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1.  Systemic lupus erythematosus associates with the decreased immunosuppressive potential of the IgG glycome 
Objectives
Glycans attached to the Fc part of immunoglobulin G (IgG) are important modulators of IgG effector functions. Inter-individual differences in IgG glycome composition are large and they strongly associate with different inflammatory and autoimmune diseases. IKZF1, HLA-DQ2A/B and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating potentially causative role of aberrant IgG glycosylation in SLE. The main objective of this first large multicentre case/control study was to determine whether SLE is associated with altered IgG glycosylation.
Methods
Using UPLC analysis of released and 2AB-labelled glycans, the composition of IgG glycome was analysed in 251 SLE patients and 252 matching controls of Latin American mestizo origin (discovery cohort) and in two independent replication cohorts of different ethnicity (108 cases and 193 controls from Trinidad, and 107 cases and 200 controls from China).
Results
Multiple statistically significant differences in the IgG glycome composition between patients and controls were observed. The most significant changes included decreased galactosylation and sialylation of IgG (that regulate pro- and anti-inflammatory action of IgG) as well as decreased core-fucose and increased bisecting GlcNAc (that affects antibody dependent cellular cytotoxicity).
Conclusions
IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes associated with the intensity of the disease, indicating that aberrant IgG glycome composition, or changes in IgG glycosylation may be an important molecular mechanism in SLE.
doi:10.1002/art.39273
PMCID: PMC4626261  PMID: 26200652
2.  Efficacy and Safety of Subcutaneous Golimumab in Methotrexate‐Naive Patients With Rheumatoid Arthritis: Five‐Year Results of a Randomized Clinical Trial 
Arthritis Care & Research  2016;68(6):744-752.
Objective
To evaluate the safety and efficacy of golimumab through 5 years in adults with active rheumatoid arthritis (RA) who had not previously received methotrexate (MTX).
Methods
In the GO‐BEFORE study, 637 MTX‐naive adult patients with active RA were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4). Inadequate responders in groups 1, 2, and 3 entered early escape at week 28 to golimumab 50 mg + MTX, golimumab 100 mg + MTX, or golimumab 100 mg + MTX, respectively; remaining patients in group 1 could cross over to golimumab 50 mg + MTX at week 52. Assessments included the American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response, the Disease Activity Score in 28 joints (DAS28) using C‐reactive protein (CRP) level, and the modified Sharp/van der Heijde score (SHS). Efficacy was analyzed using an intent‐to‐treat (ITT) analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits.
Results
A total of 422 patients completed golimumab treatment through week 256. At week 256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n = 637) had an ACR20/50/70 response, respectively; 84.1% had a good or moderate DAS28‐CRP response; and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week 256, and the overall mean change from baseline in SHS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week 256. Antibodies to golimumab occurred in 9.6% of patients through week 256. Infections were the most common type of adverse event (AE); 204 of 616 patients (33.1%) had ≥1 serious AE.
Conclusion
Clinical efficacy with golimumab treatment was maintained through week 256 of the GO‐BEFORE trial of MTX‐naive RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports.
doi:10.1002/acr.22759
PMCID: PMC5089605  PMID: 26474452
3.  GWAS in an Amerindian ancestry population reveals novel systemic lupus erythematosus risk loci and the role of European admixture 
OBJECTIVES
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage.
MATERIALS and METHODS
We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles.
RESULTS
The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, Pgcadj = 2.61×10−29, OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, Pgcadj = 1.11 × 10−16, OR = 1.62, 95% CI: 1.46–1.80; rs9271366, Pgcadj=6.46 × 10−12, OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, Pgcadj =1.4×10−8) with a eQTL effect (Peqtl=8.0 × 10−37 at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection.
CONCLUSIONS
Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases.
doi:10.1002/art.39504
PMCID: PMC4829354  PMID: 26606652
5.  Association of Systemic Lupus Erythematosus With Decreased Immunosuppressive Potential of the IgG Glycome 
Objective
Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.
Methods
Using ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).
Results
Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).
Conclusion
The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.
doi:10.1002/art.39273
PMCID: PMC4626261  PMID: 26200652
6.  Prevalence of musculoskeletal disorders and rheumatic diseases in the indigenous Qom population of Rosario, Argentina 
Clinical Rheumatology  2016;35(Suppl 1):5-14.
This study aimed to estimate the prevalence of musculoskeletal disorders and rheumatic diseases among the indigenous Qom (Toba) population in the city of Rosario, Santa Fe, Argentina. An analytical cross-sectional study using methodology of the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) was performed. Subjects ≥18 years of age were interviewed by advanced students of medicine and nursing, bilingual translator-facilitators, and coordinators. Individuals with musculoskeletal pain (positive cases) were evaluated sequentially for 7 days by internists and rheumatologists for diagnosis and treatment. The study included 1656 individuals (77 % of the census population). Of these, 1020 (61.5 %) were female, with mean age of 35.3 (SD 13.9) years, and 1028 (62.0 %) were bilingual. The public health care system covers 87.1 % of the population. Musculoskeletal pain in the previous 7 days and/or at some time during their life was present in 890 subjects (53.7 %). Of those with pain in the last 7 days, 302 (64.1 %) subjects had an Health Assessment Questionnaire Disability Index (HAQ-DI) score ≥0.8. The most frequent pain sites were lumbar spine (19.3 %), knees (13.0 %), and hands (12.0 %). The prevalence of rheumatic diseases was as follows: mechanical back pain (20.1 %), rheumatic regional pain syndrome (2.9 %), osteoarthritis (4.0 %) rheumatoid arthritis (2.4 %), inflammatory back pain (0.2 %), systemic sclerosis (0.1 %), Sjögren syndrome (0.1 %), fibromyalgia (0.1 %), mixed connective tissue disease (0.06 %), and systemic lupus erythematosus (0.06 %). The prevalence of musculoskeletal disorders was 53.7 % and rheumatic diseases 29.6 %. Rheumatoid arthritis prevalence was 2.4 % using COPCORD methodology, one of the highest reported at present.
doi:10.1007/s10067-016-3192-2
PMCID: PMC4954830  PMID: 26852314
COPCORD methodology; Indigenous people; Latin America; Prevalence; Qom; Rheumatic diseases
7.  Prevalence of rheumatic regional pain syndromes in Latin-American indigenous groups: a census study based on COPCORD methodology and syndrome-specific diagnostic criteria 
Clinical Rheumatology  2016;35(Suppl 1):63-70.
This study assessed the overall and specific prevalence of the main rheumatic regional pain syndromes (RRPS) in four Latin-American indigenous groups. A Community Oriented Program for Control of Rheumatic Diseases (COPCORD) methodology-based census study was performed in 4240 adults (participation rate: 78.88 %) in four indigenous groups: Chontal (Oaxaca, Mexico, n = 124), Mixteco (Oaxaca, Mexico; n = 937), Maya-Yucateco (Yucatán, Mexico; n = 1523), and Qom (Rosario, Argentina; n = 1656). Subjects with musculoskeletal pain were identified using a cross-cultural, validated COPCORD questionnaire administered by bilingual personnel, and reviewed by general practitioners or rheumatologists using standardized case definitions for the 12 most frequent RRPS. The overall prevalence of RRPS was confirmed in 239 cases (5.64 %, 95 % CI: 4.98–6.37). The prevalence in each group was Chontal n = 19 (15.32 %, 95 % CI: 10.03–22.69); Maya-Yucateco n = 165 (10.83 %, 95 % CI: 9.37–12.49); Qom n = 48 (2.90 %, 95 % CI: 2.19–3.82); and Mixteco n = 7 (0.75 %, 95 % CI: 0.36–1.53). In the whole sample, the syndrome-specific prevalence was rotator cuff tendinopathy: 1.98 % (95 % CI: 1.60–2.45); lateral epicondylalgia: 0.83 % (95 % CI: 0.59–1.15); medial epicondylalgia: 0.73 % (95 % CI: 0.52–1.04); biceps tendinopathy: 0.71 % (95 % CI: 0.50–1.01); anserine syndrome: 0.64 % (95 % CI: 0.44–0.92); inferior heel pain: 0.61 % (95 % CI: 0.42–0.90); trochanteric syndrome: 0.49 % (95 % CI: 0.25–0.64); de Quervain’s tendinopathy: 0.45 % (95 % CI: 0.29–0.70); trigger finger: 0.42 % (95 % CI: 0.27–0.67); carpal tunnel syndrome: 0.28 % (95 % CI: 0.16–0.49); Achilles tendinopathy (insertional): 0.12 % (95 % CI: 0.05–0.28); and Achilles tendinopathy (non-insertional): 0.07 % (95 % CI: 0.02–0.21). Leaving aside the comparison between Maya-Yucateco and Chontal groups (p = 0.18), we found significant differences (p < 0.001) in overall RRPS prevalence between the remaining pairs of indigenous groups. Syndrome-specific prevalences were also different between groups. Our findings support the hypothesis that overall RRPS prevalence and syndrome-specific prevalences are modulated by population-specific factors.
doi:10.1007/s10067-016-3188-y
PMCID: PMC4954835  PMID: 26833395
Soft tissue rheumatology; Rheumatic regional pain syndrome; Tendonitis; Bursitis; Epidemiology; Prevalence; Ethnicity
8.  Genomic Insights into the Ancestry and Demographic History of South America 
PLoS Genetics  2015;11(12):e1005602.
South America has a complex demographic history shaped by multiple migration and admixture events in pre- and post-colonial times. Settled over 14,000 years ago by Native Americans, South America has experienced migrations of European and African individuals, similar to other regions in the Americas. However, the timing and magnitude of these events resulted in markedly different patterns of admixture throughout Latin America. We use genome-wide SNP data for 437 admixed individuals from 5 countries (Colombia, Ecuador, Peru, Chile, and Argentina) to explore the population structure and demographic history of South American Latinos. We combined these data with population reference panels from Africa, Asia, Europe and the Americas to perform global ancestry analysis and infer the subcontinental origin of the European and Native American ancestry components of the admixed individuals. By applying ancestry-specific PCA analyses we find that most of the European ancestry in South American Latinos is from the Iberian Peninsula; however, many individuals trace their ancestry back to Italy, especially within Argentina. We find a strong gradient in the Native American ancestry component of South American Latinos associated with country of origin and the geography of local indigenous populations. For example, Native American genomic segments in Peruvians show greater affinities with Andean indigenous peoples like Quechua and Aymara, whereas Native American haplotypes from Colombians tend to cluster with Amazonian and coastal tribes from northern South America. Using ancestry tract length analysis we modeled post-colonial South American migration history as the youngest in Latin America during European colonization (9–14 generations ago), with an additional strong pulse of European migration occurring between 3 and 9 generations ago. These genetic footprints can impact our understanding of population-level differences in biomedical traits and, thus, inform future medical genetic studies in the region.
Author Summary
South America is home to over 400 million people who share a rich demographic history, including settlement by Native Americans, European colonization, and the African slave trade. We use genomic data to infer which populations from Europe and the Americas contributed to these admixture events. We provide evidence for multiple origins of the Native American ancestry of admixed South American Latinos. The Native American ancestral component correlates strongly with geography, indicating that admixture occurred between European colonists and local Native American populations throughout South America. We also show that the European ancestry of South American Latinos comes mainly from the Iberian peninsula, however, a significant number of Argentinians have European ancestry from other Southern European regions. The genetic signal of European admixture in South American populations is younger than the signal observed in Mexico and the Caribbean. We find evidence for a second pulse of European migration to many regions of South America subsequent to the original colonization. These results demonstrate the heterogeneous nature of the Latino population in South America and help elucidate the complex genetic and admixture events that shaped the population structure of the region.
doi:10.1371/journal.pgen.1005602
PMCID: PMC4670080  PMID: 26636962
9.  Access to an optimal treatment. Current situation 
Clinical Rheumatology  2015;34(Suppl 1):59-66.
Access to an optimal treatment is determined by several factors, like availability, pricing/funding, and acceptability. In Latin America (LA), one of the regions with more disparities particularly on healthcare in the world, access is affected by other factors, including socio-demographic factors like poverty, living in rural regions, and/or health coverage. Regarding rheumatoid arthritis (RA), an inadequate access to specialists leads to diagnosis and treatment delays diminishing the probability of remission or control. Unfortunately, in almost every LA country, there are cities with more than 100,000 inhabitants without rheumatologists; furthermore, a primary care reference system is present in only about half the countries. In the public health system, coverage of biologic disease-modifying antirheumatic drugs occurs for less than 10 % of the patients in about half of the countries. Also, as healthcare providers based their funding decisions mainly in direct costs instead of on patient-centered healthcare quality indicators, access to new drugs is more complicated in this region than in high-income countries. More accurate epidemiological data from LA need to be obtained in order to improve the management of patients with rheumatic diseases in general and RA in particular.
doi:10.1007/s10067-015-3018-7
PMCID: PMC4617843  PMID: 26188617
Rheumatoid arthritis; Drug therapy; Health service accessibility; Access to healthcare
10.  REAL-PANLAR Project for the Implementation and Accreditation of Centers of Excellence in Rheumatoid Arthritis Throughout Latin America 
Journal of Clinical Rheumatology  2015;21(4):175-180.
Objective
A consensus meeting of representatives of 16 Latin American and Caribbean countries and the REAL-PANLAR group met in the city of Bogota to provide recommendations for improving quality of care of patients with rheumatoid arthritis (RA) in Latin America, defining a minimum standards of care and the concept of center of excellence in RA.
Methods
Twenty-two rheumatologists from 16 Latin American countries with a special interest in quality of care in RA participated in the consensus meeting. Two RA Colombian patients and 2 health care excellence advisors were also invited to the meeting. A RAND-modified Delphi procedure of 5 steps was applied to define categories of centers of excellence. During a 1-day meeting, working groups were created in order to discuss and validate the minimum quality-of-care standards for the 3 proposed types of centers of excellence in RA. Positive votes from at least 60% of the attending leaders were required for the approval of each standard.
Results
Twenty-two opinion leaders from the PANLAR countries and the REAL-PANLAR group participated in the discussion and definition of the standards. One hundred percent of the participants agreed with setting up centers of excellence in RA throughout Latin America. Three types of centers of excellence and its criteria were defined, according to indicators of structure, processes, and outcomes: standard, optimal, and model. The standard level should have basic structure and process indicators, the intermediate or optimal level should accomplish more structure and process indicators, and model level should also fulfill outcome indicators and patient experience.
Conclusions
This is the first Latin American effort to standardize and harmonize the treatment provided to RA patients and to establish centers of excellence that would offer to RA patients acceptable clinical results and high levels of safety.
doi:10.1097/RHU.0000000000000247
PMCID: PMC4450904  PMID: 26010179
rheumatoid arthritis; Latin America; quality of care; centers of excellence
11.  Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations 
Human Molecular Genetics  2013;23(6):1656-1668.
Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (PEA = 1.01 × 10−54, PHS = 3.68 × 10−10, PAA = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10−9), and rs13306575 in HS and KR (PHS = 7.04 × 10−7, PKR = 3.30 × 10−3). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10−7), implying that SLE predisposing variants were tagged. Significant SNP–SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance (‘missing heritability’) of complex diseases like SLE.
doi:10.1093/hmg/ddt532
PMCID: PMC3929085  PMID: 24163247
13.  Mestizos with Systemic Lupus Erythematosus Develop Renal Disease Early while Antimalarials Retard its Appearance: Data from a Latin American Cohort 
Lupus  2013;22(9):899-907.
Objectives
To assess the predictors of time-to-lupus renal disease in Latin American patients.
Methods
SLE patients (n=1480) from GLADEL’s (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time-dependent in alternative analyses.
Results
Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.8% were African-Latin Americans, 52.5% Mestizos, 34.7% Caucasians (p=0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19–2.17), hypertension (HR 3.99, 95% CI 3.02–5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01–1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43–0.77), older age at onset (HR 0.90, 95% CI 0.85–0.95, for every 5 years) and photosensitivity (HR 0.74, 95% CI 0.56–0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50–0.99).
Conclusions
Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location.
doi:10.1177/0961203313496339
PMCID: PMC3943422  PMID: 23857989
14.  STAT4 Associates with SLE Through Two Independent Effects that Correlate with Gene Expression and Act Additively with IRF5 to Increase Risk 
Annals of the rheumatic diseases  2008;68(11):10.1136/ard.2008.097642.
Objectives
To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5.
Methods
30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5’-RACE PCR and sequencing. Expression levels were measured by quantitative PCR.
Results
In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis.
Conclusions
These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
doi:10.1136/ard.2008.097642
PMCID: PMC3878433  PMID: 19019891
Association studies; systemic lupus erythematosus; STAT4 transcription factor; Interferon regulatory factor; genetic predisposition to disease
15.  Replication of the TNFSF4 (OX40L) Promoter Region Association with Systemic Lupus Erythematosus 
Genes and immunity  2008;10(3):10.1038/gene.2008.95.
The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a co-stimulatory molecule involved in T-cell activation. A recent study demonstrated the association ofTNFSF4 haplotypes located in the upstream region with risk for- or protection from Systemic Lupus Erythematosus (SLE) (Graham et al, 2008). In order to replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain, and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled OR=1.39, p=0.0009) and rs12039904 (pooled OR=1.38, p=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This is the first replication study that confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.
doi:10.1038/gene.2008.95
PMCID: PMC3867640  PMID: 19092840
Systemic lupus erythematosus; TNFSF4; OX40L; genetic association study
16.  Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(11):3695-3705.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1002/art.34642
PMCID: PMC3485412  PMID: 22833143
17.  Impact of Genetic Ancestry and Socio-Demographic Status on the Clinical Expression of Systemic Lupus Erythematosus in Amerindian-European Populations 
Arthritis and rheumatism  2012;64(11):3687-3694.
Objective
Amerindian-Europeans, Asians and African-Americans have an excess morbidity from SLE and higher prevalence of lupus nephritis than Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and socio-demographic characteristics and clinical features in a large cohort of Amerindian-European SLE patients.
Methods
A total of 2116 SLE patients of Amerindian-European origin and 4001 SLE patients of European descent with clinical data were used in the study. Genotyping of 253 continental ancestry informative markers was performed on the Illumina platform. The STRUCTURE and ADMIXTURE software were used to determine genetic ancestry of each individual. Correlation between ancestry and socio-demographic and clinical data were analyzed using logistic regression.
Results
The average Amerindian genetic ancestry of 2116 SLE patients was 40.7%. There was an increased risk of having renal involvement (P<0.0001, OR= 3.50 95%CI 2.63-4.63) and an early age of onset with the presence of Amerindian genetic ancestry (P<0.0001). Amerindian ancestry protected against photosensitivity (P<0.0001, OR= 0.58 95%CI 0.44-0.76), oral ulcers (P<0.0001, OR= 0.55 95%CI 0.42-0.72), and serositis (P<0.0001, OR= 0.56 95%CI 0.41-0.75) after adjustment by age, gender and age of onset. However, gender and age of onset had stronger effects on malar rash, discoid rash, arthritis and neurological involvement than genetic ancestry.
Conclusion
In general, genetic Amerindian ancestry correlates with lower socio-demographic status and increases the risk for developing renal involvement and SLE at an earlier age of onset.
doi:10.1002/art.34650
PMCID: PMC3485439  PMID: 22886787
18.  Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression 
PLoS Genetics  2013;9(10):e1003870.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Author Summary
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
doi:10.1371/journal.pgen.1003870
PMCID: PMC3794920  PMID: 24130510
19.  The Impact of Rural Residency on the Expression and Outcome of Systemic Lupus Erythematosus: Data From a Multiethnic Latin American Cohort 
Lupus  2012;21(13):1397-1404.
Objective
To examine the role of place of residency in the expression and outcomes of SLE in a multi-ethnic Latin American cohort.
Patients and Methods
SLE patients (<2 years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory, and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses.
Results
122 (8.6%) of 1426 patients were rural residents. Their median age (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and a lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses, and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in both, rural and urban patients.. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06–2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00–3.11).
Conclusions
Rural residency associates with Mestizo ethnicity, lower socioeconomic status, and renal disease occurrence. It also plays a role on disease activity at diagnosis and kidney involvement but not on the other end-points examined.
doi:10.1177/0961203312458465
PMCID: PMC3758687  PMID: 22941567
20.  PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes 
PLoS ONE  2013;8(8):e69404.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
doi:10.1371/journal.pone.0069404
PMCID: PMC3737240  PMID: 23950893
21.  Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4 
PLoS Genetics  2013;9(7):e1003554.
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10−34, OR = 1.43[1.26–1.60]) and rs1234317-T (P = 1.16×10−28, OR = 1.38[1.24–1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
Author Summary
Systemic lupus erythematosus (SLE/lupus) is a complex disease in which the body's immune cells cause inflammation in one or more systems to cause the associated morbidity. Hormones, the environment and genes are all causal contributors to SLE and over the past several years the genetic component of SLE has been firmly established. Several genes which are regulators of the immune system are associated with disease risk. We have established one of these, the tumour-necrosis family superfamily member 4 (TNFSF4) gene, as a lupus susceptibility gene in Northern Europeans. A major obstacle in pinpointing the marker(s) at TNFSF4 which best explain the risk of SLE has been the strong correlation (linkage disequilibrium, LD) between adjacent markers across the TNFSF4 region in this population. To address this, we have typed polymorphisms in several populations in addition to the European groups. The mixed ancestry of these populations gives a different LD pattern than that found in Europeans, presenting a method of pinpointing the section of the TNFSF4 region which results in SLE susceptibility. The Non-European populations have allowed identification of a polymorphism likely to regulate expression of TNFSF4 to increase susceptibility to SLE.
doi:10.1371/journal.pgen.1003554
PMCID: PMC3715547  PMID: 23874208
22.  Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort 
Rheumatology (Oxford, England)  2012;51(7):1293-1298.
Objective. To examine the role of ethnicity and the use of anti-malarials (protective) on lupus renal disease.
Methods. A nested case–control study (1:2 proportion, n = 265 and 530) within GLADEL's (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort was carried out. The end-point was ACR renal criterion development after diagnosis. Cases and controls were matched for follow-up time (end-point or a comparable time, respectively). Renal disease predictors were examined by univariable and multivariable analyses. Additional analyses were done to determine if the protective effect of anti-malarials persisted after adjusting for intake-associated confounders.
Results. Of the cases, 233 (87.9%) were women; their mean (s.d.) age at diagnosis was 28.0 (11.9) years and their median (Q3–Q1 interquartile range) follow-up time for cases and controls was 8.3 months (Q3–Q1: 23.5); 56.6% of the cases and 74.3% of the controls were anti-malarial users. Mestizo ethnicity [odds ratio (OR) 1.72, 95% CI 1.19, 2.48] and hypertension (OR 2.26, 95% CI 1.38, 3.70) were independently associated with a higher risk of renal disease, whereas anti-malarial use (OR 0.39, 95% CI 0.26, 0.58), older age at disease onset (OR 0.98, 95% CI 0.96, 0.99) and female gender (OR 0.56, 95% CI 0.32, 0.99) were negatively associated with such occurrence. After adjusting for variables associated with their intake, the protective effect of anti-malarials on renal disease occurrence persisted (OR 0.38, 95% CI 0.25, 0.58).
Conclusion. Mestizo patients are at increased risk of developing renal disease, whereas anti-malarial use protects patients from such an occurrence.
doi:10.1093/rheumatology/ker514
PMCID: PMC3380245  PMID: 22389125
LN; renal disease; SLE; anti-malarials; HCQ; chloroquine; ethnicity; race; mestizo; Latin America
23.  Evaluation of TRAF6 in a Large Multi-Ancestral Lupus Cohort 
Arthritis and Rheumatism  2012;64(6):1960-1969.
Objective
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Methods
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Results
Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Conclusion
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
doi:10.1002/art.34361
PMCID: PMC3380425  PMID: 22231568
TRAF6; polymorphism; systemic lupus erythematosus
24.  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.
Objectives
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.
Methods
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.
Results
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).
Conclusion
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
doi:10.1136/annrheumdis-2012-201851
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
25.  MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus 
PLoS Genetics  2013;9(2):e1003336.
We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Author Summary
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease contributed to by excessive innate immune activation involving toll-like receptors (TLRs, particularly TLR7/8/9) and type I interferon (IFN) signaling pathways. TLR7 responds against RNA–containing nuclear antigens and activates IFN-α pathway, playing a pivotal role in the development of SLE. While a genomic duplication of Tlr7 promotes lupus-like disease in the Y-linked autoimmune accelerator (Yaa) murine model, the lack of common copy number variations at TLR7 in humans led us to identify a functional single nucleotide polymorphism (SNP), rs3853839 at 3′ UTR of the TLR7 gene, associated with SLE susceptibility in Eastern Asians. In this study, we fine-mapped the TLR7-TLR8 region and confirmed rs3853839 exhibiting the strongest association with SLE in European Americans, African Americans, and Amerindian/Hispanics. Individuals carrying the risk G allele of rs3853839 exhibited increased TLR7 expression at the both mRNA and protein level and decreased transcript degradation. MicroRNA-3148 (miR-3148) downregulated the expression of non-risk allele (C) containing transcripts preferentially, suggesting a likely mechanism for increased TLR7 levels in risk-allele carriers. This trans-ancestral mapping provides evidence for the global association with SLE risk at rs3853839, which resides in a microRNA–gene regulatory site affecting TLR7 expression.
doi:10.1371/journal.pgen.1003336
PMCID: PMC3585142  PMID: 23468661

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