Association of SLC11A1 promoter polymorphisms with the incidence of autoimmune and inflammatory diseases: A meta-analysis (original) (raw)
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Genes and Immunity, 2015
A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT) n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis [OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively] and infectious disease [OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively]. However, while no association was observed with autoimmune disease, a modest significant association was observed with Type 1 diabetes [allele 2 OR=0.94 (0.89-0.98)]. Based on the stronger association of (GT) n allele 2 with tuberculosis, compared to the protective effect of allele 3, we hypothesise that allele 2 is likely the disease causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease [OR=1.30 (1.04-1.64)] and rheumatoid arthritis [OR=1.60 (1.20-2.13)] and between the-237C/T polymorphism (rs7573065) and inflammatory bowel disease [OR=0.60 (0.43-0.84)]. Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.
BMC Medical Genetics BioMed Central
…, 2009
Background: Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods: We investigated the role of the-2221Msp(C/T) and-23HphI(A/T) polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317), Addison's disease (AD, n = 107) or Hashimoto's thyroiditis (HT, n = 61)], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62) as well as in healthy controls (HC, n = 275). Results: T1D patients carried significantly more often the homozygous genotype "CC"-2221Msp(C/T) and "AA"-23HphI(A/T) polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8 , respectively). The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion: We demonstrate that the allele "C" of the-2221Msp(C/T) and "A"-23HphI(A/T) insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II. Background Type 1 diabetes (T1D) has a multifactorial pathogenesis, partly caused by environment but also by genetic predisposition. The association of the MHC class II genes with T1D is well known, but there are also non-MHC genes
Evaluation of SLC11A1 as an inflammatory bowel disease candidate gene
BMC medical genetics, 2005
Significant evidence suggests that a promoter polymorphism within the gene SLC11A1 is involved in susceptibility to both autoimmune and infectious disorders. The aim of this study was to evaluate whether SLC11A1 has a role in the susceptibility to inflammatory bowel disease (IBD) by characterizing a promoter polymorphism within the gene and two short tandem repeat (STR) markers in genetic proximity to SLC11A1. The studied population consisted of 484 Caucasians with IBD, 144 population controls, and 348 non-IBD-affected first-degree relatives of IBD patients. IBD subjects were re-categorized at the sub-disease phenotypic level to characterize possible SLC11A1 genotype-phenotype correlations. Polymorphic markers were amplified from germline DNA and typed using gel electrophoresis. Genotype-phenotype correlations were defined using case-control, haplotype, and family-based association studies. This study did not provide compelling evidence for SLC11A1 disease association; most signific...
International Journal of Colorectal Disease, 2006
The −237C→T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population Abstract The purpose of this study was to assess the likelihood that variation in the promoter region of the solute carrier family 11 member 1 gene (SLC11A1) contributes to inflammatory bowel disease (IBD) susceptibility in the South African population. The study cohort included 102 IBD patients, 47 with Crohn's disease (CD) and 55 with ulcerative colitis, and 192 population-matched controls. Mutation analysis revealed two novel alleles for the 5′-(GT)n repeat polymorphism, t(gt) 5 ac(gt) 5 ac (gt) 6 ggcaga(g) 6 (allele 8) and t(gt) 5 ac (gt) 5 ac(gt) 8 ggcaga(g) 6 (allele 9), and one previously documented point mutation −237C→T. A significantly decreased frequency of the −237C→T promoter polymorphism was observed in the patient group with IBD (p<0.001) and CD (p<0.0006) compared with the population-matched control group. These findings may be related to previous in vitro studies, which demonstrated that the point mutation at nucleotide position −237 represents a functional polymorphism that affects regulation of the upstream 5′-(GT)n repeat polymorphism differentially upon iron loading. Our findings raise the possibility that iron dysregulation mediated by allelic effects of SLC11A1 may contribute to IBD susceptibility.
Interleukin 12 (IL-12) is a heterodimeric, pro-inflammatory cytokine that plays a central role in activation and differentiation of CD4 + T cells into interferon-γ secreting T-helper type 1 cells. IL-12B, a gene encoding the larger subunit of active IL-12, has been reported to be down-regulated by the nuclear hormone 1α,25dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ), but the mechanism of the regulation is unknown. In this study, we have examined the molecular mechanism of transcriptional regulation of the IL-12B gene by 1α,25(OH) 2 D 3 in lipopolysaccharide (LPS)-treated human monocytes (THP-1). Quantitative RT-PCR showed that IL-12B mRNA displays a cyclical expression profile and is down-regulated 2.8-fold during the first 8 h and even 12.1-fold 24 h after exposure to 1α,25(OH) 2 D 3 . Gel shift and quantitative chromatin immunoprecipitation (ChIP) assays demonstrated vitamin D receptor (VDR) binding to genomic regions 480 and 6300 bp upstream of the IL-12B transcription start site (TSS). Quantitative ChIP assays also revealed that together with VDR and its partner RXR the above regions recruited the co-repressor NCOR2/SMRT and histone deacetylase 3 leading to a decreased histone 4 acetylation and increased histone 3 trimethylation at the IL-12B promoter and its TSS. We suggest that these repressive epigenetic changes eventually cause down-regulation of IL-12 expression. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a m c r
Frontiers in Immunology, 2022
Autoimmune diseases share a general mechanism of auto-antigens harming tissues. Still. they are phenotypically diverse, with genetic as well as environmental factors contributing to their etiology at varying degrees. Associated genomic loci and variants have been identified in numerous genome-wide association studies (GWAS), whose results are increasingly used for polygenic scores (PGS) that are used to predict disease risk. At the same time, a technological shift from genotyping arrays to next generation sequencing (NGS) is ongoing. NGS allows the identification of virtually allincluding rare-genetic variants, which in combination with methodological developments promises to improve the prediction of disease risk and elucidate molecular mechanisms underlying disease. Here we review current, publicly available autoimmune disease GWAS and PGS data based on information from the GWAS and PGS catalog, respectively. We summarize autoimmune diseases investigated, respective studies conducted and their results. Further, we review genetic data and autoimmune disease patients in the UK Biobank (UKB), the largest resource for genetic and phenotypic data available for academic research. We find that only comparably prevalent autoimmune diseases are covered by the UKB and at the same time assessed by both GWAS and PGS catalogs. These are systemic (systemic lupus erythematosus) as well as organspecific, affecting the gastrointestinal tract (inflammatory bowel disease as well as specifically Crohn's disease and ulcerative colitis), joints (juvenile ideopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), glands (Sjögren syndrome), the nervous system (multiple sclerosis), and the skin (vitiligo).
International Journal of Immunogenetics, 2013
Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to autoimmune diseases, but the mechanisms responsible for the associations are poorly understood. To test the hypothesis that the variation of the basal levels of the gene products is significantly influenced by genetic polymorphism, we investigated whether SNPs in genes CD40, CD28, CTLA4, CD80, CD86, BAFF and IL6 are affecting mRNA or protein expression. The surface expression of the proteins on unstimulated monocytes,
is the key enzyme in the biosynthesis of proinflammatory leukotrienes. The 5-LO gene is a primary target of 1α,25dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) and its expression is prominently increased during myeloid cell differentiation. Since no functional vitamin D response element (VDRE) has been reported for this gene so far, we performed in silico screening of the whole 5-LO gene area (84 kb, including 10 kb promoter region) and identified 22 putative VDREs. Both gelshift and reporter gene assays identified four of these candidates as functional VDREs. Their approximate positions are −2,250 (promoter), + 21,400 (intron 2), + 42,000 (intron 4) and + 50,600 (intron 5) in relation to the transcription start site (TSS). Remarkably, the VDRE at position +42,000 is one of the strongest known VDREs of the human genome. Chromatin immunoprecipitation (ChIP) assays demonstrated simultaneous association of vitamin D receptor (VDR), retinoid X receptor (RXR) and RNA polymerase II (Pol II) to the 5-LO gene regions containing two of these four putative VDREs. This indicates DNA looping of the TSS to even very distant gene regions. In summary, we suggest that the upregulation of the primary 1α,25(OH) 2 D 3 target 5-LO is mediated in vivo by a prominent VDRE in intron 4.
Faculty of public health medicine
Irish Journal of Medical Science, 1993
... WHAT IS THE UTILITY OF A CLINICAL GENETICS SERVICE AS AN EPIDEMIOLOGICAL DATABASE: A "DOUBLE BLIND RANDOMISED TRIAL" PJ Morrison , PM Darragh 2. tDepartment of Clinical Genetics, Belfast City Hospital Trust. ...
Cancer Genetics and Cytogenetics, 2005
Several environmental factors have been implicated in the etiology of esophageal cancer (EC). The purpose of this study was to assess the likelihood that variation in the SLC11A1 gene contributes to EC susceptibility, possibly due to its role in inflammation and iron metabolism. The regions of the gene containing potential functional polymorphisms, including the promoter region and exon 2, were investigated. The study cohort included 105 EC South African Colored patients with squamous cell carcinoma (SCC) and 110 population-matched controls, with South African Colored referring to individuals of mixed ancestry. A significantly decreased frequency of the Ϫ237C→T promoter polymorphism was observed in the patient group with EC compared with the population-matched control group (P Ͻ 0.002, χ 2 with Yates's correction ϭ 7.87). A statistically significant disease association was also observed with allele 3 of the 5′-(GT)n promoter polymorphism (P Ͻ 0.0006, χ 2 with Yates's correction ϭ 10.16), but only in the absence of the T-allele at nucleotide position Ϫ237 following allelic stratification. Four novel variants were identified in intron 1 (IVS1-28C→T) and exon 2 (112G→A, 148delGACCAGCCC, 157insGACCAGCCCAG). The novel intronic polymorphism, IVS1-28C→T, was also significantly associated with EC (P Ͻ 0.05, χ 2 with Yates's correction ϭ 2.52). We demonstrate association of genetic variation in both the promoter region and intron 1 of the SLC11A1 gene with EC susceptibility. Ć