Genetic Variants of <i>RAMP2</i> and <i>CLR</i> are Associated with Stroke

Abstract

Aim: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions.Methods: Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis.Results: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076–0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke.Conclusions: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.

Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study

“…www.nature.com/scientificreports/ ADM has also been shown also to have anti-inflammatory and anti-oxidative properties and to limit the arterial intimal hyperplasia, a response to protect organs from damage [21][22][23][24] . Indeed, the relationship between ADM signal and vascular integrity has been investigated in many experimental 4,[25][26][27] and some epidemiological studies [28][29][30] . As a consequence, the increase of ADM levels found in these pathological disorders affecting the vascular system may be seen as a counter-regulatory (compensatory) mechanism for vascular damage.…”

Substantially Increased Plasma Coproporphyrin‐I Concentrations Associated With OATP1B1*15 Allele in Japanese General Population

“…The 14,539 study participants in the J‐MICC study from 12 areas of Japan were genotyped at RIKEN Center for Integrative Medicine using a Human OmniExpressExome‐8 version 1.2 BeadChip array (Illumina, San Diego, CA, USA) 31 . Quality control filtering of samples and single nucleotide polymorphisms (SNPs) have been reported previously 31 .…”

“…The 14,539 study participants in the J‐MICC study from 12 areas of Japan were genotyped at RIKEN Center for Integrative Medicine using a Human OmniExpressExome‐8 version 1.2 BeadChip array (Illumina, San Diego, CA, USA) 31 . Quality control filtering of samples and single nucleotide polymorphisms (SNPs) have been reported previously 31 . Briefly, for quality control filtering, samples with inconsistent sex information, one of each pair of samples found to be closely related by descent, and samples with ancestry estimated to be outside the Japanese population were excluded.…”

“…31 Quality control filtering of samples and single nucleotide polymorphisms (SNPs) have been reported previously. 31 Briefly, for quality control filtering, samples with inconsistent sex information, one of each pair of samples found to be closely related by descent, and samples with ancestry estimated to be outside the Japanese population were excluded. SNPs with a call rate < 0.98 or a Hardy Weinberg equilibrium P value < 1 × 10 −6 were also filtered out.…”

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

“…FAM213A encodes for the peroxiredoxin like 2A protein, which is an antioxidant associated with endothelial activation 60 . The CALCRL gene encodes the calcitonin receptor like receptor and modulates the calcitonin signaling system, implicated in ischemic stroke 61 .…”