Advanced

Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX

Hom, Geoffrey; Graham, Robert R.; Modrek, Barmak; Taylor, Kimberly E.; Ortmann, Ward; Garnier, Sophie; Lee, Annette T.; Chung, Sharon A.; Ferreira, Ricardo C. and Pant, P. V. Krishna, et al. (2008) In New England Journal of Medicine 358(9). p.900-909
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... (More)
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=1 x 10(-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=3 x 1 (-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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
New England Journal of Medicine
volume
358
issue
9
pages
900 - 909
publisher
Massachusetts Medical Society
external identifiers
  • wos:000253430200005
  • scopus:40049108936
ISSN
0028-4793
DOI
10.1056/NEJMoa0707865
language
English
LU publication?
yes
id
36bdc761-030a-4622-b23b-7fbe9650d71c (old id 1196373)
date added to LUP
2008-09-10 11:12:58
date last changed
2017-11-12 03:23:10
@article{36bdc761-030a-4622-b23b-7fbe9650d71c,
  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=1 x 10(-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=3 x 1 (-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.},
  author       = {Hom, Geoffrey and Graham, Robert R. and Modrek, Barmak and Taylor, Kimberly E. and Ortmann, Ward and Garnier, Sophie and Lee, Annette T. and Chung, Sharon A. and Ferreira, Ricardo C. and Pant, P. V. Krishna and Ballinger, Dennis G. and Kosoy, Roman and Demirci, F. Yesim and Kamboh, M. Ilyas and Kao, Amy H. and Tian, Chao and Gunnarsson, Iva and Bengtsson, Anders and Rantapaa-Dahlqvist, Solbritt and Petri, Michelle and Manzi, Susan and Seldin, Michael F. and Ronnblom, Lars and Syvanen, Ann-Christine and Criswell, Lindsey A. and Gregersen, Peter K. and Behrens, Timothy W.},
  issn         = {0028-4793},
  language     = {eng},
  number       = {9},
  pages        = {900--909},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX},
  url          = {http://dx.doi.org/10.1056/NEJMoa0707865},
  volume       = {358},
  year         = {2008},
}