Haplotype-based case–control study of receptor (calcitonin) activity-modifying protein-1 gene in cerebral infarction

Nakazato, Tatsuo; Nakayama, Tomohiro; Naganuma, Takahiro; Sato, Naoyuki; Fu, Zhen-Yan; Wang, Z; Soma, Masayoshi; Sugama, Kaoru; Hinohara, Shigeaki; Doba, Nobutaka

doi:10.1038/jhh.2009.68

Cited by 12 publications

(5 citation statements)

References 16 publications

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“…A significant difference in the RAMP1 single nucleotide polymorphism rs3754701 frequency was identified between Swedish CH patients and controls. Moreover, RAMP1 polymorphisms have previously been suggested to be implicated in both migraine and medication overuse headache [60,61], and the associated SNPs, rs3754701 and rs7590387, are part of a risk haplotype for cerebral infarction reported in a Japanese case-control study [111]. In addition, RAMP1 mRNA expression was shown to be enhanced in primary fibroblasts from CH patients compared to controls [110].…”

Section: Cgrp and Geneticsmentioning

confidence: 89%

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

2020

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Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

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Section: Cgrp and Geneticsmentioning

confidence: 89%

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

2020

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“…40 A human study also revealed the relationship between RAMP1 singlenucleotide polymorphisms and the incidence of cerebral infarction. 41 Some human mutations of RAMP3 gene have also been reported. 42 On the other hand, there have been no reports on human RAMP2 gene mutation.…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

et al. 2013

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Background-Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. Methods and Results-We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2 −/− and E-AM−/− mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2 −/− mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2 −/− mice (DI-E-RAMP2 −/− ) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. Conclusions -Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. (Circulation. 2013;127:842-853.)

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“…Although no significant association with migraine susceptibility in general and both with and without aura [ 45 ] and with the response to triptans in all the three genotypes under study [ 46 ], the rs7590387G allele and the rs7590387GG genotype have been found to reduce significantly the risk of transformation MOH [ 46 ]. Interestingly, the relationship of this SNP with cerebral infarction has been examined in a Japanese population, suggesting the T-A-C haplotype to represent a genetic marker for cerebral infarction [ 56 ]. Only one study investigating the methylation pattern with regard to CGRP pathway has resulted from the search.…”

Section: Resultsmentioning

confidence: 99%

Role of CGRP pathway polymorphisms in migraine: a systematic review and impact on CGRP mAbs migraine therapy

et al. 2021

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Background the interest of clinical reaseach in polymorphisms and epigenetics in migraine has been growing over the years. Due to the new era of preventative migraine treatment opened by monoclonal antibodies (mAbs) targeting the signaling of the calcitonin-gene related peptide (CGRP), the present systematic review aims at identifying genetic variants occurring along the CGRP pathway and at verifying whether these can affect the clinical features and the course of disease and the responsiveness of patients to therapy. Methods the literature search has been conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science, the Human Genome Epidemiology (HuGE) Published Literature database (Public Health Genomics Knowledge Base) and Clinicaltrials.gov from database inception until April 1, 2021. The process of identification and selection of the studies included in the analysis has followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses and the guidance from the Human Genome Epidemiology Network for reporting gene-disease associations. Results the search has retrieved 800 results, among which only 7 studies have met the eligibility criteria for inclusion in the analysis. The latter are case-control studies of genetic association and an exploratory analysis and two polymorphisms have been detected as the most recurring: the rs3781719 (T > C) of the CALC A gene encoding CGRP and the rs7590387 of the gene encoding the receptor activity-modifying protein (RAMP) 1 (C > G). Only one study assessing the methylation pattern with regard to CGRP pathway has been found from the search. No genetic association studies investigating the possible effect of genetic variants affecting CGRP signaling on the responsiveness to the most recent pharmacological approaches, i.e. anti-CGRP(R) mAbs, gepants and ditans, have been published. According to the Human Genome Epidemiology (HuGE) systematic reviews and meta-analyses risk-of-bias score for genetic association studies, the heterogeneity between and across studies and the small sample size do not allow to draw conclusions and prompt future studies. Conclusions adequately powered, good quality genetic association studies are needed to understand the impact of genetic variants affecting the pathway of CGRP on migraine susceptibility and clinical manifestation and to predict the response to therapy in terms of efficacy and safety.

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Haplotype-based case–control study of receptor (calcitonin) activity-modifying protein-1 gene in cerebral infarction

Cited by 12 publications

References 16 publications

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

Role of CGRP pathway polymorphisms in migraine: a systematic review and impact on CGRP mAbs migraine therapy

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