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1.  Multiple Lupus Associated ITGAM Variants Alter Mac-1 Function on Neutrophils 
Arthritis and rheumatism  2013;65(11):2907-2916.
Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the non-synonymous SNPs rs1143679, rs1143678, rs1143683) are associated with SLE. ITGAM encodes the protein CD11b, a subunit of the β2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biological functions of neutrophil Mac-1.
Neutrophils from ITGAM genotyped and sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement coated erythrocytes, serum treated zymosan, heat treated zymosan and IgG coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor α-stimulated endothelial cells was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry.
Mac-1–mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the β-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fcγ receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation.
The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE.
PMCID: PMC3969028  PMID: 23918739
2.  SNPs in VKORC1 are Risk Factors for Systemic Lupus Erythematosus in Asians 
Arthritis and rheumatism  2013;65(1):211-215.
The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. In a case-control analysis, we investigated whether 33 established and novel single nucleotide polymorphisms (SNP) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis in the general population were risk factors for SLE development among Asians.
Patients in the discovery cohort were enrolled in one of two North American SLE cohorts. Patients in the replication cohort were enrolled in one of four Asian or two North American cohorts. SLE cases met American College of Rheumatology classification criteria. We first genotyped 263 Asian SLE and 357 healthy Asian control individuals for 33 SNPs using Luminex multiplex technology in the discovery phase, and then used Taqman and Immunochip assays to examine 5 SNPs in up to an additional 1496 cases and 993 controls in the Replication phase. SLE patients were compared to healthy controls for association with minor alleles in allelic models. Principal components analysis was used to control for intra-Asian ancestry in an analysis of the replication cohort.
Two genetic variants in the gene VKORC1, rs9934438 and rs9923231, were highly significant in both the discovery and replication cohorts: OR(disc) = 2.45 (p=2×10−9), OR(rep) = 1.53 (p=5×10−6) and OR(disc) = 2.40 (p=6×10−9), OR(rep) = 1.53 (p=5×10−6), respectively. These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: rs9934438 OR(adj) = 1.34 (p=0.0029) and rs9923231 OR(adj) = 1.34 (p=0.0032).
Genetic variants in VKORC1, involved in vitamin K reduction and associated with DVT, are associated with SLE development in Asians. These results suggest intersecting genetic pathways for the development of SLE and thrombosis.
PMCID: PMC3670944  PMID: 23124848
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
3.  Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(11):3695-3705.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins.
We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines.
We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.
Our results confirmed the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
PMCID: PMC3485412  PMID: 22833143
4.  Impact of Genetic Ancestry and Socio-Demographic Status on the Clinical Expression of Systemic Lupus Erythematosus in Amerindian-European Populations 
Arthritis and rheumatism  2012;64(11):3687-3694.
Amerindian-Europeans, Asians and African-Americans have an excess morbidity from SLE and higher prevalence of lupus nephritis than Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and socio-demographic characteristics and clinical features in a large cohort of Amerindian-European SLE patients.
A total of 2116 SLE patients of Amerindian-European origin and 4001 SLE patients of European descent with clinical data were used in the study. Genotyping of 253 continental ancestry informative markers was performed on the Illumina platform. The STRUCTURE and ADMIXTURE software were used to determine genetic ancestry of each individual. Correlation between ancestry and socio-demographic and clinical data were analyzed using logistic regression.
The average Amerindian genetic ancestry of 2116 SLE patients was 40.7%. There was an increased risk of having renal involvement (P<0.0001, OR= 3.50 95%CI 2.63-4.63) and an early age of onset with the presence of Amerindian genetic ancestry (P<0.0001). Amerindian ancestry protected against photosensitivity (P<0.0001, OR= 0.58 95%CI 0.44-0.76), oral ulcers (P<0.0001, OR= 0.55 95%CI 0.42-0.72), and serositis (P<0.0001, OR= 0.56 95%CI 0.41-0.75) after adjustment by age, gender and age of onset. However, gender and age of onset had stronger effects on malar rash, discoid rash, arthritis and neurological involvement than genetic ancestry.
In general, genetic Amerindian ancestry correlates with lower socio-demographic status and increases the risk for developing renal involvement and SLE at an earlier age of onset.
PMCID: PMC3485439  PMID: 22886787
5.  Meta-analysis in granulomatosis with polyangiitis reveals shared susceptibility loci with rheumatoid arthritis 
Arthritis and rheumatism  2012;64(10):3463-3471.
To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and determine whether genetic susceptibility profiles of other autoimmune diseases are associated with GPA
Genetic data from two cohorts were meta-analyzed. Genotypes for 168 previously identified single nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained for a total of 880 GPA cases and 1969 controls of European descent. Single marker associations were identified using additive logistic regression models. Multi-SNP associations with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn’s disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses using ancestry informative markers and principal components analysis.
Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (OR 0.79. 95% CI 0.70–0.89, p=9.8×10−5). A genetic risk score based on rheumatoid arthritis susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02–1.08, p=5.1×10−5).
Rheumatoid arthritis and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically associated with GPA in this study.
PMCID: PMC3425721  PMID: 22508400
genetics; vasculitis; granulomatosis with polyangiitis; rheumatoid arthritis; CTLA4
6.  Identification of novel genetic susceptibility loci in African-American lupus patients using a candidate gene association study 
Arthritis and rheumatism  2011;63(11):3493-3501.
Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have been largely performed in European-derived and Asian lupus patients. In this study, we examine if some of these same susceptibility loci increase lupus risk in African-American individuals.
Single nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1,724 lupus patients and 2,024 normal healthy controls of African-American descent. The loci examined included: PTPN22, FCGR2A, TNFSF4, STAT4, CTLA4, PDCD1, PXK, BANK1, MSH5 (HLA region), CFB (HLA region), C8orf13-BLK region, MBL2, KIAA1542, ITGAM, and MECP2/IRAK1.
We provide the first evidence for genetic association between lupus and five susceptibility loci in African-American patients (C8orf13-BLK, BANK1, TNFSF4, KIAA1542 andCTLA4; P values= 8.0 × 10−6, 1.9 × 10−5, 5.7 × 10−5, 0.00099, 0.0045, respectively). Further, we confirm the genetic association between lupus and five additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P values= 7.5 × 10−11, 5.2 × 10−8, 8.7 × 10−7, 0.0058, and 0.0070, respectively), and provide evidence for a genome-wide significance for the association between ITGAM and MSH5 (HLA region) for the first time in African-American lupus patients.
These findings provide evidence for novel genetic susceptibility loci for lupus in African-Americans and demonstrate that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicities.
PMCID: PMC3205224  PMID: 21792837
7.  Association of PPP2CA polymorphisms with SLE susceptibility in multiple ethnic groups 
Arthritis and rheumatism  2011;63(9):2755-2763.
T cells from patients with SLE express increased amounts of PP2Ac which contribute to decreased production of IL-2. Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
We conducted a trans-ethnic study consisting of 8,695 SLE cases and 7,308 controls from four different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across the PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time PCR.
A 32-kb haplotype comprised of multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans (HA), European Americans (EA) and Asians but not in African-Americans (AA). Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, EA and HA populations (pmeta=3.8×10−7, OR=1.3[1.14–1.31]). In EA, the largest ethnic dataset, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-dsDNA and anti-RNP antibodies. PPP2CA expression was approximately 2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying GG genotype (p = 0.008).
Our data provide the first evidence for an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in EA, HA and Asians.
PMCID: PMC3163110  PMID: 21590681
8.  Genetic Analyses of Interferon Pathway-Related Genes Reveals Multiple New Loci Associated with Systemic Lupus Erythematosus (SLE) 
Arthritis and rheumatism  2011;63(7):2049-2057.
The overexpression of interferon (IFN)-inducible genes is a prominent feature of SLE, serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. The genetic variations responsible for sustained activation of IFN responsive genes are unknown.
We systematically evaluated association of SLE with a total of 1,754 IFN-pathway related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We performed a three-stage design where two cohorts (total n=939 SLE cases, 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons.
A total of 16,137 SNPs passed all quality control filters of which 316 demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including the transmembrane receptor CD44 (rs507230, P = 3.98×10−12), cytokine pleiotrophin (PTN) (rs919581, P = 5.38×10−04), the heat-shock DNAJA1 (rs10971259, P = 6.31×10−03), and the nuclear import protein karyopherin alpha 1 (KPNA1) (rs6810306, P = 4.91×10−02).
This study expands the number of candidate genes associated with SLE and highlights the potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.
PMCID: PMC3128183  PMID: 21437871
9.  Fine mapping and trans-ethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21 
Arthritis and rheumatism  2011;63(6):1689-1697.
Genetic association of the IL2/IL21 region at 4q27 has been previously reported in lupus and a number of autoimmune and inflammatory diseases. Herein, using a very large cohort of lupus patients and controls, we localize this genetic effect to the IL21 gene.
We genotyped 45 tag SNPs across the IL2/IL21 locus in two large independent lupus sample sets. We studied a European-derived set consisting of 4,248 lupus patients and 3,818 healthy controls, and an African-American set of 1,569 patients and 1,893 healthy controls. Imputation in 3,004 WTCCC additional control individuals was also performed. Genetic association between the genotyped markers was determined, and pair-wise conditional analysis was performed to localize the independent genetic effect in the IL2/IL21 locus in lupus.
We established and confirmed the genetic association between IL2/IL21 and lupus. Using conditional analysis and trans-ethnic mapping, we localized the genetic effect in this locus to two SNPs in high linkage disequilibrium; rs907715 located within IL21 (OR=1.16 (1.10–1.22), P= 2.17 ×10−8), and rs6835457 located in the 3’-UTR flanking region of IL21 (OR= 1.11 (1.05–1.17), P= 9.35×10−5).
We have established the genetic association between lupus and IL2/IL21 with a genome-wide level of significance. Further, we localized this genetic association within the IL2/IL21 linkage disequilibrium block to IL21. If other autoimmune IL2/IL21 genetic associations are similarly localized, then the IL21 risk alleles would be predicted to operate in a fundamental mechanism that influences the course of a number of autoimmune disease processes.
PMCID: PMC3106139  PMID: 21425124
10.  Alpha1-Antitrypsin Deficiency–Related Alleles Z and S and the Risk of Wegener’s Granulomatosis 
Arthritis and rheumatism  2010;62(12):3760-3767.
Deficiency of α1-antitrypsin (α1AT) may be a determinant of susceptibility to Wegener’s granulomatosis (WG). Several previous, mainly small, case–control studies have shown that 5–27% of patients with WG carried the α1AT deficiency Z allele. It is not clear whether the S allele, the other major α1AT deficiency variant, is associated with WG. This study investigated the relationship of the α1AT deficiency Z and S alleles with the risk of developing WG in a large cohort.
We studied the distribution of the α1AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods.
Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98–2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33–∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele.
Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α1AT deficiency and susceptibility to WG.
PMCID: PMC3123032  PMID: 20827781
12.  A polymorphism within interleukin-21 receptor (IL21R) confers risk for systemic lupus erythematosus 
Arthritis and rheumatism  2009;60(8):2402-2407.
Interleukin (IL) 21 is a member of the type I cytokine superfamily that exerts a variety of effects on the immune system including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL21R is reduced in B cells from lupus patients, while IL21 serum levels are increased in both lupus patients and some lupus-murine models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to lupus. Herein, we examined the genetic association between SNPs within IL21R and lupus.
We genotyped 17 SNPs in the IL21R gene in two large cohorts of lupus patients and ethnically-matched healthy controls. Genotyping was performed with the Illumina BeadStation 500GX instrument using Illumina Infinum II genotyping assays.
We identified and confirmed the association between rs3093301 within the IL21R gene and lupus in two independent European-derived and Hispanic cohorts (meta analysis odds ratio= 1.16, 95% CI= 1.08-1.25, meta analysis p=1.0×10-4).
We identified IL21R as a novel susceptibility gene for lupus.
PMCID: PMC2782592  PMID: 19644854
13.  Clinical and Genetic Risk Factors for Pneumonia in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2007;56(8):2679-2686.
To define the contribution of polymorphisms in genes encoding tumor necrosis factor (TNF), mannose-binding lectin (MBL), and Fcγ receptor IIa (FCGR2A) as well as clinical factors, to the development of pneumonia in patients with systemic lupus erythematosus (SLE).
We studied 282 SLE patients from a multiethnic cohort. Pneumonia events and clinical risk factors for pneumonia were identified through medical record review. Genotyping was performed for MBL (+223, +230, and +239), TNF (−308, −238, and +488), and FCGR2A (−131H/R) polymorphisms. Univariate analyses were performed to identify clinical and genetic risk factors for pneumonia. Covariates for multivariate analysis included sex, ethnicity, treatment with immunomodulators, and leukopenia.
Forty-two patients (15%) had at least 1 episode of pneumonia. Polymorphism of the TNF gene, particularly the −238A allele and a related haplotype, revealed the most striking and consistent association with pneumonia in univariate analyses. Results of multivariate analyses indicated an odds ratio (OR) for the TNF −238A allele of 3.5 (P = 0.007) and an OR for the related haplotype of 5.4 (P = 0.001). Male sex, treatment with immunomodulators, and leukopenia also influenced the risk of pneumonia.
These findings suggest that specific TNF variants may identify SLE patients who are at particularly high risk of developing pneumonia. Given the prevalence and excessive morbidity associated with pneumonia in SLE, these findings have clinical relevance and provide insight into the pathogenesis.
PMCID: PMC2875177  PMID: 17665457
14.  Features Associated With, and the Impact of, Hemolytic Anemia in Patients With Systemic Lupus Erythematosus: LX, Results From a Multiethnic Cohort 
Arthritis and rheumatism  2008;59(9):1332-1340.
To examine the clinical and genetic correlates of hemolytic anemia and its impact on damage accrual and mortality in systemic lupus erythematosus (SLE) patients.
SLE patients (American College of Rheumatology [ACR] criteria) of Hispanic (Texan or Puerto Rican), African American, and Caucasian ethnicity from the LUMINA (LUpus in MInorities, NAture versus nurture) cohort were studied. Hemolytic anemia was defined as anemia with reticulocytosis (ACR criterion). The association between degrees of hemolytic anemia and socioeconomic/demographic, clinical, pharmacologic, immunologic, psychological, and behavioral variables was examined by univariable and multivariable (proportional odds model) analyses. Genetic variables (FCGR and Fas/Fas ligand polymorphisms) were examined by 2 degrees of freedom test of association and Cochran-Armitage trend tests. The impact of hemolytic anemia on damage accrual and mortality was examined by multivariable linear and Cox regression analyses, respectively.
Of 628 patients studied, 90% were women, 19% were Texan Hispanic, 16% were Puerto Rican Hispanic, 37% were African American, and 28% were Caucasian. Sixty-five (10%) patients developed hemolytic anemia at some time during the disease course, 83% at or before diagnosis. Variables independently associated with degrees of hemolytic anemia were African American ethnicity, thrombocytopenia, and the use of azathioprine. Hemolytic anemia was associated with damage accrual after adjusting for variables known to affect this outcome; however, hemolytic anemia was not associated with mortality.
The association of hemolytic anemia with thrombocytopenia suggests a common mechanism in their pathophysiology. Hemolytic anemia is an early disease manifestation and is associated with African American ethnicity and the use of azathioprine; it appears to exert an impact on damage but not on mortality.
PMCID: PMC2760833  PMID: 18759263

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