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

Geoffrey Hom, Robert R. Graham, Barmak Modrek, Kimberly E. Taylor, Ward Ortmann, Sophie Garnier, Annette T. Lee, Sharon A. Chung, Ricardo C. Ferreira, P. V Krishna Pant, Dennis G. Ballinger, Roman Kosoy, F. Yesim Demirci, M. Ilyas Kamboh, Amy H. Kao, Chao Tian, Iva Gunnarsson, Anders A. Bengtsson, Solbritt Rantapää-Dahlqvist, Michelle PetriSusan Manzi, Michael F. Seldin, Lars Rönnblom, Ann Christine Syvänen, Lindsey A. Criswell, Peter K. Gregersen, Timothy W. Behrens

Research output: Contribution to journalArticle

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 = 1×10-10) 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 = 3×10-11). 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.

Original languageEnglish (US)
Pages (from-to)900-909
Number of pages10
JournalNew England Journal of Medicine
Volume358
Issue number9
DOIs
StatePublished - Feb 28 2008

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Integrin alpha Chains
Systemic Lupus Erythematosus
Protein-Tyrosine Kinases
Single Nucleotide Polymorphism
CD11b Antigens
Chromosomes
Alleles
Odds Ratio
Genes
HLA-DRB1 Chains
Genetic Loci
Transcription Initiation Site
Genetic Promoter Regions
Sweden
Quality Control
Artifacts
B-Lymphocytes
Genotype
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hom, G., Graham, R. R., Modrek, B., Taylor, K. E., Ortmann, W., Garnier, S., ... Behrens, T. W. (2008). Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. New England Journal of Medicine, 358(9), 900-909. https://doi.org/10.1056/NEJMoa0707865

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.; Pant, P. V Krishna; Ballinger, Dennis G.; Kosoy, Roman; Demirci, F. Yesim; Kamboh, M. Ilyas; Kao, Amy H.; Tian, Chao; Gunnarsson, Iva; Bengtsson, Anders A.; Rantapää-Dahlqvist, Solbritt; Petri, Michelle; Manzi, Susan; Seldin, Michael F.; Rönnblom, Lars; Syvänen, Ann Christine; Criswell, Lindsey A.; Gregersen, Peter K.; Behrens, Timothy W.

In: New England Journal of Medicine, Vol. 358, No. 9, 28.02.2008, p. 900-909.

Research output: Contribution to journalArticle

Hom, G, Graham, RR, Modrek, B, Taylor, KE, Ortmann, W, Garnier, S, Lee, AT, Chung, SA, Ferreira, RC, Pant, PVK, Ballinger, DG, Kosoy, R, Demirci, FY, Kamboh, MI, Kao, AH, Tian, C, Gunnarsson, I, Bengtsson, AA, Rantapää-Dahlqvist, S, Petri, M, Manzi, S, Seldin, MF, Rönnblom, L, Syvänen, AC, Criswell, LA, Gregersen, PK & Behrens, TW 2008, 'Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX', New England Journal of Medicine, vol. 358, no. 9, pp. 900-909. https://doi.org/10.1056/NEJMoa0707865
Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. New England Journal of Medicine. 2008 Feb 28;358(9):900-909. https://doi.org/10.1056/NEJMoa0707865
Hom, Geoffrey ; Graham, Robert R. ; Modrek, Barmak ; Taylor, Kimberly E. ; Ortmann, Ward ; Garnier, Sophie ; Lee, Annette T. ; Chung, Sharon A. ; Ferreira, Ricardo C. ; Pant, P. V Krishna ; Ballinger, Dennis G. ; Kosoy, Roman ; Demirci, F. Yesim ; Kamboh, M. Ilyas ; Kao, Amy H. ; Tian, Chao ; Gunnarsson, Iva ; Bengtsson, Anders A. ; Rantapää-Dahlqvist, Solbritt ; Petri, Michelle ; Manzi, Susan ; Seldin, Michael F. ; Rönnblom, Lars ; Syvänen, Ann Christine ; Criswell, Lindsey A. ; Gregersen, Peter K. ; Behrens, Timothy W. / Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. In: New England Journal of Medicine. 2008 ; Vol. 358, No. 9. pp. 900-909.
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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 = 1×10-10) 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 = 3×10-11). 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.",
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T1 - Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX

AU - Hom, Geoffrey

AU - Graham, Robert R.

AU - Modrek, Barmak

AU - Taylor, Kimberly E.

AU - Ortmann, Ward

AU - Garnier, Sophie

AU - Lee, Annette T.

AU - Chung, Sharon A.

AU - Ferreira, Ricardo C.

AU - Pant, P. V Krishna

AU - Ballinger, Dennis G.

AU - Kosoy, Roman

AU - Demirci, F. Yesim

AU - Kamboh, M. Ilyas

AU - Kao, Amy H.

AU - Tian, Chao

AU - Gunnarsson, Iva

AU - Bengtsson, Anders A.

AU - Rantapää-Dahlqvist, Solbritt

AU - Petri, Michelle

AU - Manzi, Susan

AU - Seldin, Michael F.

AU - Rönnblom, Lars

AU - Syvänen, Ann Christine

AU - Criswell, Lindsey A.

AU - Gregersen, Peter K.

AU - Behrens, Timothy W.

PY - 2008/2/28

Y1 - 2008/2/28

N2 - 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 = 1×10-10) 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 = 3×10-11). 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.

AB - 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 = 1×10-10) 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 = 3×10-11). 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.

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