FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 358:900-909 February 28, 2008 Number 9 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Purchase this article Editorial by Crow, M. K. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.

Methods We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.

Results Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1x10^–10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10^–11).

Conclusions We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM–ITGAX region.

Source Information

The authors' affiliations are listed in the Appendix.

Drs. Hom and Graham contributed equally to this article.

This article (10.1056/NEJMoa0707865) was published at www.nejm.org on January 20, 2008.

Address reprint requests to Dr. Behrens at Genentech, 1 DNA Way, 45-3B, South San Francisco, CA 94080, or at behrens.timothy{at}gene.com.

Full Text of this Article

This article has been cited by other articles:

• Crow, M. K. (2008). Collaboration, Genetic Associations, and Lupus Erythematosus. NEJM 358: 956-961 [Full Text]  
• (2008). Unraveling the Genetic Predisposition to Systemic Lupus Erythematosus. Journal Watch Dermatology 2008: 1-1 [Full Text]