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1.  A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus 
Objective
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
Methods
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
Results
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10−5, false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10−4) and European Americans (OR 3.47, P = 0.024).
Conclusion
TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
doi:10.1002/art.38520
PMCID: PMC4269184  PMID: 24578102
2.  NCR3/NKp30 contributes to pathogenesis in primary Sjögren’s syndrome 
Science translational medicine  2013;5(195):195ra96.
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity and they are at markedly increased risk for the development of non- Hodgkin’s lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, though the precise etiology remains uncertain. NCR3/NKp30 is a NK-specific activating receptor regulating the cross-talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were markedly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands, and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.
doi:10.1126/scitranslmed.3005727
PMCID: PMC4237161  PMID: 23884468
Sjögren’s syndrome; autoimmunity; NK cells; innate immunity; NKp30/NCR3
4.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
doi:10.1038/gene.2009.80
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
5.  Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus 
Nature genetics  2008;40(9):1062-1064.
The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
doi:10.1038/ng.202
PMCID: PMC3897246  PMID: 19165919
6.  SNPs in VKORC1 are Risk Factors for Systemic Lupus Erythematosus in Asians 
Arthritis and rheumatism  2013;65(1):211-215.
OBJECTIVE
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.
METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1002/art.37751
PMCID: PMC3670944  PMID: 23124848
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
7.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
8.  Sequencing of TNFAIP3 and Association of Variants with Multiple Autoimmune Diseases 
Genes and immunity  2011;12(3):176-182.
The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). Here, we sequence the coding portions of the gene in order to identify contributing causal polymorphisms that may explain some of the observed associations. A collection of 123 individuals from the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection, each with multiple AIDs (mean=2.2 confirmed diagnoses), and 397 unrelated healthy controls were used for initial sequencing. Thirty-two polymorphisms were identified in the sequencing experiments, including 16 novel and 11 coding variants. Association testing in the entire MADGC collection (1,008 Caucasians with one or more AIDs and 770 unaffected family controls) revealed association of a novel intronic insertion/deletion polymorphism with rheumatoid arthritis (OR = 2.48, p = 0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed significant association with Sjögren’s syndrome (OR = 3.38, p = 0.038), Crohn’s disease (OR = 2.25, p = 0.041), psoriasis (OR = 0.037, p = 0.036) and rheumatoid arthritis (OR = 1.9, p = 0.025). Lastly, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5’ and 3’ untranslated region (UTR) variants (one-sided p-value=0.04), but not specifically for common (>2% MAF), rare, exonic, intronic, non-synonymous, or synonymous variants.
doi:10.1038/gene.2010.64
PMCID: PMC3152744  PMID: 21326317
resequencing; genetic association study; autoimmunity; a20; TNFAIP3
9.  Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production 
PLoS Genetics  2011;7(3):e1001323.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.
doi:10.1371/journal.pgen.1001323
PMCID: PMC3048371  PMID: 21408207
10.  European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus 
Arthritis and rheumatism  2009;60(8):2448-2456.
Objective
To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.
Methods
SLE patients of European descent (n=1754) from 8 case collections were genotyped for over 1,400 ancestry informative markers that define a north/south gradient of European substructure. Based on these genetic markers, we used the STRUCTURE program to characterize each SLE patient in terms of percent northern (vs. southern) European ancestry. Non-parametric methods, including tests of trend, were used to identify associations between northern European ancestry and specific SLE manifestations.
Results
In multivariate analyses, increasing levels of northern European ancestry were significantly associated with photosensitivity (ptrend=0.0021, OR for highest quartile of northern European ancestry compared to lowest quartile 1.64, 95% CI 1.13–2.35) and discoid rash (ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98–3.83). In contrast, northern European ancestry was protective for anticardiolipin (ptrend=1.6 × 10−4, ORhigh-low 0.46, 95% CI 0.30–0.69) and anti-dsDNA (ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46–0.96) autoantibody production.
Conclusions
This study demonstrates that specific SLE manifestations vary according to northern vs. southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure due to genetic ancestry.
doi:10.1002/art.24707
PMCID: PMC2739103  PMID: 19644962
11.  Clinical and Genetic Risk Factors for Pneumonia in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2007;56(8):2679-2686.
Objective
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/art.22804
PMCID: PMC2875177  PMID: 17665457
12.  High-Density SNP Screening of the Major Histocompatibility Complex in Systemic Lupus Erythematosus Demonstrates Strong Evidence for Independent Susceptibility Regions 
PLoS Genetics  2009;5(10):e1000696.
A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10−13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.
Author Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and involvement of multiple organ systems. Although the cause of SLE remains unknown, several lines of evidence underscore the importance of genetic factors. As is true for most autoimmune diseases, a substantial genetic contribution to disease risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6. This region of the genome contains a large number of genes that participate in the immune response. However, the full contribution of this genomic region to SLE risk has not yet been defined. In the current study we characterize a large number of SLE patients and family members for approximately 2,000 MHC region variants to identify the specific genes that influence disease risk. Our results, for the first time, implicate four different MHC regions in SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.
doi:10.1371/journal.pgen.1000696
PMCID: PMC2758598  PMID: 19851445
13.  Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus 
PLoS Genetics  2008;4(5):e1000084.
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
Author Summary
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
doi:10.1371/journal.pgen.1000084
PMCID: PMC2377340  PMID: 18516230

Results 1-13 (13)