Genome, epigenome and transcriptome analyses of a pair of monozygotic twins discordant for systemic lupus erythematosus.

Hum Immunol. 2013 Feb;74(2):170-5

Authors: Furukawa H, Oka S, Matsui T, Hashimoto A, Arinuma Y, Komiya A, Fukui N, Tsuchiya N, Tohma S

Abstract
Information to distinguish genetic and environmental factors in the pathogenesis of multifactorial diseases can be obtained by investigation of disease development in monozygotic twins. Recent reports have shown that there are genomic and epigenomic differences between monozygotic twins. Genomic/epigenomic and gene expression analyses were performed in monozygotic twins discordant for systemic lupus erythematosus (SLE) to find the genes playing important roles in SLE pathogenesis. Single nucleotide polymorphism (SNP) and copy number variation (CNV) typing, CpG methylation and gene expression were analyzed. The discordances in SNPs and CNVs were not confirmed. Both CpG methylation and gene expression levels were different for 10 genes. There were no genomic differences between monozygotic twins discordant for SLE, but epigenomic and gene expression differences were detected. These findings provide information for better understanding of SLE pathogenesis.

PMID: 23200755 [PubMed - indexed for MEDLINE]

Indoleamine 2,3 dioxygenase gene polymorphisms correlate with CD8+ Treg impairment in systemic sclerosis.

Hum Immunol. 2013 Feb;74(2):166-9

Authors: Tardito S, Negrini S, Conteduca G, Ferrera F, Parodi A, Battaglia F, Kalli F, Fenoglio D, Cutolo M, Filaci G

Abstract
Systemic sclerosis (SSc) is characterized by tissue fibrosis, vasculopathy and autoimmunity. Indoleamine 2,3 dioxygenase (IDO) plays a pivotal role in immunological tolerance modulating regulatory T cell (Treg) generation and function. Single nucleotide polymorphisms (SNPs) of IDO gene could impact on Treg function and predispose to autoimmunity. Here, the existence of an association between specific IDO SNPs and SSc was analyzed. Five specific SNPs in IDO gene were searched in 31 SSc patients and 37 healthy controls by gene sequencing or restriction fragment length polymorphism. The function of both CD4+CD25+ and CD8+ Treg from SSc patients was analyzed by proliferation suppression assay. SNP rs7820268 was statistically more frequent in SSc patients than in controls. Notably, SSc patients bearing the T allelic variant of the rs7820268 SNP showed impaired CD8+ Treg function. Our unprecedented data show that a specific IDO gene SNP is associated with an autoimmune disease such as SSc.

PMID: 23200754 [PubMed - indexed for MEDLINE]

Variation in selenoenzyme genes and prostate cancer risk and survival.

Prostate. 2013 May;73(7):734-42

Authors: Geybels MS, Hutter CM, Kwon EM, Ostrander EA, Fu R, Feng Z, Stanford JL, Peters U

Abstract
BACKGROUND: While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival.
METHODS: We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively.
RESULTS: Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44-0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4, and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons.
CONCLUSIONS: We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.

PMID: 23143801 [PubMed - indexed for MEDLINE]

Association analysis of toll-like receptor 4 polymorphisms in Japanese primary biliary cirrhosis.

Hum Immunol. 2013 Feb;74(2):219-22

Authors: Morita S, Joshita S, Umemura T, Katsuyama Y, Kimura T, Komatsu M, Matsumoto A, Yoshizawa K, Kamijo A, Yamamura N, Tanaka E, Ota M

Abstract
Primary biliary cirrhosis (PBC) is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often result in liver failure. Toll-like receptor (TLR) 4 recognizes lipopolysaccharides of Gram-negative bacteria. Infectious agents have been suspected to play a crucial role in PBC pathogenesis since TLR4 expression was found in bile duct epithelial cells and periportal hepatocytes in liver tissues of PBC. To assess the potential contribution of TLR4 SNPs to the development of this disease, we genotyped five SNPs in TLR4 in 261 PBC patients and 359 controls using a TaqMan assay. No significant positive associations with either PBC susceptibility or progression were uncovered. These results indicate that TLR4 polymorphisms do not play a prominent role in the development of PBC in Japanese patients.

PMID: 23142582 [PubMed - indexed for MEDLINE]

Evaluation of IL17A expression and of IL17A, IL17F and IL23R gene polymorphisms in Brazilian individuals with periodontitis.

Hum Immunol. 2013 Feb;74(2):207-14

Authors: Saraiva AM, Alves e Silva MR, Correia Silva Jde F, da Costa JE, Gollob KJ, Dutra WO, Moreira PR

Abstract
The IL23/Th17 axis plays an important role in the pathogenesis of cell-mediated tissue damage caused either by autoimmunity or immune responses against bacterial infection. Single nucleotide polymorphisms in the IL17A, IL17F and IL23R genes have been associated with several inflammatory diseases. However, these polymorphisms have not yet been studied in periodontitis. The aim of present study was to evaluate the expression of IL17A and occurrence of the IL17A (rs2275913), IL17F (rs763780) and IL23R (rs11209026) gene polymorphisms in different clinical forms or severity of periodontitis in a sample of Brazilian individuals. Peripheral blood was obtained from 30 non-smoker individuals and analyzed by flow cytometry to determine IL-17 expression. Genomic DNA was obtained from oral swabs in 180 individuals and analyzed by Real-time PCR. The study group was composed by individuals without periodontitis (control), with aggressive periodontitis (AP) and with chronic periodontitis (CP). Higher frequency of IL17A+CD4+ T cells was observed in control group. The A+ genotype from IL17A (rs2275913) was associated with lack of disease. No association was found considering the IL17F and IL23R polymorphisms. Our data suggest that IL17A and the presence of IL17A (rs2275913) A allele are associated with the absence of periodontal disease.

PMID: 23137879 [PubMed - indexed for MEDLINE]

Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival.

Prostate. 2013 May;73(7):700-5

Authors: Penney KL, Li H, Mucci LA, Loda M, Sesso HD, Stampfer MJ, Ma J

Abstract
BACKGROUND: Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.
METHODS: The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n = 80), we evaluated SEPP1 mRNA expression in tumors.
RESULTS: Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.02,1.69; P(trend)  = 0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR = 0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (P(interaction)  = 0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors.
CONCLUSIONS: SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.

PMID: 23129481 [PubMed - indexed for MEDLINE]

Influence of the STAT3 genetic variants in the susceptibility to psoriatic arthritis and Behcet's disease.

Hum Immunol. 2013 Feb;74(2):230-3

Authors: Cénit MC, Ortego-Centeno N, Raya E, Callejas JL, García-Hernandez FJ, Castillo-Palma MJ, Fernandez-Sueiro JL, Magro C, Solans R, Castañeda S, Camps M, Hidalgo A, Espinosa G, González-Gay MA, González-Escribano MF, Martín J

Abstract
OBJECTIVE: Signal-transducer and activator of transcription protein 3 (STAT3) gene encodes a transducer and transcription factor that plays an important role in many cellular processes such as cell growth, apoptosis and immune response. Several STAT3 genetic variants have been associated to different autoimmune diseases. Our aim was to reveal the possible STAT3 influence in other immune-mediated diseases such as psoriatic arthritis (PsA) and Behcet disease (BD).
METHODS: The STAT3 rs744166 and rs2293152 polymorphisms were genotyped using predesigned TaqMan® assays in a total of 335 PsA patients, 217 BD patients, and 1844 ethnically matched healthy controls of Spanish Caucasian origin.
RESULTS: A statistically significant association of the STAT3 rs744166(∗)G allele with PsA was observed (P-value=1.36×10(-3), OR 1.35). The detected effect was more evident when the rs744166(∗)GG homozygote frequencies were compared between PsA patients and controls (genotype P-value=9.77×10(-5), OR 1.82). In contrast, the allele and genotypic distributions of rs744166 polymorphism showed no significant differences between patients with BD and control subjects (allelic P-value=0.80, OR 1.03). Additionally, no evidence of association was detected between the rs2293152 genetic variant and both studied diseases.
CONCLUSION: Our results suggest for the first time that the STAT3 gene might be involved in PsA but not in Behcet's disease predisposition.

PMID: 23127549 [PubMed - indexed for MEDLINE]

CD226 Gly307Ser association with multiple autoimmune diseases: a meta-analysis.

Hum Immunol. 2013 Feb;74(2):249-55

Authors: Qiu ZX, Zhang K, Qiu XS, Zhou M, Li WM

Abstract
BACKGROUND: Recently, there has been increasing evidence shown that a non-synonymous exchange (Gly307Ser/rs763361) of the CD226 gene on chromosome 18q22 is linked to several autoimmune diseases (ADs) including type 1 diabetes (T1D), celiac disease (CED), rheumatoid arthritis (RA), multiple sclerosis (MS), Grave's disease, Wegener's granulomatosis (WG), psoriasis, and primary sicca syndrome (pSS). Taking into consideration that different autoimmune diseases may share some common pathogenic pathways and in order to assess the overall relationship between CD226 Gly307Ser (rs763361) polymorphism and multiple autoimmune diseases, we performed this meta-analysis.
METHOD: All eligible case-control studies were searched in the US National Library of Medicine's PubMed and Embase database. Crude odds ratios (OR) with 95% confidence intervals (CI) were conducted to assess the association.
RESULTS: 7876 cases and 8558 controls from 7 published studies which were selected from 149 articles identified by a search of the US National Library of Medicine's PubMed and Embase databases for the period up to 25th April 2012. The total OR for ADs associated with the T allele was 1.19 (95%CI=1.12-1.27) by random effects model. Significantly increased risks were also observed in the South American (OR=1.72, 95%CI=1.34-2.20), Asian (OR=1.46, 95%CI=1.01-2.10), and European (OR=1.29, 95%CI=1.07-1.58). Similarly, significant associations were observed in two genetic models (OR=1.41, 95%CI=1.23-1.62 in a codominant model; OR=1.33, 95%CI=1.18-1.50 in a recessive model).
CONCLUSION: This meta-analysis provided evidence that CD226 Gly307Ser (rs763361) is significantly associated with the risk of multiple autoimmune diseases.

PMID: 23073294 [PubMed - indexed for MEDLINE]