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1.  Lupus risk variants in the PXK locus alter B-cell receptor internalization 
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
doi:10.3389/fgene.2014.00450
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
2.  PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes 
PLoS ONE  2013;8(8):e69404.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
doi:10.1371/journal.pone.0069404
PMCID: PMC3737240  PMID: 23950893
3.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
4.  Evaluation of TRAF6 in a Large Multi-Ancestral Lupus Cohort 
Arthritis and Rheumatism  2012;64(6):1960-1969.
Objective
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Methods
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Results
Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Conclusion
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
doi:10.1002/art.34361
PMCID: PMC3380425  PMID: 22231568
TRAF6; polymorphism; systemic lupus erythematosus
5.  The Lupus Family Registry and Repository 
Rheumatology (Oxford, England)  2010;50(1):47-59.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR’s effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.
doi:10.1093/rheumatology/keq302
PMCID: PMC3307518  PMID: 20864496
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women
6.  Male only Systemic Lupus 
The Journal of rheumatology  2010;37(7):1480-1487.
Systemic lupus erythematosus (SLE) is more common among women than men with a ratio of about 10 to 1. We undertook this study to describe familial male SLE within a large cohort of familial SLE. SLE families (two or more patients) were obtained from the Lupus Multiplex Registry and Repository. Genomic DNA and blood samples were obtained using standard methods. Autoantibodies were determined by multiple methods. Medical records were abstracted for SLE clinical data. Fluorescent in situ hybridization (FISH) was performed with X and Y centromere specific probes, and a probe specific for the toll-like receptor 7 gene on the X chromosome. Among 523 SLE families, we found five families in which all the SLE patients were male. FISH found no yaa gene equivalent in these families. SLE-unaffected primary female relatives from the five families with only-male SLE patients had a statistically increased rate of positive ANA compared to SLE-unaffected female relatives in other families. White men with SLE were 5 times more likely to have an offspring with SLE than were White women with SLE but there was no difference in this likelihood among Black men. These data suggest genetic susceptibility factors that act only in men.
doi:10.3899/jrheum.090726
PMCID: PMC2978923  PMID: 20472921
Systemic lupus erythematosus; men; autoantibodies; genetics
7.  Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort 
Genes and immunity  2011;12(4):270-279.
Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors play a role. Rare mutations in the TREX1 gene, the major mammalian 3′-5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurologic condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls.
Methods
Forty single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Results
The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (MAF >10%) revealed a relatively common risk haplotype in European SLE patients with neurologic manifestations, especially seizures, with a frequency of 58% in lupus cases compared to 45% in normal controls (p=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (p=2.99E-13, OR=5.2, 95% CI=3.18-8.56).
Conclusion
Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.
doi:10.1038/gene.2010.73
PMCID: PMC3107387  PMID: 21270825
8.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Objective
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Methods
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
Results
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Conclusion
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
doi:10.1002/art.24387
PMCID: PMC2776081  PMID: 19333953
9.  Evaluation of C1q genomic region in minority racial groups of lupus 
Genes and immunity  2009;10(5):517-524.
Complement cascade plasma proteins have a complex role in the etiopathogenesis of SLE. Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of the genes encoding for C1q (A, B, and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, B and C in a lupus cohort of peoples of African-American and Hispanic origin. In a case only analysis, significant association at multiple SNPs in the C1QA gene was detected in African-Americans with kidney nephritis (best p=4.91 × 10−6). In addition, C1QA was associated with SLE in African-Americans with a lack of nephritis and accompanying photosensitivity when compared to normal controls (p=6.80 × 10−6). A similar trend was observed in the Hispanic subjects (p=0.003). Quantitative analysis demonstrates that some SNPs in the C1q genes might be correlated with C3 complement levels in an additive model among African-Americans (best p=0.0001). The CIQA gene is associated with subphenotypes of lupus in African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.
doi:10.1038/gene.2009.33
PMCID: PMC2769492  PMID: 19440201
10.  Osteopontin and Systemic Lupus Erythematosus Association: A Probable Gene-Gender Interaction 
PLoS ONE  2008;3(3):e1757.
Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28–2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08–1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51–3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
doi:10.1371/journal.pone.0001757
PMCID: PMC2258418  PMID: 18335026

Results 1-10 (10)