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1.  Interaction between glutathione and Apoptosis in Systemic Lupus Erythematosus 
Autoimmunity reviews  2012;12(7):741-751.
Systemic lupus erythematosus (SLE) is characterized by imbalance redox state and increased apoptosis. The activation, proliferation and cell death of lymphocytes are dependent on intracellular levels of glutathione and controlled production of reactive oxygen species (ROS). Changes in the intracellular redox environment of cells, through oxygen-derived free radical production known as oxidative stress, have been reported to be critical for cellular immune dysfunction, activation of apoptotic enzymes and apoptosis. The shift in the cellular GSH-to-GSSG redox balance in favor of the oxidized species, GSSG, constitutes an important signal that can decide the fate of the abnormal apoptosis in the disease. The current review will focus on four main areas: (1) general description of oxidative stress markers in SLE, (2) alteration of redox state and complication of disease (3) role of redox mechanisms in the initiation and execution phases of apoptosis, and (4) intracellular glutathione and its checkpoints with lymphocyte apoptosis represent novel targets for pharmacological intervention in SLE.
doi:10.1016/j.autrev.2012.12.007
PMCID: PMC3625500  PMID: 23279845
Reactive oxygen species; redox state; apoptosis; glutathione; systemic lupus erythematosus (SLE)
2.  Evaluation of SLE Susceptibility Genes in Malaysians 
Autoimmune Diseases  2014;2014:305436.
Systemic Lupus Erythematosus (SLE) is a clinically heterogeneous autoimmune disease with strong genetic and environmental components. Our objective was to replicate 25 recently identified SLE susceptibility genes in two distinct populations (Chinese (CH) and Malays (MA)) from Malaysia. We genotyped 347 SLE cases and 356 controls (CH and MA) using the ImmunoChip array and performed an admixture corrected case-control association analysis. Associated genes were grouped into five immune-related pathways. While CH were largely homogenous, MA had three ancestry components (average 82.3% Asian, 14.5% European, and 3.2% African). Ancestry proportions were significantly different between cases and controls in MA. We identified 22 genes with at least one associated SNP (P < 0.05). The strongest signal was at HLA-DRA (PMeta = 9.96 × 10−9; PCH = 6.57 × 10−8, PMA = 6.73 × 10−3); the strongest non-HLA signal occurred at STAT4 (PMeta = 1.67 × 10−7; PCH = 2.88 × 10−6, PMA = 2.99 × 10−3). Most of these genes were associated with B- and T-cell function and signaling pathways. Our exploratory study using high-density fine-mapping suggests that most of the established SLE genes are also associated in the major ethnicities of Malaysia. However, these novel SNPs showed stronger association in these Asian populations than with the SNPs reported in previous studies.
doi:10.1155/2014/305436
PMCID: PMC3948475  PMID: 24696779
3.  Gene Network Analysis of Small Molecules with Autoimmune Disease Associated Genes Predicts a Novel Strategy for Drug Efficacy 
Autoimmunity reviews  2012;12(4):510-522.
Numerous genes/SNPs in autoimmune diseases (ADs) are identified through genome-wide association studies (GWAS) and likely to contribute in developing autoimmune phenotypes. Constructions of biologically meaningful pathways are necessary to determine how these genes interact each other and with other small molecules to develop various complex ADs phenotypes prior to beginning time-consuming rigorous experimentation. We have constructed biological pathways with genetically identified genes leading to shared ADs phenotypes. Various environmental and endogenous factors interact with these ADs associated genes suggesting their critical role in developing diseases and further association studies could be designed for assessing the role of these factors with risk allele in a specific gene. Additionally, existing drugs that have been used long before the identification of these genetically associated genes also interact with these newly associated genes. Thus advanced therapeutic strategies could be designed by grouping patients with risk allele(s) in particular genes that directly or closely interact with the specified drugs. This drug-susceptible gene network will not only increase our understanding about the additional molecular basis for effectiveness against these diseases but also which drug could be more effective for those patients carrying risk allele(s) in that gene. Additionally, we have also identified several interlinking genes in the pathways that could be used for designing future association studies.
doi:10.1016/j.autrev.2012.09.001
PMCID: PMC3577986  PMID: 23000205
4.  Drug risk factors associated with a sustained outbreak of Clostridium difficile diarrhea in a teaching hospital 
A case-control study was undertaken to identify and quantify antimicrobial and nonantimicrobial drug risk factors associated with a sustained outbreak of Clostridium difficile diarrhea on two medical (teaching and nonteaching) units and an oncology unit. In total, 80 cases associated with an endemic clone of toxigenic C difficile were compared with controls. Eighty controls were selected from a group of 290 controls randomly chosen from the outbreak period. The controls were matched to cases according to age, admitting diagnosis and unit of admission. Seventy (88%) patients in the case group received at least one antibiotic before diarrhea, compared with 37 (46%) patients in the control group. Major risk factors implicated in the development of C difficile diarrhea in hospitalized patients were the following antimicrobial agents: ceftazidime (adjusted odds ratio [aor]=26.01, 95% ci 5.67 to 119.19, P=0.0001); cefuroxime (aor=5.17, ci 1.86 to 14.36, P=0.005); ciprofloxacin (aor=3.81, ci 1.05 to 13.79, P=0.04); and clindamycin (aor=15.16, ci 2.93 to 78.44, P=0.004). This is the first time that the use of ciprofloxacin has been linked to the development of C difficile diarrhea. Use of gastrointestinal drugs (ranitidine, famotidine, cimetidine, omeprazole and sucralfate) was also an added risk (aor=3.20, ci 1.39 to 7.34, P=0.01); however, antineoplastic therapy was not significant (P<0.53). Recognition of the specific high risk drugs may spur more restricted use of these agents, which may help in controlling C difficile diarrhea in hospitalized patients.
PMCID: PMC3250863  PMID: 22346513
Clostridium difficile diarrhea; Logistic regression; Risk factors; Selected drugs
5.  Gene–Gene Interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(1):222-231.
Objective
Although the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene–gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene–gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways.
Methods
The SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2 × 2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation.
Results
Single-marker analysis validated the association of BLK rs2736340 (P = 4.25 × 10–6) as well as TNFSF4 rs2205960 (P = 2.82 × 10–5) and TNFAIP3 rs5029939 (P = 1.92 × 10–3) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P = 6.57 × 10–4). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P = 2.18 × 10–3) and Caucasians (P = 2.86 × 10–4). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased.
Conclusion
The results of this study provide evidence of the possible gene–gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.
doi:10.1002/art.33318
PMCID: PMC3994469  PMID: 21905002
6.  Oxidative stress and its biomarkers in systemic lupus erythematosus 
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.
doi:10.1186/1423-0127-21-23
PMCID: PMC3995422  PMID: 24636579
Oxidative stress; Biomarkers; Antioxidant therapy; Systemic lupus erythematosus
7.  Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus 
European Journal of Human Genetics  2012;20(10):1032-1036.
Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus.
doi:10.1038/ejhg.2012.60
PMCID: PMC3449080  PMID: 22490987
nystagmus; FRMD7 gene; mutation analysis
8.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
9.  Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases 
Autoimmunity Reviews  2011;11(4):276-280.
Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (pmeta=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.
doi:10.1016/j.autrev.2011.07.007
PMCID: PMC3224188  PMID: 21840425
ITGAM; autoimmune diseases; genetic susceptibility
10.  Multiple Autoantibodies Display Association with Lymphopenia, Proteinuria, and Cellular Casts in a Large, Ethnically Diverse SLE Patient Cohort 
Autoimmune Diseases  2012;2012:819634.
Purpose. This study evaluates high-throughput autoantibody screening and determines associated systemic lupus erythematosus (SLE) clinical features in a large lupus cohort. Methods. Clinical and demographic information, along with serum samples, were obtained from each SLE study participant after appropriate informed consent. Serum samples were screened for 10 distinct SLE autoantibody specificities and examined for association with SLE ACR criteria and subcriteria using conditional logistic regression analysis. Results. In European-American SLE patients, autoantibodies against 52 kD Ro and RNP 68 are independently enriched in patients with lymphopenia, anti-La, and anti-ribosomal P are increased in patients with malar rash, and anti-dsDNA and anti-Sm are enriched in patients with proteinuria. In African-American SLE patients, cellular casts associate with autoantibodies against dsDNA, Sm, and Sm/nRNP. Conclusion. Using a high-throughput, bead-based method of autoantibody detection, anti-dsDNA is significantly enriched in patienets with SLE ACR renal criteria as has been previously described. However, lymphopenia is associated with several distinct autoantibody specificities. These findings offer meaningful information to allow clinicians and clinical investigators to understand which autoantibodies correlate with select SLE clinical manifestations across common racial groups using this novel methodology which is expanding in clinical use.
doi:10.1155/2012/819634
PMCID: PMC3439936  PMID: 22988489
11.  Evaluation of 19 Autoimmune Disease-associated Loci with Rheumatoid Arthritis in a Colombian Population: Evidence for Replication and Gene-Gene Interaction 
The Journal of rheumatology  2011;38(9):1866-1870.
Objective
Recent studies have identified several common genes associated with multiple autoimmune diseases that support the hypothesis of the presence of shared or general autoimmunity genes. However, most of this work has been performed in populations of white origin. The main objectives of this study are to replicate the genotype-phenotype correlation between 19 such variants and rheumatoid arthritis (RA), and to evaluate gene-gene interactions between these genes in individuals from an ethnically homogenous nonwhite Colombian population.
Methods
Nineteen single-nucleotide polymorphisms (SNP) from 16 genes/loci were genotyped in 353 RA cases and 368 controls. For each SNP, allelic and genotype-based association tests were applied to evaluate genotype-phenotype correlation. Permutation-based tests were used to validate the statistical significance. Gene-gene interactions were assessed by logistic regression.
Results
We replicated the genetic association with rs13277113 (p = 0.0009, OR 1.46) and rs2736340 (p = 0.0001, OR 1.63) from C8orf13-BLK (8p23.1, associated with RA and systemic lupus erythematosus), and rs763361 (p = 0.03) from CD226 (18q22.3, associated with multiple sclerosis and type 1 diabetes) in the Colombian population. The population-attributable risks were estimated as 27%, 34%, and 16% for rs13277113, rs2736340, and rs763361, respectively. We also detected evidence for gene-gene interaction between SNP in MMEL1 (rs3890745) and C80rf13-BLK (rs13277113; p = 0.0002).
Conclusion
Our results demonstrate that the IL2/IL21 region, C8orf13-BLK, and CD226 influence RA in Colombians, and RA shares some of the pathogenic mechanisms associated with other autoimmune diseases.
doi:10.3899/jrheum.110199
PMCID: PMC3170719  PMID: 21765104
RHEUMATOID ARTHRITIS; LATIN AMERICA; GENETIC ASSOCIATION; GENE-GENE INTERACTION
12.  Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing 
Myopia affects more people worldwide than any other chronic condition, and it is increasing in all populations across the globe. It affects ∼25% of the U.S. general population between the ages of 12 and 54 years. The present study is a genetic investigation of X-linked high-grade myopia that maps to Xq28.
Purpose.
Myopia is a common vision problem affecting almost one third of the world's population. It can occur as an isolated genetic condition or be associated with other anomalies and/or syndromes. Seventeen myopia loci have been identified on various chromosomes; however, no specific gene mutations have yet been identified.
Methods.
Two large multigeneration Asian Indian pedigrees (UR006 and UR077) with isolated, nonsyndromic myopia were studied, in which the condition appeared to segregate as an X-linked recessive trait (MYP1; MIM 310460). The degree of myopia was variable in both families, ranging from −6 to −23 D (mean, –8.48 D) with the majority >7.0 D. To map the myopia locus in these families, polymorphic microsatellite markers covering the entire X chromosome were used in linkage analyses performed on 42 genomic DNA samples (13 affected and 29 normal) from both families.
Results.
Marker DXYS154, which is located within the pseudoautosomal region in distal Xq28 (PAR2; pseudoautosomal region 2), gave a combined maximum LOD score of 5.3 at θ = 0 under an autosomal recessive model. Other markers in the region (near but not within the PAR2 region) that showed no recombination with the phenotype in both the families included DXS1108, DXS8087, and F8i13.
Conclusions.
Observation of recombination in family UR006 refined the disease locus to a ∼1.25-Mb region flanked by the proximal marker DXS1073 and distal marker DXYS154. Mutation search in exons and splice junctions of candidate genes CTAG2, GAB3, MPP1, F8Bver, FUNDC2, VBP1, RAB39B, CLIC2, TMLHE, SYBL, IL9R, SPRY3, and CXYorf1 did not detect a pathogenic or predisposing variant.
doi:10.1167/iovs.10-6815
PMCID: PMC3176007  PMID: 21357393
13.  Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients 
Annals of the rheumatic diseases  2010;70(1):151-156.
Background
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.
Objectives
To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.
Methods
The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.
Results
Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.
Conclusions
The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
doi:10.1136/ard.2010.141697
PMCID: PMC3034281  PMID: 20881011
14.  Genome-Wide Association Scan of Dupuytren's Disease 
The Journal of hand surgery  2010;35(12):2039-2045.
Purpose
Dupuytren's disease (DD) has strong genetic component that is suggested by population studies and family clustering. Genetic studies have yet to identify the gene(s) involved in DD. The purpose of this study was to identify regions of the entire genome (Chromosome 1 – 23) associated with the disease by performing a genome-wide association scan (GWAS) on DD patients and controls.
Methods
Genomic DNA (gDNA) was isolated from saliva collected from 40 unrelated DD patients and 40 unaffected controls. The genotyping was conducted using CytoSNP™ - Infinium® HD Ultra genotyping assay on the Illumina platform. The single nucleotides polymorphism (SNP) genotyping data was analyzed using both log regression and mapping by admixture linkage disequilibrium (MALD) analysis methods.
Results
The single SNP analysis revealed significant association in chromosomes 1, 3, 4, 5, 6, 11, 16, 17 and 23 regions. MALD analysis showed ancestry-associated regions in chromosomes 2, 6, 8, 11, 16 and 20, which may harbor DD susceptibility genes. Both analyses methods revealed loci association in chromosomes 6, 11 and 16.
Conclusions
Our data suggest that chromosome 6, 11 and 16 may contain the genes for DD and that multiple genes may be involved in DD. Future genetic studies on DD should focus on these areas of the genome.
doi:10.1016/j.jhsa.2010.08.008
PMCID: PMC2998563  PMID: 20971583
Dupuytren's disease; Dupuytren's disease genetics
15.  Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases 
Rheumatology (Oxford, England)  2010;49(7):1239-1244.
Objectives. Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations.
Methods. To replicate this association in non-European populations, we evaluated case–control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using χ2-test. For each association, odds ratio (OR) and 95% CI were calculated.
Results. We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 × 10−9 (OR = 1.14), respectively.
Conclusions. Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.
doi:10.1093/rheumatology/kep470
PMCID: PMC2909799  PMID: 20338887
CD226; Autoimmunity; Latin-America; Asia
16.  Confirmation of an Association Between rs6822844 at the IL2–IL21 Region and Multiple Autoimmune Diseases 
Arthritis and rheumatism  2010;62(2):323-329.
Objective
Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2–IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies.
Methods
We evaluated case–control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies.
Results
We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (FST = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (Pmeta = 3.61 × 10–6), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (Pmeta = 3.48 × 10–12), type 1 DM (Pmeta = 5.33 × 10–5), and CD (Pmeta = 5.30 × 10–3). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; Pmeta = 2.61 × 10–25, odds ratio 0.73 [95% confidence interval 0.69–0.78]).
Conclusion
Our results indicate that there is an association between rs6822844 and multiple auto-immune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.
doi:10.1002/art.27222
PMCID: PMC3028384  PMID: 20112382
17.  Identification of novel suggestive loci for high-grade myopia in Polish families 
Molecular Vision  2011;17:2028-2039.
Purpose
Myopia is the most common human eye disorder with complex genetic and environmental causes. To date, several myopia loci have been identified in families of different geographic origin. However, no causative gene(s) have yet been identified. The aim of this study was the characterization of Polish families with high-grade myopia, including genetic analysis.
Methods
Forty-two multiplex Polish families with non–syndromic high-grade myopia participated in the study. All family members underwent detailed ophthalmic examination and high-grade myopia was defined as ≤-6.0 diopters (D) based on the spherical refractive error. A genome-wide single nucleotide polymorphism (SNP)-based high-density linkage scan was performed using Affymetrix Human SNP Array 6.0 on a selected family (HM-32) with multiple affected individuals.
Results
Nonparametric linkage analysis identified three novel loci in family HM-32 at chromosome 7p22.1–7p21.1 ([NPL] 8.26; p=0.006), chromosome 7p12.3–7p11.2 ([NPL] 8.23; p=0.006), and chromosome 12p12.3–12p12.1 ([NPL] 8.02; p=0.006), respectively. The effect of linkage disequilibrium on linkage due to dense SNP map was addressed by systematically pruning SNPs from the linkage panel.
Conclusions
Haplotype analysis with informative crossovers in affected individuals defined a 12.2; 10.9; and 9.5 Mb genomic regions for high-grade myopia spanned between SNP markers rs11977885/rs10950639, rs11770622/rs9719399, and rs4763417/rs10842388 on chromosomes 7p22.1–7p21.1, 7p12.3–7p11.2, and 12p12.3–12p12.1, respectively.
PMCID: PMC3154124  PMID: 21850178
18.  Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma 
Background
There is a paucity of information about the molecular perturbations involved in MPM tumor formation. We previously reported that EGFR-TK mutations in MPM were predictive of achieving optimal surgical cytoreduction, but the status of EGFR pathway activation potential of these mutations was not known. Here we present the mutant EGFR activating potential and the matured survival data of the EGFR mutant(mut+) relative to wild type EGFR(mut-) mesothelioma.
Methods
Twenty-nine patients were evaluated and their tumors were probed for mutations in the catalytic TK-domain. Twenty-five patients were treated with cytoreductive surgery and complete clinical data was available for comparison of the mut+ and mut- groups. A COS-7 cell expression model was used to determine mutation activating profiles and response to erlotinib.
Results
Functional mutations were found in 31%(9/29) of patients; 7 of these mutations were novel and another was the L858R mutation. All missense mutations were found to be activating mutations and responsive to erlotinib. Of the 25 patients managed surgically, there were 7 mut+ and 18 mut-. Two of 7 (29%) mut+ developed progressive disease and died with a median follow-up time of 22 months; while 13/18 (72%) mut- developed progressive disease and 10/18 (56%) died with median TTP of 12 months and median survival of 14 months.
Conclusions
The novel EGFR mutations identified are activating mutations responsive to erlotinib. The mut+ subset have a 'relative' improved outcome. Erlotinib may have a role in MPM and exploration for mutations in a larger patient cohort is warranted.
doi:10.1186/1477-7819-8-88
PMCID: PMC2970593  PMID: 20942962
19.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Objective
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Methods
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
Results
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Conclusion
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
doi:10.1002/art.24387
PMCID: PMC2776081  PMID: 19333953
20.  Admixture in Hispanic-Americans: Its impact on ITGAM association and implications for admixture mapping in SLE 
Genes and immunity  2009;10(5):539-545.
Systemic Lupus Erythematosus (SLE) disproportionately affects minorities, such as Hispanic-Americans. Prevalence of SLE is 3–5 times higher in Hispanic Americans (HA) than European derived populations, and have more active disease at the time of diagnosis, with more serious organ system involvement. HA is an admixed population, it is possible that there is an effect of admixture on the relative risk of disease. This admixture can create substantial increase of linkage disequilibrium (LD) in both magnitude and range, which can provide a unique opportunity for admixture mapping. Main objectives of this study are to (a) estimate hidden population structure in HA individuals; (b) estimate individual ancestry proportions and its impact on SLE risk; (c) assess impact of admixture on ITGAM association, a recently identified SLE susceptibility gene; and (d) estimate power of admixture mapping in HA. Our dataset contained 1,125 individuals, of whom 884 (657 SLE cases and 227 controls) were self classified as HA. Using 107 unlinked ancestry informative markers (AIMs) we estimated hidden population structure and individual ancestry in HA. Out of 5,671 possible pair-wise LD, 54% were statistically significant, indicating recent population admixture. The best fitted model for HA was a four population model with average ancestry of European (48%), American-Indian (40%), African (8%) and a fourth population (4%) with unknown ancestry. We also identified significant higher risk associated with American-Indian ancestry (OR=4.84, P=0.0001, 95%CI=2.14—10.95) on overall SLE. We showed that ITGAM is associated as a risk factor for SLE (OR= 2.06, P=8.74×10−5, 95%CI=1.44–2.97). This association is not affected by population substructure or admixture. We have demonstrated that HA have great potential and are an 3 appropriate population for admixture mapping. As expected, the case-only design is more powerful than case-control design, for any given admixture proportion or ancestry risk ratio.
doi:10.1038/gene.2009.30
PMCID: PMC2714406  PMID: 19387459
SLE; Association; Hispanics; Admixture mapping; Hispanic-American; Population structure
21.  Replication of recently identified associated single-nucleotide polymorphisms from six autoimmune diseases in Genetic Analysis Workshop 16 rheumatoid arthritis data 
BMC Proceedings  2009;3(Suppl 7):S31.
Many autoimmune diseases share similar underlying pathology and have a tendency to cluster within families, giving rise to the concept of shared susceptibility genes among them. In the Genetic Analysis Workshop 16 rheumatoid arthritis (RA) data we sought to replicate the genetic association between single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies (GWAS) on RA and five other autoimmune diseases. We identified 164 significantly associated non-HLA SNPs (p < 10-5) from 16 GWAS and 13 candidate gene studies on six different autoimmune diseases, including RA, systemic lupus erythematosus, type 1 diabetes, Crohn disease, multiple sclerosis, and celiac disease. Using both direct and imputation-based association test, we replicated 16 shared susceptibility regions involving RA and at least one of the other autoimmune diseases. We also identified hidden population structure within cases and controls in Genetic Analysis Workshop 16 RA data and assessed the effect of population structure on the shared autoimmunity regions. Because multiple autoimmune diseases share common genetic origin, these could be areas of immense interest for further genetic and clinical association studies.
PMCID: PMC2795929  PMID: 20018022
22.  A genome-wide ordered-subset linkage analysis for rheumatoid arthritis 
BMC Proceedings  2007;1(Suppl 1):S101.
Rheumatoid arthritis (RA) is a chronic, complex autoimmune inflammatory disorder with poorly known etiology. Approximately 1% of the adult population is afflicted with RA. Linkage analysis of RA can be complicated by the presence of phenotypic and genetic heterogeneity. It is shown that the ordered-subset analysis (OSA) technique reduces heterogeneity, increases statistical power for detecting linkage and helps to define the most informative data set for follow-up analysis. We applied OSA to the family data from the North American Rheumatoid Arthritis Consortium study as part of the Genetic Analysis Workshop 15 (GAW15). We have incorporated two continuous covariates, 'age of onset' and 'anti-CCP level' (anti-cyclic citrinullated peptide), into our genome-wide ordered-subset linkage analysis using 809 Illumina SNP markers in 5713 individuals from 606 Caucasian RA families. A statistically significant increase in nonparametric linkage (NPL) scores was observed with covariate 'age of onset' in chromosomes 4 (p = 0.000003) and 9 (p = 0.002). With the covariate 'anti-CCP level', statistically significant increases in NPL scores were observed in chromosomes 2 (p = 0.0001), 18 (p = 0.00007), and 19 (p = 0.0003). Once we identified the linked genomic region, we then attempted to identify the best plausible parametric model at that linked locus. Our results show significant improvement in evidence for linkage and demonstrate that OSA is a useful technique to detect linkage under heterogeneity.
PMCID: PMC2367502  PMID: 18466441
23.  Current status of lupus genetics 
Over the past 40 years more than 100 genetic risk factors have been defined in systemic lupus erythematosus through a combination of case studies, linkage analyses of multiplex families, and case-control analyses of single genes. Multiple investigators have examined patient cohorts gathered from around the world, and although we doubt that all of the reported associations will be replicated, we have probably already discovered many of the genes that are important in lupus pathogenesis, including those encoding human leukocyte antigen-DR, Fcγ receptor 3A, protein tyrosine phosphatase nonreceptor 22, cytotoxic T lymphocyte associated antigen 4, and mannose-binding lectin. In this review we will present what is known, what is disputed, and what remains to be discovered in the world of lupus genetics.
doi:10.1186/ar2176
PMCID: PMC2206359  PMID: 17509159
24.  Antimicrobial activity of ceftriaxone compared with cefotaxime in the presence of serum albumin 
The effect of serum albumin on the antimicrobial activity of ceftriaxone, cefotaxime, and a 1:1 ratio of cefotaxime and its desacetyl metabolite against nonpseudomonal Gram-negative bacilli was determined. Antimicrobial activity of drugs was evaluated by measuring minimum inhibitory (mic) and bactericidal (mbc) concentrations in broth with and without human serum albumin. The analysis of logarithmically transformed mean mics and mbcs showed that there was a highly significant interaction between drug and serum albumin (P<0.0001). The inhibitory and bactericidal activities were greatest for cefotaxime followed by cefotaxime/desacetylcefotaxime and ceftriaxone (P<0.01). Time-kill kinetics demonstrated that ceftriaxone was less bactericidal than cefotaxime in broth with albumin. On the basis of these results it was concluded that the in vitro antimicrobial activity of ceftriaxone compared with that of cefotaxime was significantly diminished in the presence of serum albumin.
PMCID: PMC3327896  PMID: 22514377
Antimicrobial activity; Cefotaxime; Ceftriaxone; Serum albumin
25.  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

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