Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients

Kumamoto, Teruhiko; Kawai, Yasuyuki; Arakawa, Kazuhisa; Morikawa, Norihiro; Kuribara, Jun; Tada, Hiroshi; Taniguchi, Koichi; Tatami, Ryozo; Miyamori, Isamu; Kominato, Yoshihiko; Kishi, Koichiro; Yasuda, Toshihiro

doi:10.1093/eurheartj/ehl177

Cited by 32 publications

(23 citation statements)

References 33 publications

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“…40 A single-nucleotide polymorphism in the DNase-1 gene, which leads to impaired DNase activity, was independently associated with a higher incidence of myocardial infarction. 41 In animal models, medicinal DNase was successfully used to prevent venous thrombogenesis. 10 Inhibiting peptidylarginine deiminase 4, a key factor in NETosis, prolonged time to carotid artery thrombosis in a photochemical injury model.…”

Section: Discussionmentioning

confidence: 99%

Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

Mangold

Alias

Scherz

et al. 2015

Circulation Research

401

398

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Rationale: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. Objective: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. Methods and Results: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. Conclusions: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.

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Section: Discussionmentioning

confidence: 99%

Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

Mangold

Alias

Scherz

et al. 2015

Circulation Research

401

398

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“…Less functional polymorphisms of DNase I exist in the human population 33, 34 . These polymorphisms or the presence of inhibitors impairing DNase 1 function 35 predisposes individuals to cardiovascular and autoimmune disease, likely because DNA (NETs) are not dismantled and removed in a timely manner 33–35 .…”

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confidence: 99%

Diabetes primes neutrophils to undergo NETosis, which impairs wound healing

Wong

Demers

Martinod

et al. 2015

Nat Med

889

858

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Wound healing is impaired in diabetes resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins1. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed, NETosis). Expression of peptidylarginine deiminase 4 (PAD4), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4−/− mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds and healing was delayed. Wound healing was accelerated in Padi4−/− mice as compared to WT mice, and was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes where neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

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“…Previously, we clarified the allele distribution of four (three in DNase 1L1 and one in DNase 1L2) non-synonymous SNPs and demonstrated that the non-synonymous ones identified in the DNase 1L1 and 1L2 genes may exert no influence on the activity levels of DNases 1L1 and 1L2 in human [14]. Human DNases have been investigated for their involvement in the pathophysiology of various diseases as genetic factors [13,[15][16][17]. In this context, the clarification of genetic aspects of all SNPs, including synonymous ones in the DNase 1L1 and 1L2 genes, would allow us to gain a comprehensive understanding of the association of DNase 1L1 and/or 1L2 with the risk of various diseases as the genetic background of disease susceptibility.…”

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confidence: 99%

Global analysis of single nucleotide polymorphisms in the exons of human deoxyribonuclease I‐like 1 and 2 genes

et al. 2010

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Several SNPs in the deoxyribonuclease I-like 1 (DNase 1L1) and DNase 1L2 were investigated. In the present study, the genotype distributions of three synonymous SNPs (V59V, rs1050095; P67P, rs1130929; A277A, rs17849495) in the DNase 1L1 gene and four non-synonymous SNPs, V122I (rs34952165), Q170H (rs6643670), and D227A (rs5987256) in the DNase 1L1 gene, as well as D197A (rs62621282) in the DNase 1L2 gene were investigated in 13 populations. In all the populations, no variation was found in four SNPs (V59V, Q170H, D227A, and A277A) in DNASE1L1 or in D197A in DNASE1L2. As for V122I, only the German population showed a low degree of polymorphism. The SNP V122I in DNASE1L1 was monoallelic for the G-allele in all of the Asian and African populations examined, with no polymorphism being evident. Since the A-allele in SNP V122I was distributed in only the Caucasian populations, not in the other ethnic groups, it was confirmed that the A-allele in SNP V122I was Caucasian-specific. On the other hand, only P67P in DNASE1L1 was polymorphic among three synonymous SNPs. The effect of nucleotide substitution corresponding to polymorphic SNP P67P on DNase 1L1 activity was examined: the corresponding nucleotide substitution in polymorphic SNP P67P has little effect on the DNase activity.

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Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients

Abstract: Our data demonstrate that Gln222Arg polymorphism in the DNase I gene is associated with MI in the Japanese patients.

Cited by 32 publications

References 33 publications

Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

Diabetes primes neutrophils to undergo NETosis, which impairs wound healing

Global analysis of single nucleotide polymorphisms in the exons of human deoxyribonuclease I‐like 1 and 2 genes

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