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1.  A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis 
Fogh, Isabella | Ratti, Antonia | Gellera, Cinzia | Lin, Kuang | Tiloca, Cinzia | Moskvina, Valentina | Corrado, Lucia | Sorarù, Gianni | Cereda, Cristina | Corti, Stefania | Gentilini, Davide | Calini, Daniela | Castellotti, Barbara | Mazzini, Letizia | Querin, Giorgia | Gagliardi, Stella | Del Bo, Roberto | Conforti, Francesca L. | Siciliano, Gabriele | Inghilleri, Maurizio | Saccà, Francesco | Bongioanni, Paolo | Penco, Silvana | Corbo, Massimo | Sorbi, Sandro | Filosto, Massimiliano | Ferlini, Alessandra | Di Blasio, Anna M. | Signorini, Stefano | Shatunov, Aleksey | Jones, Ashley | Shaw, Pamela J. | Morrison, Karen E. | Farmer, Anne E. | Van Damme, Philip | Robberecht, Wim | Chiò, Adriano | Traynor, Bryan J. | Sendtner, Michael | Melki, Judith | Meininger, Vincent | Hardiman, Orla | Andersen, Peter M. | Leigh, Nigel P. | Glass, Jonathan D. | Overste, Daniel | Diekstra, Frank P. | Veldink, Jan H. | van Es, Michael A. | Shaw, Christopher E. | Weale, Michael E. | Lewis, Cathryn M. | Williams, Julie | Brown, Robert H. | Landers, John E. | Ticozzi, Nicola | Ceroni, Mauro | Pegoraro, Elena | Comi, Giacomo P. | D'Alfonso, Sandra | van den Berg, Leonard H. | Taroni, Franco | Al-Chalabi, Ammar | Powell, John | Silani, Vincenzo | Brescia Morra, Vincenzo | Filla, Alessandro | Massimo, Filosto | Marsili, Angela | Viviana, Pensato | Puorro, Giorgia | La Bella, Vincenzo | Logroscino, Giancarlo | Monsurrò, Maria Rosaria | Quattrone, Aldo | Simone, Isabella Laura | Ahmeti, Kreshnik B. | Ajroud-Driss, Senda | Armstrong, Jennifer | Birve, Anne | Blauw, Hylke M. | Bruijn, Lucie | Chen, Wenjie | Comeau, Mary C. | Cronin, Simon | Soraya, Gkazi Athina | Grab, Josh D. | Groen, Ewout J. | Haines, Jonathan L. | Heller, Scott | Huang, Jie | Hung, Wu-Yen | Jaworski, James M. | Khan, Humaira | Langefeld, Carl D. | Marion, Miranda C. | McLaughlin, Russell L. | Miller, Jack W. | Mora, Gabriele | Pericak-Vance, Margaret A. | Rampersaud, Evadnie | Siddique, Nailah | Siddique, Teepu | Smith, Bradley N. | Sufit, Robert | Topp, Simon | Vance, Caroline | van Vught, Paul | Yang, Yi | Zheng, J.G.
Human Molecular Genetics  2013;23(8):2220-2231.
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10−9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10−9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
PMCID: PMC3959809  PMID: 24256812
2.  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.
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
3.  Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis 
Nature genetics  2013;45(6):664-669.
Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time. Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6). Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis. The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively. Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.
PMCID: PMC3673707  PMID: 23603761
4.  Enrichment of Associations in Genes with Fibrosis, Apoptosis, and Innate Immunity Functions with Cardiac Manifestation of Neonatal Lupus 
Arthritis and rheumatism  2012;64(12):4060-4065.
The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the ribonucleoproteins SSA/Ro and SSB/La enhanced by as yet unknown factors likely to involve the dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biological functions.
Using data from our genome-wide association study (GWAS) in 116 cardiac-NL Caucasian children and 3,351 Caucasian controls, we tested for enrichment of SNP associations in genes with candidate biological functions related to fibrosis, immune, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll like receptors and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained.
A highly significant enrichment of P-values was observed in genes related to fibrosis (P=2.27×10−9), apoptosis (P=7.67×10−7), innate immune cell (P=2.53×10−6), immune (P=5.01×10−4), T cell (P=2.23×10−4), and interferon functions (P=1.64×10−3). The most significant non-HLA associations included the sialyltransferase ST8SIA2 (rs1487982, P=3.38×10−5, OR [95%CI]=2.20 [1.52–3.19]), the integrin ITGA1 (rs2432143, P=4.54×10−5, OR [95%CI]=2.31 [1.54–3.45]), and the complement regulator CSMD1 (rs7002001, P=6.33×10−5, OR [95%CI]=2.41 [1.57–3.72]).
This study identified novel candidate genes associated with cardiac-NL and highlights the value of this cohort in advancing our knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.
PMCID: PMC3541680  PMID: 22886516
5.  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
6.  Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13 
Arthritis and rheumatism  2012;64(8):2781-2791.
We have conducted a GWAS in a Caucasian cohort of juvenile idiopathic arthritis (JIA) patients and have previously published findings limited to autoimmune loci shared with other diseases. The goal of this study was to identify novel JIA predisposing loci using genome-wide approaches.
The Discovery cohort consisted of Caucasian JIA cases (814) and local controls (658) genotyped on the Affymetrix SNP 6.0 Array along with 2400 out-of-study controls. A replication study consisted of 10 SNPs genotyped in 1744 cases and 7010 controls from the US and Europe.
Analysis within the Discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011, OR=1.37, P=1.88×10−6), and 10q21 near the gene JMJD1C [rs6479891, odds ratio (OR) =1.59, P=6.1×10−8; rs12411988, OR=1.57, P=1.16×10−7 and rs10995450, OR = 1.31, P=6.74×10−5]. Meta-analysis continued to provide evidence for association for these 4 SNPs (rs4688011, P=3.6×10−7, rs6479891, P=4.33×10−5; rs12411988, P=2.71×10−5; and rs10995450, 5.39×10−5;). Gene expression data from 68 JIA cases and 23 local controls showed cis eQTL associations for C3orf1 SNP rs4688011 (P=0.024 or P=0.034, depending on probe set) and the JMJD1C SNPs rs6479891 and rs12411988 (P=0.01 and P=0.008, respectively). A variance component liability model estimated that common SNP variation accounts for ~1/3 of JIA susceptibility.
Genetic association results and correlated gene expression findings provide evidence of association at 3q13 and 10q21 for JIA and offer novel genes as plausible candidates in disease pathology.
PMCID: PMC3366043  PMID: 22354554
7.  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.
PMCID: PMC3712260  PMID: 18204446
8.  Identification of Candidate Loci at 6p21 and 21q22 in a Genome-Wide Association Study of Cardiac Manifestations of Neonatal Lupus 
Arthritis and rheumatism  2010;62(11):3415-3424.
Cardiac manifestations of neonatal lupus, comprising atrioventricular conduction defects and cardiomyopathy, occur in fetuses exposed to anti-Ro/SSA antibodies, and carry substantial mortality. There is strong evidence of a genetic contribution to the risk. This study was undertaken to evaluate single-nucleotide polymorphisms (SNPs) for associations with cardiac neonatal lupus.
Children of European ancestry with cardiac neonatal lupus (n = 116) were genotyped using the Illumina 370K SNP platform and merged with 3,351 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for association with cardiac neonatal lupus were determined.
The 17 most significant associations with cardiac neonatal lupus were found in the HLA region. The region near the MICB gene showed the strongest variant (rs3099844; Pdom = 4.52 × 10−10, OR 3.34 [95% CI 2.29–4.89]), followed by a missense variant within C6orf10 (rs7775397; Pdom = 1.35 × 10−9, OR 3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the tumor necrosis factor α gene, including rs2857595 (Padd = 1.96 × 10−9, OR 2.37), rs2230365 (Padd = 1.00 × 10−3, OR 0.46), and rs3128982 (Padd = 6.40 × 10−6, OR 1.86). Outside the HLA region, an association was detected at 21q22, upstream of the transcription regulator ets-related isoform 1 (rs743446; P = 5.45 × 10−6, OR 2.40). HLA notwithstanding, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance.
These results suggest that variation near genes related to inflammatory and apoptotic responses may promote cardiac injury initiated by passively acquired autoantibodies.
PMCID: PMC3593718  PMID: 20662065
9.  Preferential Transmission of Genetic Risk Variants of Candidate Loci at 6p21 from Asymptomatic Grandparents to Mothers of Children with Neonatal Lupus 
Arthritis and Rheumatism  2012;64(3):931-939.
Neonatal lupus (NL) occurs in fetuses exposed to maternal anti-SSA/Ro and/or SSB/La antibodies, although the mothers may not manifest any clinical disease. A focus on transmission of risk factors for NL from maternal grandparents to mothers may yield dividends towards understanding the aggregation of autoantibodies and genetic factors in families.
51 mothers of children with cardiac and/or cutaneous NL, 48 maternal grandmothers and 35 maternal grandfathers in the Research Registry for Neonatal Lupus were interrogated for clinical symptoms (questionnaire) and laboratory assessments including anti-SSA/Ro and SSB/La antibodies (ELISA) and genotype at rs1800629 (TNFα-308) and rs7775397 (C6orf10) (allelic discrimination). The transmission disequilibrium test (TDT) was computed to test for nonrandom transmission from maternal grandparents to the NL mothers.
The phenotypic feature held in common in NL mothers was the autoantibody, and not the clinical profile; 7 had lupus, 14 had Sjogren's syndrome, 7 had both, and 23 were asymptomatic. NL mothers were significantly enriched in variant allelic frequencies at both TNFα-308 and C6orf10. The grandparents of NL children carried minimal burden for autoimmune disease or abnormal antibody production and were not enriched in the genetic risk factors. However, the TDT analysis showed significant excess transmission of the risk alleles at both TNFα-308 (P=3.93×10−4, OR=6.67) and C6orf10 (P=3.74×10−5, OR=35) to NL mothers.
NL mothers are enriched for the TNFα-308 and C6orf10 variant alleles, which are preferentially inherited from the asymptomatic maternal grandparents. These findings support the hypothesis that the development of NL and genetic etiology are multigenerational.
PMCID: PMC3270151  PMID: 22031281
10.  Fine Mapping of Xq28: Both MECP2 and IRAK1 Contribute to Risk for Systemic Lupus Erythematosus in Multiple Ancestral Groups 
Annals of the rheumatic diseases  2012;72(3):437-444.
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
11.  A functional haplotype of UBE2L3 confers risk for Systemic Lupus Erythematosus 
Genes and immunity  2012;13(5):380-387.
Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni corrected threshold (P < 1 × 10−4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P = 0.0004) and UBCH7 protein expression (P = 0.0068). The results suggest that variants carried on the SLE associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.
PMCID: PMC3411915  PMID: 22476155
Systemic Lupus Erythematosus; UBE2L3; Multi Ethnic Association Study; UBCH7 Expression
12.  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
14.  Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility 
PLoS Genetics  2011;7(5):e1002079.
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10−7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10−4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing CFH and CFHRs with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of CFHR3 and CFHR1 genes but not previously identified disease-associated exonic variants of CFH. This study provides the first evidence for consistent association between CFH/CFHRs and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.
PMCID: PMC3102741  PMID: 21637784
15.  Genetic Associations of LYN with Systemic Lupus Erythematosus 
Genes and immunity  2009;10(5):397-403.
We targeted LYN, a src-tyosine kinase involved in B cell activation, in case-control association studies using populations of European American, African American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, demonstrates significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (p=1.1 × 10−4, OR=0.81 (95% CI: 0.73 – 0.90)). This SNP is located in the 5′ UTR within the first intron near the transcription initiation site of LYN. Additional SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for SLE susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European American female cases by ACR classification criteria reveals a reduction in the risk of hematologic disorder with rs6983130 compared to cases without hematologic disorders (p=1.5 × 10−3, OR=0.75 (95% C.I.=0.62-0.89)). None of the 90 SNPs tested demonstrate significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
PMCID: PMC2750001  PMID: 19369946
systemic lupus erythematosus; association; LYN; SNP
16.  Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-Derived Population 
Genes and immunity  2009;10(5):531-538.
Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T cell, B cell and accessory cell functions. B cells are hyperactive in SLE patients. An adaptor protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study is to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected p-value=1.97 × 10−5, OR=1.22, 95% C.I.(1.12–1.34)) and rs10516487 (corrected p-value=2.59 × 10−5, OR=1.22, 95% C.I.(1.11–1.34)). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.
PMCID: PMC2736873  PMID: 19339986
systemic lupus erythematosus; replication; association; European; BANK1
17.  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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