Dataset Information

Association of the Gelatinase B/Metalloproteinase 9 (MMP-9) Gene Haplotype in Systemic Lupus Erythematosus (SLE) in the Pediatric Egyptian Population.

ABSTRACT: Permanent systemic inflammation is a defining feature of systemic lupus erythematosus (SLE), which affects multiple organs. Gelatinase B/matrix metalloproteinase-9 (MMP-9) is an essential protease investigated in inflammation that has been linked to SLE. The study’s objective was to investigate the relationship between the rs3918249 T/C and rs17576 A/G SNPs in the MMP-9 gene with SLE. The study was conducted with 100 SLE cases and 100 age/sex-matched healthy individuals. TaqManTM SNP was used for genotyping by real time PCR on the Artus Rotor-Gene Qiagen equipment. Haplotypes (TG: OR = 0.226, 95% CI = 0.119−0.429) and (CA: OR = 0.36, 95% CI = 0.2206−0.631), both with a p-value < 0.001 were substantially linked to a lower incidence of SLE. Conversely, the risk of SLE was not associated with the individual SNPs studied. The haplotype analysis was more significant than the SNP analysis and may correlate with the decreased risk of SLE in children and adolescents in Egypt.

SUBMITTER: Attia ZR

PROVIDER: S-EPMC9496982 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Association of the Gelatinase B/Metalloproteinase 9 (MMP-9) Gene Haplotype in Systemic Lupus Erythematosus (SLE) in the Pediatric Egyptian Population.

Attia Zeinab R ZR Zedan Mohamed M MM Mutawi Thuraya M TM Saad Entsar A EA Abd El Azeem Rania A RA El Basuni Mohamed A MA

Children (Basel, Switzerland) 20220824 9

Permanent systemic inflammation is a defining feature of systemic lupus erythematosus (SLE), which affects multiple organs. Gelatinase B/matrix metalloproteinase-9 (MMP-9) is an essential protease investigated in inflammation that has been linked to SLE. The study’s objective was to investigate the relationship between the rs3918249 T/C and rs17576 A/G SNPs in the MMP-9 gene with SLE. The study was conducted with 100 SLE cases and 100 age/sex-matched healthy individuals. TaqManTM SNP was used fo ...[more]

PMID: 36138580

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Project description:Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P ?=?1.34×10(-8), OR ?=?1.22, CI 95% ?=?1.14-1.30; rs2004640: P ?=?4.60×10(-7), OR ?=?0.84, CI 95% ?=?0.78-0.90; rs10488631: P ?=?7.53×10(-20), OR ?=?1.63, CI 95% ?=?1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P ?=?0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P ?=?9.04×10(-22), OR ?=?1.75, CI 95% ?=?1.56-1.97) better explained the observed association (likelihood P-value ?=?1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

Project description:An in-depth literature review of up to 2023 reveals 330 risk loci found by genetic association at p ≤ 5 × 10-8, with systemic lupus erythematosus (SLE) in at least one study of 160 pertinent publications. There are 225 loci found in East Asian (EAS), 106 in European (EU), 11 in African-American (AA), 18 Mixed American (MA), and 1 in Egyptian ancestries. Unexpectedly, most of these associations are found to date at p ≤ 5 × 10-8 in a single ancestry. However, the EAS and EU share 40 risk loci that are independently established. The great majority of the identified loci [250 (75.8%) of 330] do not contain a variant that changes an amino acid sequence. Meanwhile, most overlap with known regulatory elements in the genome [266 (80.6%) of 330], suggesting a major role for gene regulation in the genetic mechanisms of SLE. To evaluate the pathways altered by SLE-associated variants, we generated gene sets potentially regulated by SLE loci that consist of the nearest genes, published attributions, and genes predicted by computational tools. The most useful insights, at present, suggest that SLE genetic mechanisms involve (1) the regulation of both adaptive and innate immune responses including immune cell activation and differentiation; (2) the regulation of production and response to cytokines, including type I interferon; (3) apoptosis; (4) the sensing and removal of immune complexes and apoptotic particles; and (5) immune response to infections, including Epstein-Barr Virus, and symbiont microorganisms. These mechanisms affected by SLE genes involve multiple cell types, including B cells/plasma cells, T cells, dendritic cells, monocytes/macrophages, natural killer cells, neutrophils, and endothelial cells. The genetics of SLE from GWAS data reveal an incredibly complex profusion of interrelated molecular processes and interacting cells participating in SLE pathogenesis, mostly unified in the molecular regulation of inflammatory responses. These genetic associations in lupus and affected molecular pathways not only give us an understanding of the disease pathogenesis but may also help in drug discoveries for SLE treatment.

Dataset Information

Association of the Gelatinase B/Metalloproteinase 9 (MMP-9) Gene Haplotype in Systemic Lupus Erythematosus (SLE) in the Pediatric Egyptian Population.

Publications

Association of the Gelatinase B/Metalloproteinase 9 (MMP-9) Gene Haplotype in Systemic Lupus Erythematosus (SLE) in the Pediatric Egyptian Population.

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