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A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

ABSTRACT: BACKGROUND AND PURPOSE: Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies. METHODS: Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular risk factors. Eleven SNPs in a 250 kb region on chromosome 12 spanning P2RX7 as well as neighboring genes OASL, P2RX4 and CAMKK2 were genotyped in 4138 individuals with IS and 2528 controls. Association was examined using linear and logistic regression models with an additive genetic model. RESULTS: The common loss-of-function variant rs3751143 was significantly associated with a decreased risk of IHD in smokers (P?=?0.03) as well as decreased risk of IS (OR 0.89; 95% CI?=?0.81-0.97; P?=?0.012). In addition, an intronic SNP in CAMKK2, rs2686342, were associated with a decreased risk of IS (OR 0.89; 95% CI?=?0.82-0.97; P?=?0.011). In subgroup analyses, both SNPs were associated with decreased risk of IS in individuals with hypertension (P?=?0.045 and 0.015, respectively). CONCLUSIONS: A common loss-of-function missense variant in the gene encoding the P2X(7) receptor is associated with reduced risk of IS and with IHD in smokers. These findings might implicate a role of purinergic signaling in atherogenesis or atherothrombosis.

SUBMITTER: Gidlof O

PROVIDER: S-EPMC3360776 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

Gidlöf Olof O Smith J Gustav JG Melander Olle O Lövkvist Håkan H Hedblad Bo B Engström Gunnar G Nilsson Peter P Carlson Joyce J Berglund Göran G Olsson Sandra S Jood Katarina K Jern Christina C Norrving Bo B Lindgren Arne A Erlinge David D

PloS one 20120525 5

<h4>Background and purpose</h4>Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies.<h4>Methods</h4>Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular ...[more]

PMID: 22662160

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Project description:Study questionIs the increased future cardiovascular risk seen in women with endometriosis or polycystic ovary syndrome (PCOS) mitigated by functional insulin-like growth factor-1 receptor (IGF1R) single-nucleotide polymorphism (SNP) rs2016347 as previously shown in women with hypertensive disorders of pregnancy?Summary answerThis cohort study found that women with endometriosis or PCOS who carry a T allele of IGF1R SNP rs2016347 had a reduced future risk of developing cardiovascular disease (CVD) and associated risk factors, with risk reduction dependent on cohort era.What is known alreadyWomen with endometriosis or PCOS have been shown to have an increased future risk of CVD and associated risk factors with limited predictive ability.Study design, size, durationThis retrospective cohort study took place in the Nurses' Health Study 2 (NHS2), which enrolled 116 430 participants in 1989 who were followed through 2015. The study population was analyzed in its entirety, and subdivided into entry (pre-1989) and after entry (post-1989) exposure cohorts. All NHS2 participants were eligible for inclusion in the study, 9599 (8.2%) were excluded for missing covariates.Participants/materials, setting, methodsThe NHS2 enrolled female registered nurses from 14 different states who ranged in age from 25 to 42 years at study entry. Data were collected from entry and biennial questionnaires, and analysis conducted from November 2020 to June 2021. Cox proportional hazard models were used to assess risk of CVD, hypertension (HTN), hypercholesterolemia (HC) and type 2 diabetes, both with and without genotyping for rs2016347.Main results and the role of chanceWhile women without endometriosis or PCOS, as a whole, demonstrated no impact of genotype on risk in either cohort, women with endometriosis carrying a T allele had a lower risk of CVD (hazard ratio (HR), 0.48; 95% CI, 0.27-0.86, P = 0.02) and HTN (HR, 0.80; 95% CI, 0.66-0.97, P = 0.03) in the pre-1989 cohort, while those in the post-1989 cohort had a decrease in risk for HC (HR, 0.76; 95% CI, 0.62-0.94, P = 0.01). Women with PCOS in the post-1989 cohort showed a significant protective impact of the T allele on HTN (HR, 0.44; 95% CI, 0.27-0.73, P = 0.002) and HC (HR, 0.62; 95% CI, 0.40-0.95, P = 0.03).Limitations, reasons for cautionData on specific endometriosis lesion locations or disease stage, as well as on PCOS phenotypes were lacking. In addition, data on systemic medical treatments beyond the use of oral contraceptives were missing, and these treatments may have confounded the results.Wider implications of the findingsThese findings implicate systemic dysregulation of the insulin-like growth factor-1 axis in the development of HTN, HC and clinical CVD in endometriosis and PCOS, suggesting a common underlying pathogenetic mechanism.Study funding/competing interest(s)The NHS2 infrastructure for questionnaire data collection was supported by National Institute of Health (NIH) grant U01CA176726. This work was also supported in part by NIH and National Cancer Institute grant U24CA210990; as well, research effort and publication costs were supported by the Elizabeth MA Stevens donor funds provided to the Buck Institute for Research on Aging. The authors declare they have no conflicts of interest.Trial registration numberN/A.

Dataset Information

A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

Publications

A common missense variant in the ATP receptor P2X7 is associated with reduced risk of cardiovascular events.

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