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Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.

ABSTRACT: INTRODUCTION: We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci. METHODS: We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of allele frequencies between cases and controls was done with the Mantel-Haenszel approach to account for heterogeneity between sample collections. RESULTS: A previously controversial association with a SNP in the TYK2 gene was replicated (odds ratio (OR) = 0.79, P = 2.5 x 10-5), as well as association with the X chromosome MECP2 gene (OR = 1.26, P = 0.00085 in women), which had only been reported in a single study, and association with four other loci, 1q25.1 (OR = 0.81, P = 0.0001), PXK (OR = 1.19, P = 0.0038), BANK1 (OR = 0.83, P = 0.006) and KIAA1542 (OR = 0.84, P = 0.001), which have been identified in a genome-wide association study, but not found in any other study. All these replications showed the same disease-associated allele as originally reported. No association was found with the LY9 SNP, which had been reported in a single study. CONCLUSIONS: Our results confirm nine SLE loci. For six of them, TYK2, MECP2, 1q25.1, PXK, BANK1 and KIAA1542, this replication is important. The other three loci, ITGAM, STAT4 and C8orf13-BLK, were already clearly confirmed. Our results also suggest that MECP2 association has no influence in the sex bias of SLE, contrary to what has been proposed. In addition, none of the other associations seems important in this respect.

SUBMITTER: Suarez-Gestal M

PROVIDER: S-EPMC2714115 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.

Suarez-Gestal Marian M Calaza Manuel M Endreffy Emöke E Pullmann Rudolf R Ordi-Ros Josep J Sebastiani Gian Domenico GD Ruzickova Sarka S Jose Santos Maria M Papasteriades Chryssa C Marchini Maurizio M Skopouli Fotini N FN Suarez Ana A Blanco Francisco J FJ D'Alfonso Sandra S Bijl Marc M Carreira Patricia P Witte Torsten T Migliaresi Sergio S Gomez-Reino Juan J JJ Gonzalez Antonio A

Arthritis research & therapy 20090514 3

<h4>Introduction</h4>We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci.<h4>Methods</h4>We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of allele frequencies between cases and controls was done with the Mantel-Haenszel approach to account for heterogeneity between sample collections.<h4>Results</h4>A previously controvers ...[more]

PMID: 19442287

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Project description:Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10?¹²?) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p?=?4 x 10??. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low)?=?2.36, p?=?9e-9), the immunologic criterion (OR(high-low)?=?2.23, p?=?3e-7), and age at diagnosis (OR(high-low)?=?1.45, p?=?0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR?=?1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR?=?0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

Dataset Information

Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.

Publications

Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study.

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