Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus
1Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
2Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
3US Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
4Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
5Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
6Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
7Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
8Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
9Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
10Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
11Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
12Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
13Department of Medicine, University of Texas-Houston Health Science Center, Houston, Texas, USA
14Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
15Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
16Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Colombia
17Sanatorio Parque, Rosario, Argentina
18Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
19Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
20Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, Guy's Hospital, London, UK
21Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, California, USA
22Department of Medicine, Division of Rheumatology, University of California, Los Angeles, Los Angeles, California, USA
23Department of Medicine, University of Southern California, Los Angeles, California, USA
24Rheumatology Division and Autoimmune Genomics Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
25US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
26Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucía, Granada, Spain
Characteristics of the patients with SLE in each cohort are given in . Our clinical data confirmed a higher prevalence of renal disorder in African-American (50.1%), Asian (46.9%) and Hispanic individuals (46%) compared with European-derived lupus patients (34.7%).
Characteristics and clinical features of SLE patients included in this study
Of the studied SNP, rs2476601 (PTPN22), rs11568821 (PDCD1), rs1143679 (ITGAM), rs3131379 (MSH5) and rs1270942 (CFB) were excluded from further analysis in the Asian samples as a result of a minor allele frequency of less than 0.01. All 16 SNP passed the inclusion criteria in European-derived, African-American and Hispanic samples. To investigate if the SLE susceptibility loci predispose to any particular disease manifestation in SLE, we calculated allele frequencies in each locus in patients with and without the various ACR clinical SLE features and determined OR adjusted for admixture in each ethnic group, then performed a meta-analysis across ethnicities.
We identified no significant differences with the PTPN22, CTLA4, PDCD1, BANK1, PXK, MSH5, CFB, C8orf13-BLK, MBL2, KIAA1542 and MECP2 in any of the above clinical ACR criteria (data not shown). However, we found a statistically significant association between some clinical manifestations and the lupus risk alleles in the FCGR2A, ITGAM, STAT4, TNFSF4 and IL21 genes. The most significant was the association between renal disorder and the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35, pBonferroni=7.99×10−5). This association seems to be driven by the European-derived cohort (p=4.7×10−7, OR 1.39, 95% CI 1.22 to 1.58; ). We also detected a significant association between the TNFSF4 risk allele and renal disorder (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25, pBonferroni=0.020). This association is driven mainly by the European component because the strongest association was found in the European-derived cohort (p=0.0030, OR 1.18, 95% CI 1.06 to 1.33) and only a trend of association was shown in Hispanic individuals (p=0.052, OR 1.17, 95% CI 1.00 to 1.37), but not in African-American (p=0.74, OR 1.05, 95% CI 0.80 to 1.38) or Asian individuals (p=0.81, OR 1.02, 95% CI 0.85 to 1.22). In addition, we also found an association between FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33, pBonferroni=0.049), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33, pBonferroni=0.031), STAT4 and oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96, pBonferroni=0.042) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22, pBonferroni=0.042). We next performed a genetic model analysis testing for a dominant, recessive and additive model for the associations detected. Model analysis was performed in the European-derived set as all the associations detected are primarily driven by the European-derived lupus patients (). Our data suggest an additive model for the association between FCGR2A and malar rash, ITGAM and discoid rash, ITGAM and renal disorder, TNFSF4 and renal disorder and IL21 and haematological disorder. An accurate model could not be predicted for the association between STAT4 and oral ulcers.
Genotypic–phenotypic associations in SLE
Genetic model analysis in the European-derived samples for the genetic phenotype associations reported in this study
In order to investigate further the role of IL21 in the presence of haematological manifestations in SLE, we examined the specific ACR haematological subphenotypes when available. We failed to find an association between IL21 and the presence of lymphopenia, haemolytic anaemia or thrombocytopenia. However, a statistically significant association was found between the IL21 risk allele and leucopenia (p=0.0039, OR 1.14, 95% CI 1.04 to 1.24).
An additional ethnicity-specific association between disease susceptibility loci and clinical manifestations is the association between the risk allele in KIAA1542 and serositis in Hispanic individuals (p=0.0021, OR 1.35, 95% CI 1.12 to 1.64, pBonferroni=0.033).