Abstract
Objective. Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.
Methods. A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.
Results. The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09–1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23–3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44–0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10–1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.
Conclusion. These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
- SYSTEMIC LUPUS ERYTHEMATOSUS
- AFRICAN AMERICANS
- OXYGEN COMPOUNDS
- GENETIC ASSOCIATION STUDIES
- SINGLE-NUCLEOTIDE POLYMORPHISM
Footnotes
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Supported by the South Carolina Clinical and Translational Research (SCTR) Institute, through US National Institutes of Health (NIH) grant numbers UL1 RR029882 and UL1 TR000062; by NIH grant numbers R01 AR45476 (JCO), U54 RR026107 (JCO), R01 AI063274 (PMG), P01 AR49084 (RPK, CDL, JBH, EEB, JCE, JDR, RRG, MAP, LMV), R01 AR043274 (CDL, KLM), R01 AR33062 (RPK), R01 AR445650 (COJ), R01 AR043814 (BPT), P01 AR49084 (GSA), P30 AR055385 (EEB), 5UL1 RR025777 (JCE), AR43727 (MAP), K24 AR002138 (RRG), P60 2 AR30692 (RRG), UL 1 RR025741 (RRG), AI082714 (JAJ, JMG), AI101934 (JAJ), AR053843 (JAJ, JMG), AR058554 (JAJ, JMG), RR031152 (JAJ, JMG), R01 AR44804 (LAC), K24 AR02175 (LAC), P60 AR053308 (LAC), 5 M01 RR-00079 (LAC), RR020143 (KLM, MAR), AR042460 (JBH), AI024717 (JBH), AR062277 (JBH); and by the US Department of Veterans Affairs (JBH), the Mary Kirkland Scholarship (JBH, LAC), the Instituto de Salud Carlos III (PS09/00129 to MAR), FEDER funds of the European Union (MAR), the Lupus Foundation of Minnesota (KLM), arc project grant 17761 (TJV), Wellcome Trust programme grant 085492 (TJV), the Lupus Research Institute (BPT), Wake Forest School of Medicine Center for Public Health Genomics, and the Alliance for Lupus Research (COJ, LAC).
- Accepted for publication February 14, 2013.