliwalla, Ph.D., Wentian Li, Ph.D., Seth L. Masters, Ph.D.,

G. Booty, B.S., P. Carulli, Ph.D., Leonid Padyukov, M.D.,

Ph.D., Lars Alfredsson, Ph.D., Lars Klareskog, M.D., Ph.D., Wei V. Chen,

M.S., I. Amos, Ph.D., Lindsey A. Criswell, M.D., M.P.H.,

F. Seldin, M.D., Ph.D., L. Kastner, M.D., Ph.D., and K.

Gregersen, M.D.

ABSTRACT

Background Rheumatoid arthritis is a chronic inflammatory disease with a

substantial genetic component. Susceptibility to disease has been linked

with a region on chromosome 2q.

Methods We tested single-nucleotide polymorphisms (SNPs) in and around 13

candidate genes within the previously linked chromosome 2q region for

association with rheumatoid arthritis. We then performed fine mapping of the

STAT1-STAT4 region in a total of 1620 case patients with established

rheumatoid arthritis and 2635 controls, all from North America. Implicated

SNPs were further tested in an independent case-control series of 1529

patients with early rheumatoid arthritis and 881 controls, all from Sweden,

and in a total of 1039 case patients and 1248 controls from three series of

patients with systemic lupus erythematosus.

Results A SNP haplotype in the third intron of STAT4 was associated with

susceptibility to both rheumatoid arthritis and systemic lupus

erythematosus. The minor alleles of the haplotype-defining SNPs were present

in 27% of chromosomes of patients with established rheumatoid arthritis, as

compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10-7;

odds ratio for having the risk allele in chromosomes of patients vs. those

of controls, 1.32). The association was replicated in Swedish patients with

recent-onset rheumatoid arthritis (P=0.02) and matched controls. The

haplotype marked by rs7574865 was strongly associated with lupus, being

present on 31% of chromosomes of case patients and 22% of those of controls

(P=1.87x10-9; odds ratio for having the risk allele in chromosomes of

patients vs. those of controls, 1.55). Homozygosity of the risk allele, as

compared with absence of the allele, was associated with a more than doubled

risk for lupus and a 60% increased risk for rheumatoid arthritis.

Conclusions A haplotype of STAT4 is associated with increased risk for both

rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared

pathway for these illnesses.

http://content.nejm.org/cgi/content/short/357/10/977

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