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MHC region and risk of systemic lupus erythematosus in African American women

Abstract

The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case–control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 × 10−5) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 × 10−4), rs2071349 (OR = 1.53, p = 1.0 × 10−3), and rs2844580 (OR = 1.43, p = 1.3 × 10−3), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.

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Acknowledgments

This work was supported by Grant U01 AI067146 from the National Institute of Allergy and Infectious Diseases, and by grants R01CA058420 and R01CA098663 from the National Cancer Institute. The genotyping for the present project was subsidized by a grant to the Broad Institute Center for Genotyping and Analysis Grant U54 RR020278 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, or the National Institutes of Health. We thank Dr. Timothy McAlindon and Dr. Elizaveta Vaysbrot for their medical record reviews.

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Correspondence to Edward A. Ruiz-Narvaez.

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Ruiz-Narvaez, E.A., Fraser, P.A., Palmer, J.R. et al. MHC region and risk of systemic lupus erythematosus in African American women. Hum Genet 130, 807–815 (2011). https://doi.org/10.1007/s00439-011-1045-2

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Keywords

  • Systemic Lupus Erythematosus
  • Major Histocompatibility Complex
  • Human Leukocyte Antigen Class
  • Major Histocompatibility Complex Region
  • Systemic Lupus Erythematosus Case