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Genetic variation was first shown to be part of the cause of systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen (HLA) region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past two years, underscoring the extraordinary success of recent genome-wide association approaches in SLE. The now well established genetic risk factors include alleles in the MHC region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, ATG5, XKR6, PXK, some of the Fcγ receptors, and deficiencies in several complement components, including C1q, C4, and C2. As reviewed here, many of these genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction, and interferon pathways in the pathogenesis of SLE. Other genetic loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more targeted and effective diagnostic and clinical management tools for this complex autoimmune disease.

Objective

Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis is established in lupus. We test for gene-gene interactions in a number of known lupus susceptibility loci.

Methods

Eighteen SNPs tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 lupus patients and 3,818 normal healthy controls of European descent. Epistasis was tested using a 2-step approach utilizing both parametric and non-parametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.

Results

We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM, and between PDCD1 and IL21 in lupus patients. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (Interaction odds ratio=1.19, z-score= 3.95, P= 7.8×10−5 (FDR≤0.05), PMDR= 5.9×10−45). Importantly, our data suggest that in lupus patients the presence of the HLA lupus-risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus-risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P= 0.0028 and 0.0047).

Conclusion

We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.

Objective

Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus.

Materials and methods

4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.

Results

Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.

Conclusion

Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

Background

Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases.

Objective

To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls.

Methods

3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test.

Results

The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10−7) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10−8). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole.

Conclusion

The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE.

Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case–control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. Most SLE-associated gene products participate in key pathogenic pathways, including Toll-like receptor and type I interferon signaling pathways, immune regulation pathways and those that control the clearance of immune complexes. Disease-associated loci that have not yet been demonstrated to have important functions in the immune system might provide new clues to the underlying molecular mechanisms that contribute to the pathogenesis or progression of SLE. Of note, genetic risk factors that are shared between SLE and other immune-related diseases highlight common pathways in the pathophysiology of these diseases, and might provide innovative molecular targets for therapeutic interventions.

Objectives

To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus.

Methods

Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression.

Results

A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele.

Conclusion

Amerindian ancestry increased the number of risk alleles for lupus.

Objective

To determine the features associated with acute onset systemic lupus erythaematosus (SLE).

Methods

A total of 631 SLE patients from LUMINA (for “lupus in minority populations: nature vs nurture”), a multiethnic (Hispanics, African–Americans and Caucasians) cohort, were studied. Acute disease onset was defined as the accrual of ≥4 American College of Rheumatology (ACR) criteria for the classification of SLE in ≤4 weeks. Socioeconomic demographic features, clinical manifestations, disease activity, damage accrual, mortally, autoantibodies. HLA class II and FCGR alleles, behavioural/psychological variables were compared between patients with acute and insidious disease onset by univariable (χ2 and Student t test) and multivariable (stepwise logistic regression) analyses.

Results

A total of 94 (15%) patients had acute disease onset. In the multivariable analysis, patients with acute onset lupus had more renal involvement (odds ratio (OR) = 1.845, 95% CI 1.076–3.162; p = 0.026) and higher disease activity (OR = 1.057, 95% CI 1.005–1.112; p = 0.030). By contrast, age (OR = 0.976, 95% CI 0.956–0.997; p = 0.025), education (OR = 0.901, 95% CI 0.827–0.983, p = 0.019), health insurance (OR = 0.423, 95% CI 0.249–0.718; p = 0.001) and skin involvement (OR = 0.346, 95% CI 0.142–0.843; p = 0.019) were negatively associated with acute onset lupus. No differences were found regarding the serological, genetic and behavioural/psychological features; this was also the case for damage accrual and mortality.

Conclusions

Patients with acute onset lupus seem to be younger, have a lower socio-economic status and display more severe disease in terms of clinical manifestations and disease activity. However, intermediate (damage) and long-term (mortality) outcomes appear not to be influenced by the type of disease onset in SLE.

Objective

Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA.

Methods

A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls).

Results

Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA.

Conclusion

This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood.

Objective

Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.

Methods

Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.

Results

The “T” allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P=6.8×10−5, OR 1.27, 95%CI 1.1–1.4). The “A” allele at rs13277113 variant was associated with SSc in the U.S. series only (P=3.6×10−4, OR 1.32, 95%CI 1.1–1.6) and was significant in the combined analyses of the two series (P=2.0×10−3; OR 1.20, 95%CI 1.1–1.3). Both variants demonstrated an association with the anti-centromere antibody (P=2.2×10−6 and P=5.5×10−4, respectively) and limited SSc (P=3.3×10−5 and P=2.9×10−3, respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFκB signaling are dysregulated based on the risk haplotype of these variants.

Conclusion

We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that has a significantly higher prevalence, morbidity and mortality in African Americans compared with Americans of European descent. The pathogenesis of lupus is unclear but appears to be a result of environmental factors interacting with a genetically susceptible host. Despite the high disease load of SLE in African Americans, there is the perception that lupus is relatively rare in Africa. This prevalence gradient suggests that comparative studies of related cohorts from the two continents may provide insight into the genetic/environmental interactions that result in the development of lupus. To define if a lupus gradient exists, we began a study of autoimmunity prevalence utilizing two unique cohorts. The first is the Gullah population of the Sea Islands of South Carolina, who are unique in their low genetic admixture and their known ancestral heritage. The second is the population of young women served by the West Africa Fistula Foundation in Bo, Sierra Leone. Anthropologic studies indicate a direct ancestral link between the Gullah population and Sierra Leoneans. Since it is impossible to perform an epidemiologic study of lupus in Sierra Leone at this time, we assessed the prevalence of lupus serum autoantibodies, serologic evidence of specific infections and levels of serum 25-OH vitamin D in young women in the two cohorts who have no known relatives with lupus. Our results indicate similar prevalence of serum antinuclear antibodies in the two cohorts, though there was a significantly increased prevalence of antiphospholipid and anti-Sm antibodies in the Sierra Leone cohort. Seropositivity to common viral infections was significantly higher in women from Sierra Leone, while serum 25-OH vitamin D levels were markedly lower in the Gullah population. These data suggest that the prevalence of autoimmunity is similar in the two populations, but that there are significant environmental differences that may impact progression to autoimmune disease. Further studies comparing these two cohorts is likely to provide important insight into the impact of environmental factors on development of lupus.

Background

The genetic contribution to the aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not well defined. Across different autoimmune diseases some genes with immunomodulatory roles, such as PTPN22, are frequently associated with multiple diseases, whereas specific HLA associations, such as HLA-B27, tend to be disease restricted. We studied ten candidate loci on the basis of their immunoregulatory role and prior associations with type 1 diabetes (T1D). These included PTPN22, CTLA4 and CD226, which have previously been associated with AAV.

Methods

We genotyped the following 11 SNPs, from 10 loci, in 641 AAV patients using TaqMan genotyping: rs2476601 in PTPN22, rs1990760 in IFIH1, rs3087243 in CTLA4, rs2069763 in IL2, rs10877012 in CYP27B1, rs2292239 in ERBB3, rs3184504 in SH2B3, rs12708716 in CLEC16A, rs1893217 and rs478582 in PTPN2 and rs763361 in CD226. Where possible, we performed a meta-analysis with previous analyses.

Results

Both CTLA4 rs3087243 and PTPN22 rs2476601 showed association with AAV, P = 6.4 × 10-3 and P = 1.4 × 10-4 respectively. The minor allele (A) of CTLA4 rs3087243 is protective (odds ratio = 0.84), whereas the minor allele (A) of PTPN22 rs2476601 confers susceptibility (odds ratio = 1.40). These results confirmed previously described associations with AAV. After meta-analysis, the PTPN22 rs2476601 association was further strengthened (combined P = 4.2 × 10-7, odds ratio of 1.48 for the A allele). The other 9 SNPs, including rs763361 in CD226, showed no association with AAV.

Conclusion

Our study of T1D associated SNPs in AAV has confirmed CTLA4 and PTPN22 as susceptibility loci in AAV. These genes encode two key regulators of the immune response and are associated with many autoimmune diseases, including T1D, autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and now AAV.

Objective

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils that is involved in tissue damage in inflammatory renal diseases. A functional G to A single-nucleotide polymorphism (SNP) is present at position −463 of the MPO promoter region and is associated with altered MPO expression. We hypothesized that the G-463A MPO SNP is a risk factor for developing lupus nephritis (LN) due to its potential influence on the inflammatory response.

Methods

DNA from 229 patients with SLE and 277 controls from the Carolina Lupus cohort, 58 African American patients from the Sea Island Lupus Cohort, and 51 African American patients from the Lupus Multiplex Registry and Repository were genotyped by PCR. A linear regression model was used to examine relationships between the MPO genotype, case/control status, demographic characteristics, and LN.

Results

There was no association of MPO genotype with systemic lupus erythematosus (SLE). However, the odds of developing LN were significantly higher among those with an A allele, compared to those without, in African American cases of all 3 cohorts. When the likelihood of developing LN was compared across MPO genotypes, the risk of developing LN was significantly higher among cases with a GA genotype versus GG (OR 2.11, 95% CI 1.12 to 3.97) and even higher with AA versus GG (OR 3.52, 95% CI 1.41 to 8.77).

Conclusion

While the G-463A MPO SNP is not a risk factor for developing SLE, the low expressing A allele is a significant risk factor for developing LN that is gene dosage-dependent in African Americans. (First Release Sept 15 2007; J Rheumatol 2007;34:2028–34)

Objectives

Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members.

Methods

Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method.

Results

In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid Methionine to Arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient’s family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance.

Conclusion

The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)), has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in high risk African-American population.

Risk of systemic lupus erythematosus (SLE) is high in west Africans compared with Europeans, and risk of rheumatoid arthritis (RA) is high in Native Americans compared with Europeans. These differences are not accounted for by differences in allele or haplotype frequencies in the human leucocyte antigen (HLA) region or any other loci known to influence risk of rheumatic disease. Where there has been admixture between two or more ethnic groups that differ in risk of disease, studies of the relationship of disease risk to proportionate admixture can help to distinguish between genetic and environmental explanations for ethnic differences in disease risk and to map the genes underlying these differences.

Objective

To examine the clinical and genetic correlates of hemolytic anemia and its impact on damage accrual and mortality in systemic lupus erythematosus (SLE) patients.

Methods

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.

Results

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.

Conclusion

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.

Objective

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.

Methods

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.

Results

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).

Conclusion

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.

A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD.

Introduction

Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question.

Methods

European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication.

Results

There were three new associations: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, Pcorr = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci.

Conclusion

Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.

Background

Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort.

Methods

Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated.

Results

The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10−6). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10−5). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P  =  0.038), and with HLA and steroid-responsiveness (P  =  0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P  =  0.021), and with ZNF365 and ileal location (P  =  0.024) was demonstrated.

Conclusions

We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes.

Objective

To test the hypothesis that closely-related HLA haplotypes containing the DRB1*07:01 gene (“DR7” haplotypes) derived from European and African populations differ in their genetic susceptibility for type 1 diabetes (T1D) depending on the DQ-α molecule present.

Research Design and Methods

A combined total of ninety-eight African American T1D patients from the Type 1 Diabetes Genetics Consortium and from Children’s Hospital and Research Center Oakland were genotyped for the HLA class II loci DRB1, DQA1, and DQB1. DNA samples extracted from newborn blood spot cards from African Americans born in California (n=947) were used as a population-based control group.

Results

Among African American cases, the European-derived DRB1*07:01-DQA1*02:01-DQB1*02:01g haplotype was protective for T1D risk (odds ratio (OR)=0.34; 95% CI 0.14 - 0.78; p<0.011), but the African-derived DRB1*07:01-DQA1*03:01-DQB1*02:01g haplotype increased T1D risk (OR=3.96; 95% CI 1.94 - 8.08; p<5.5E-05).

Conclusions

The effect of DRB1*07:01-DQB1*02:01g on T1D susceptibility depends on the DQA1 allele. DRB1*07:01-DQA1*02:01-DQB1*02:01g is protective for T1D however, the presence of DQA1*03:01 on the DRB1*07:01-DQB1*02:01g haplotype not only renders the DR7 haplotype not protective, it creates a haplotype with significant T1D risk. These data underscore the importance of assessing genetic effects within ethnic context.

Introduction

Recent genome-wide and candidate gene association studies in large numbers of systemic lupus erythematosus (SLE) patients have suggested approximately 30 susceptibility genes. These genes are involved in three types of biological processes, including immune complex processing, toll-like receptor function and type I interferon production, and immune signal transduction in lymphocytes, and they may contribute to the pathogenesis of SLE. To better understand the genetic risk factors of SLE, we investigated the associations of seven SLE susceptibility genes in a Chinese population, including FCGR3A, FCGR2A, TNFAIP3, TLR9, TREX1, ETS1 and TNIP1.

Methods

A total of 20 SNPs spanning the seven SLE susceptibility genes were genotyped in a sample of 564 unrelated SLE patients and 504 unrelated healthy controls recruited from Yunnan, southwestern China. The associations of SNPs with SLE were assessed by statistical analysis.

Results

Five SNPs in two genes (TNFAIP3 and ETS1) were significantly associated with SLE (corrected P values ranging from 0.03 to 5.5 × 10-7). Through stratified analysis, TNFAIP3 and ETS1 showed significant associations with multiple SLE subphenotypes (such as malar rash, arthritis, hematologic disorder and antinuclear antibody) while TNIP1 just showed relatively weak association with onset age. The associations of the SNPs in the other four genes were not replicated.

Conclusions

The replication analysis indicates that TNFAIP3, ETS1 and TNIP1 are probably common susceptibility genes for SLE in Chinese populations, and they may contribute to the pathogenesis of multiple SLE subphenotypes.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22–24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ∼1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10−14; odds ratio, 95% confidence interval = 0.82 (0.78–0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10−7; 0.88 (0.84–0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10−8; 0.70 (0.62–0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Author Summary

African-Americans (AA) are at increased risk of systemic lupus erythematosus (SLE), but the genetic basis of this risk increase is largely unknown. We used admixture mapping to localize disease-causing genetic variants that differ in frequency across populations. This approach is advantageous for localizing susceptibility genes in recently admixed populations like AA. Our genome-wide admixture scan identified seven admixture signals, and we followed the best signal at 2q22–24 with fine-mapping, imputation-based association analysis and experimental validation. We identified two independent coding variants and a non-coding variant within the IFIH1 gene associated with SLE. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P ≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage (P = 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers (P = 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups (P < 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups.

Objective

It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.

Methods

A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.

Results

Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.

Conclusions

Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.