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Association between rs6759298 and Ankylosing Spondylitis in Iranian Population.

ABSTRACT: Background:Ankylosing Spondylitis (AS) is a chronic autoinflammatory Spondyloarthropathy (SpA) which is characterized by sacroiliitis, which progresses to the axial skeleton. It seems that non-Human Leukocyte Antigen (HLA) and also HLA-B27 are associated with the susceptibility and pathogenesis of the disease. The recent Ge-nome-Wide Association Studies (GWASs) have reported intergenic rs6759298 to be associated with AS etiology. The aim of this study was investigation of the rs6759298 polymorphism in Iranian AS patients. In addition, probable correlations with clinical indices and manifestations were considered. Methods:This study included 403 patients with AS. The control group consisted of 506 healthy individuals who were matched for sex, age, and ethnicity with AS group. Genotyping of rs6759298 was determined using the Amplification-Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results:The GG genotype and G allele were found to be significantly more prevalent in the patient group in comparison to the control group [(p=2×10-6 and 7.44×10-9; OR (95% CI) =2.16 (1.56-2.98) and 1.73 (1.43-2.08)], respectively. Conclusion:No associations were found between patients with three genotypes and any disease manifestations or clinical indices. This investigation confirmed a highly significant association of rs6759298 with disease susceptibility, with no effect on disease progress or clinical presentations. Since rs6759298 belongs to the 2p15 gene desert, further studies would elucidate the exact role of this polymorphism in the pathogenesis of AS.

SUBMITTER: Mahmoudi M

PROVIDER: S-EPMC6064007 | biostudies-literature | 2018 Jul-Sep

REPOSITORIES: biostudies-literature

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Project description:Ankylosing spondylitis (AS) is the most common rheumatic condition that is slowly progressive and predominantly affects adolescents. Pathological bone formation associated with AS is an important cause of disability. The aim of the study was to investigate the possible involvement of the genes related to endochondral ossification and ectopia ossification in genetic susceptibility to AS in a Chinese Han population.Sixty-eight single nucleotide polymorphisms (SNPs) from 13 genes were genotyped in discovery cohorts including 300 AS patients and 180 healthy controls. The rs10019009 in dentin matrix protein 1 (DMP1) gene shown as association with AS after multiple testing corrections in discovery cohorts was replicated in a validation independent cohort of 620 AS patients and 683 healthy controls. The rs10019009 was assessed with bioinformatics including phylogenetic context, F-SNP and FastSNP functional predictions, secondary structure prediction, and molecular modeling. We performed a functional analysis of rs10019009 via reverse transcription-polymerase chain reaction, alkaline phosphatase (ALP) activity in human osteosarcoma U 2 OS cells.Interestingly, the SNP rs10019009 was associated with AS in both the discovery cohort (P = 0.0012) and validation cohort (P = 0.0349), as well as overall (P = 0.0004) in genetic case-control association analysis. After a multivariate logistic regression analysis, the effect of this genetic variant was observed to be independent of linkage disequilibrium. Via bioinformatics analysis, it was found that the amino acid change of the rs10019009 led to changes of SNP function, secondary structure, tertiary conformation, and splice mode. Finally, functional analysis of rs10019009 in U 2 OS cells demonstrated that the risk T allele of the rs10019009 increased enzymatic activity of ALP, compared to that of the nonrisk allele (P = 0.0080).These results suggested that the DMP1 gene seems to be involved in genetic predisposition to AS, which may contribute to the ectopic mineralization or ossification in AS. In addition, DMP1 gene may be a promising intervention target for AS in the future.

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Association between rs6759298 and Ankylosing Spondylitis in Iranian Population.

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