Mitochondrial Displacement Loop Region SNPs Modify Sjögren’s Syndrome Development by Regulating Cytokines Expression in Female Patients

Abstract

Mitochondrial dysfunction could induce innate immune response with cytokines releasing to initiate Sjögren’s syndrome (SS) onset. Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number of female SS patients were evaluated for their association with SS in female patients. At the nucleotide site of 152, 16304, 16311 and 16362 in the D-loop, the frequencies for the minor alleles of 152C (p = 0.040, odds ratio [OR] = 0.504), 16304C (p = 0.045, OR = 0.406), 16311C (p = 0.045, OR = 0.406) and 16362C (p = 0.028, OR = 0.519) were significantly higher in the SS patients than those in the female controls, which indicated that 152,C, 16304C, 16311C, and 16362C allele in the D-loop of mtDNA were associated with the risk of SS. Meanwhile, the excessive SNPs were accumulated in D-loop region of SS patients (8.955 ± 2.028 versus 7.898 ± 1.987, p < 0.001, 95% confidence interval [CI]: 0.477–1.637) and mtDNA copy number increased in SS patients (1.509 ± 0.836 versus 1.221 ± 0.506, p = 0.006, 95% CI: 0.086–0.490) by a case-control analysis. The subsequent analysis showed that SS risk-related allele 16311C was associated with higher IL-2 levels (p = 0.010) at significantly statistical level whereas 152C associated with lower IL-10 levels (p = 0.058) at a borderline statistical levels. Our findings suggest that mitochondrial D-loop SNPs are predictors for SS risk, it might modify the SS development by regulating cytokine expression.

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren’s Syndrome

“…To our knowledge, this study is one of the first to compare mtDNA copy numbers in the peripheral blood of patients with SS and healthy CTRLs. However, our results contrast with the ones reported in a previously published paper, which showed an increase in mtDNA copy number in a group of Chinese SS female patients compared with controls [ 38 ]. These conflicting results suggest the need to replicate this evaluation in other populations and in larger cohorts.…”

Mitochondrial displacement loop region single nucleotide polymorphisms and mitochondrial DNA copy number associated with risk of ankylosing spondylitis

“…Subsequent investigation revealed that the ROS levels in the AS group were substantially greater than those in the control group The relationships between 16304C allele and Sjögren syndrome or idiopathic inflammatory myopathies, 16311C allele and Sjögren syndrome pathogenesis, and 152C allele and Sjögren syndrome etiology have been verified by previous research. 13,14 The present study demonstrated that the alleles mentioned above were more susceptible to AS. All these AS-associated SNPs are located in the hypervariable segment region where germline and somatic mutations occur frequently.…”

“…11 Several rheumatic diseases have been reported to be related to mtDNA single nucleotide polymorphisms (SNPs) in the D-loop, including polymyositis, dermatomyositis, Sjögren syndrome, and systemic lupus erythematosus. [12][13][14] In addition, mtDNA copy number, which can reflect gene-environment interactions among oxidative stresses and unknown hereditary factors, has been reported to be a risk predictor of Sjögren syndrome, polymyositis, and dermatomyositis based on our analysis. 13,14 However, the relationship of SNPs among the mtDNA D-loop, mtDNA copy number, and pathophysiological mechanism in AS is still unknown.…”

“…[12][13][14] In addition, mtDNA copy number, which can reflect gene-environment interactions among oxidative stresses and unknown hereditary factors, has been reported to be a risk predictor of Sjögren syndrome, polymyositis, and dermatomyositis based on our analysis. 13,14 However, the relationship of SNPs among the mtDNA D-loop, mtDNA copy number, and pathophysiological mechanism in AS is still unknown.…”

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

“…The mitochondrial coding region genome contains 37 genes, 13 of which encode polypeptides required by the electron transport chain (ETC), including 7 genes encoding complex I subunits ( MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5 , and MT-ND6 ), a gene encoding complex III ( MT-CYTB ), 3 genes encoding complex IV ( MT-COI , MT-CO II , and MT-CO III ) and 2 encoding complex V ( MT-ATP6 and MT-ATP8 ), as well as two encoding ribosomal RNAs (rRNAs) ( 12S rRNA and 16S rRNA ) and 22 encoding transport RNAs (tRNAs) [ 39 ]. The Displacement loop (D-loop) is a unique noncoding region of mtDNA that controls the replication and expression of the mitochondrial genome [ 40 ]. The mitochondrial genome coregulates the bioenergy of cells with the nuclear genome.…”