Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD ( n = 81) and in healthy subjects as control ( n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26–9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15–14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

Download Full-text

Abstract 14849: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Spasm in Patients with Vasospastic Angina (VSA)

Circulation ◽

10.1161/circ.130.suppl_2.14849 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tomonori Akasaka ◽

Seiji Hokimoto ◽

Noriaki Tabata ◽

Kenji Sakamoto ◽

Kenichi Tsujita ◽

...

Keyword(s):

Coronary Artery ◽

Coronary Artery Spasm ◽

Coronary Spasm ◽

Control Group ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Loss Of Function ◽

Hs Crp ◽

The Impact ◽

Low Grade Inflammation

Background: Several cytochrome P450 (CYP) enzyme families have been identified in extra hepatic tissues such as heart, vasculature, kidney, and lung. CYP2C19 localized in vascular smooth muscle and endothelium contributes to the regulation of vascular tone and homeostasis. However, it is unknown whether CYP2C19 genotype is associated with the vascular tonus in patients with VSA. The aim of this study was to examine the impact of CYP2C19 genotype on coronary artery spasm in patients with VSA. Methods: We examined the distribution of CYP2C19 genotype in patients with VSA (n=129) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM). Moreover, we measured the level of high-sensitive CRP (hs-CRP) as a degree of low glade inflammation in each group. Results: The ratios of CYP2C19 genotype (EM, IM, and PM) were 30, 42, and 28% in VSA group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in VSA than in control (28% vs 19%, P=0.026). In VSA group, the ratios of CYP2C19 genotype were 36, 44, and 20% in male, and 20, 39, and 41% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (41% vs 20%, P<0.001). Moreover, the level of hs-CRP was significantly higher in VSA group than in control group (0.17±0.367 vs 0.10.±0.240, P=0.02). When patients were stratified by gender, the level of hs-CRP was significantly higher in VSA group in female (0.11±0.198 vs 0.06±0.105, P=0.031) and male (0.20±0.438 vs 0.12±0.277, P=0.044). Multivariate analysis for coronary spasm indicated high age, hypertension, and high level of hs-CRP as predictive factors among all subjects. PM is a predictive factor for coronary spasm in female group only (OR3.1, 95%RI 1.525-6.317, P=0.002), but not in male (OR0.829, 95%RI 0.453-1.518, P=0.543). Conclusion: The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary artery spasm and the regulation of coronary tonus, especially in female.

Download Full-text

Abstract 17996: Is There Gender Differences in Effect of CYP2C19 Polymorphisms or Low-grade Inflammation on Coronary Microvascular Disorder (CMVD)?

Circulation ◽

10.1161/circ.132.suppl_3.17996 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

tomonori akasaka ◽

Seiji Hokimoto ◽

Hisao Ogawa

Keyword(s):

Gender Differences ◽

Coronary Artery ◽

Predictive Factors ◽

Provocation Test ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Loss Of Function ◽

Significant Difference ◽

Hs Crp ◽

Low Grade Inflammation

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 poor metabolizer(PM) is reported to be an independent risk factor for coronary artery disease. And, CYP2C19 PM is correlated with an increase in the circulating levels of hs-CRP in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disorder (CMVD).So, we examined gender differences in effect of CYP2C19 genotype and low grade inflammation on CMVD. Methods: We examined CYP2C19 genotypes in patients with CMVD (n=54) diagnosed by an intracoronary acetylcholine infusion test, with healthy subjects (n=76) serving as the control. CMVD was defined as the presentation of no coronary artery stenosis in angiography, no epicardial spasms, inversion of lactic acid levels between intracoronary and coronary sinuses in the intracoronary acetylcholine-provocation test, and an adenosine triphosphate-induced CFR<2.5. CYP2C19 genotypes were divided into 3 groups: (1) CYP2C19*1/*1 , extensive metabolizer (EM), (2) one loss-of-function allele (*1/*2, *1/*3; intermediate metabolizer [IM]), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3;[PM]). Results: The ratios of CYP2C19 genotype (EM,IM,and PM) were 31,39,and 30% in CMVD , and 32,49,and 19% in control. There is no significant difference in frequency of CYP2C19 genotype in overall (P=0.146). But, PM frequency was significantly higher in CMVD in only female (34% vs 16%, P=0.042). In level of hs-CRP, there is no significant difference between CMVD and control (0.111±0.080 vs 0.083±0.128,P=0.122), but significantly higher in CMVD in only female (0.112±0.106 vs 0.066±0.106,P=0.002). Moreover, in CMVD, mean of hs-CRP in CYP2C19 PM is significantly higher than that of EM in female (0.115±0.074 vs 0.046±0.039,P=0.034). Multivariate analysis for CMVD indicated that hypertension and chronic kidney disease are predictive factors among all subjects (OR 3.931,P=0.003, OR 3.146,P=0.026). High level of hs-CRP and CYP2C19 PM are predictive factors for CMVD in only female (OR3.864,P=0.047, OR6.079,P=0.042). Conclusion: CYP2C19 PM and low grade inflammation may be associated with CMVD, especially in female.

Download Full-text

Abstract 14862: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Microvascular Disease

Circulation ◽

10.1161/circ.130.suppl_2.14862 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tomonori Akasaka ◽

Seiji Hokimoto ◽

Noriaki Tabata ◽

Kenji Sakamoto ◽

Kenichi Tsujita ◽

...

Keyword(s):

Microvascular Disease ◽

Control Group ◽

Female Group ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Loss Of Function ◽

Disease Group ◽

Hs Crp ◽

The Impact ◽

Low Grade Inflammation

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 two loss-of-function alleles (PM) were found to be an independent risk factor for diabetic retinopathy, and PM is associated with the coronary spasm especially in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disease. The aim was to evaluate the impact of CYP2C19 genotype on coronary microvascular disease. Methods: We examined CYP2C19 genotype in patients with microvascular disease (n=40) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. We defined the coronary microvascular disease that have no epicardial spasm and have angina, ischemic ECG changes, reduced coronary blood flow, or inversion of lactic acid level between intra-coronary and coronary sinus. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM). Results: The ratios of CYP2C19 genotype (EM, IM, and PM) were 33, 35, and 32% in microvascular disease group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in microvascular disease group (32%vs19%,P=0.039). In microvascular disease group, the ratios of CYP2C19 genotype (EM, IM, and PM) were 44, 38, and 19% in male, and 25, 33, and 42% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (42%vs19%,P=0.011). Moreover, the level of hs-CRP was significantly higher in microvascular disease group (0.37±0.908 vs 0.10±0.240, P<0.001). Multivariate analysis for microvascular disease indicated that gender, high age, smoking, hypertension, and the high level of hs-CRP are predictive factors among all subjects. PM is a predictive factor for microvascular disease in female group only (OR3.214, 95%RI 1.286-8.034, P=0.012), but not in male (OR0.909, 95%RI 0.251-3.285, P=0.884). Conclusion: The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary microvascular disease, especially in female.

Download Full-text

Sex Differences on Vestibular and Ocular Motor Assessment in Youth Athletes

Journal of Athletic Training ◽

10.4085/1062-6050-220-18 ◽

2019 ◽

Vol 54 (4) ◽

pp. 445-448 ◽

Cited By ~ 3

Author(s):

Ryan N. Moran ◽

Tracey Covassin ◽

R. J. Elbin

Keyword(s):

Sex Differences ◽

Risk Factor ◽

Confidence Interval ◽

Odds Ratio ◽

Motor Symptom ◽

Ocular Motor ◽

Male And Female ◽

Youth Athletes ◽

Assessment Strategies ◽

Cutoff Levels

Context The Vestibular/Ocular Motor Screening (VOMS) is a newly developed measure that evaluates vestibular and ocular motor symptom provocation after sport-related concussion. The effects of sex on baseline VOMS scores in youth athletes have not been established. Objective To examine sex differences on baseline VOMS assessment among youth athletes. Results No sex differences were demonstrated between male and female youth athletes on individual VOMS items (P range = .07–.98). Female sex was not associated with increased odds for VOMS scores over clinical-cutoff levels (range: odds ratio = 0.64; 95% confidence interval = 0.35, 1.15; P = .13; odds ratio = 0.91; 95% confidence interval = 0.48, 1.71; P = .77). Conclusions No sex differences were present on baseline VOMS scores in youth athletes, nor was sex a risk factor for an abnormal VOMS score. These findings highlight the need for continual baseline and postconcussion assessments using multifaceted assessment strategies.

Download Full-text

The Impact of Insulin Resistance and Chronic Kidney Disease on Inflammation and Cardiovascular Disease

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.1177/1179551418792257 ◽

2018 ◽

Vol 11 ◽

pp. 117955141879225 ◽

Cited By ~ 11

Author(s):

Constantine E Kosmas ◽

Delia Silverio ◽

Christiana Tsomidou ◽

Maria D Salcedo ◽

Peter D Montan ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Risk Factor ◽

Kidney Disease ◽

Early Stage ◽

Scientific Data ◽

Low Grade ◽

The Impact ◽

Low Grade Inflammation

There is extensive evidence showing that insulin resistance (IR) is associated with chronic low-grade inflammation. Furthermore, IR has been shown to increase the risk for cardiovascular disease (CVD), even in nondiabetic patients, and is currently considered as a “nontraditional” risk factor contributing to CVD by promoting hypertension, oxidative stress, endothelial dysfunction, dyslipidemia, and type 2 diabetes mellitus. However, chronic kidney disease (CKD) is also considered a state of low-grade inflammation. In addition, CKD is considered an IR state and has been described as an independent risk factor for the development of CVD, as even early-stage CKD is associated with an estimated 40% to 100% increase in CVD risk. There is also strong evidence indicating that inflammation per se plays a crucial role in both the initiation and progression of CVD. Given the above, the combined effect of IR and CKD may significantly increase the risk of inflammation and CVD. This review aims to focus on the complex interplay between IR, CKD, inflammation, and CVD and will present and discuss the current clinical and scientific data pertaining to the impact of IR and CKD on inflammation and CVD.

Download Full-text

Dysglycemic states and hypertension: A relationship dependent on low-grade inflammation

F1000Research ◽

10.12688/f1000research.12531.1 ◽

2017 ◽

Vol 6 ◽

pp. 1953

Author(s):

Juan Salazar ◽

Valmore Bermúdez ◽

Wheeler Torres ◽

Víctor Arias ◽

María Sofía Martínez ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Adult Population ◽

Multiple Logistic Regression Analysis ◽

Population Sample ◽

High Sensitivity ◽

Low Grade ◽

Cross Sectional ◽

The Impact ◽

Low Grade Inflammation

Background: Hypertension (HTN) is a prominent cardiovascular risk factor, affecting over 1 billion people worldwide. Identification of closely associated cardiometabolic conditions may be crucial for its early detection. The objective of this study was to identify factors associated with HTN and prehypertension (PHT) in an adult population sample from Maracaibo City, Venezuela. Methods: A randomized multi-staged sampling cross-sectional study was performed in 2230 individuals from Maracaibo City Metabolic Syndrome Prevalence Study database. PHT and HTN were defined according to JNC-7 criteria. Multiple logistic regression analysis was used to assess the main risk factors for each condition. Results: 52.6% (n=1172) of the subjects were female, the prevalence of HTN was 32% (n=714), while the prevalence of PHT was 31.1% (n=693). The main risk factors for HTN were age ≥60 years (odds ratio [OR]: 40.99; 95%CI: 16.94-99.19; p<0.001) and the local indigenous ethnic group (OR: 3.06; 95%CI: 1.09-8.62; p=0.03). Adjustment for high sensitivity C-reactive protein levels increased the OR of these factors and diminished the impact of other factors. Meanwhile, age ≥60 years (OR: 3.39; 95%CI: 1.41-8.18; p=0.007) and alcohol consumption (OR: 1.49; 95%CI: 1.06-2.00; p=0.02) were the main risk factors for PHT. Conclusion: There are significant differences in the risk factor profiles for HTN and PHT. Additionally, low-grade inflammation appears to link multiple metabolic factors and preexisting vascular characteristics.

Download Full-text

Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

International Journal of Molecular Sciences ◽

10.3390/ijms22052602 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2602

Author(s):

Emilie Viennois ◽

Benoit Chassaing

Keyword(s):

Intestinal Inflammation ◽

Tumor Development ◽

Low Grade ◽

Gastrointestinal Cancers ◽

Cancer Initiation ◽

And Function ◽

The Impact ◽

Chronic Intestinal Inflammation ◽

Low Grade Inflammation ◽

Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

Download Full-text

SARS-CoV-2 and Obesity: “CoVesity”—a Pandemic Within a Pandemic

Obesity Surgery ◽

10.1007/s11695-020-04919-0 ◽

2021 ◽

Author(s):

Kimberley Zakka ◽

◽

Swathikan Chidambaram ◽

Sami Mansour ◽

Kamal Mahawar ◽

...

Keyword(s):

Systematic Review ◽

Risk Factor ◽

Viral Load ◽

Respiratory Failure ◽

Health Outcomes ◽

Severe Disease ◽

Vulnerable Population ◽

Low Grade ◽

Obesity Management ◽

Low Grade Inflammation

AbstractIndividuals who are overweight or suffering from obesity are in a chronic state of low-grade inflammation, making them particularly susceptible to developing severe forms of respiratory failure. Studies conducted in past pandemics link obesity with worse health outcomes. This population is thus of particular concern within the context of the COVID-19 pandemic, considering the cessation of obesity management services. This systematic review highlights [1] the reciprocal link between the obesity and COVID-19 pandemics, [2] obesity as a risk factor for more severe disease in past pandemics, [3] potential mechanisms that make individual’s suffering from obesity more susceptible to severe disease and higher viral load, and [4] the need to safely resume bariatric services as recommended by expert guidelines, in order to mitigate the health outcomes of an already vulnerable population.

Download Full-text

Increased Plasma Ferritin Concentration and Low-Grade Inflammation—A Mendelian Randomization Study

Clinical Chemistry ◽

10.1373/clinchem.2017.276055 ◽

2018 ◽

Vol 64 (2) ◽

pp. 374-385 ◽

Cited By ~ 13

Author(s):

Ingrid W Moen ◽

Helle K M Bergholdt ◽

Thomas Mandrup-Poulsen ◽

Børge G Nordestgaard ◽

Christina Ellervik

Keyword(s):

Odds Ratio ◽

Mendelian Randomization ◽

Iron Concentration ◽

Complement C3 ◽

Incomplete Penetrance ◽

Low Grade ◽

Ferritin Concentration ◽

Mediation Analyses ◽

All Cause Mortality ◽

Low Grade Inflammation

Abstract BACKGROUND It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09–1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01–1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21–1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03–1.12). Mediation analyses showed that 74% (95% CI, 24–123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%–96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.

Download Full-text

Abstract 11600: Long Sleep Duration and Low-Grade Inflammation: New Indicators of Arterial Stiffness in the Japanese at High-risk of Cardiovascular Disease

Circulation ◽

10.1161/circ.130.suppl_2.11600 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Satoshi Niijima ◽

Michiaki Nagai ◽

Satoshi Hoshide ◽

Mami Takahashi ◽

Masahisa Shimpo ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

High Risk ◽

Sleep Duration ◽

Aortic Stiffness ◽

The Other ◽

Low Grade ◽

Long Sleep ◽

Hs Crp ◽

Low Grade Inflammation

Background: Recently, several studies have reported that long sleep duration was independently associated with increased aortic stiffness. On the other hand, high-sensitive C-reactive protein (hs-CRP) was associated with increased aortic stiffness. In this study, the relationships among self-reported sleep duration, hs-CRP and pulse wave velocity (PWV) were investigated in the Japanese at high-risk of cardiovascular disease. In addition, we investigated whether antihypertensive treatment moderated these relationships or not. Methods: Among 4310 patients with one or more cardiovascular risks recruited for the Japan Morning Surge-Home Blood Pressure Study, brachial-ankle PWV and hs-CRP measurement were performed in the 2304 patients (64.7 years old, male 49.6%). A self-administered questionnaire included items on daily sleep duration was used. Results: According to the sleep duration (6h or less,6h to 8h,8h or more per night), significant associations of sleep duration were observed with PWV (1594 vs 1644 vs 1763 cm/s, p<0.0001).In the multiple regression analysis adjustment for confounders including age body mass index, total cholesterol, HbA1c and clinic systolic blood pressure (SBP), long sleep duration (8h or more per night) (B: 29, 95%CI: 1.0-56, p<0.05) and log hs-CRP (B: 25, 95%CI: 3.1-48, p<0.05) were significantly positively associated with PWV. A significant interaction was found between long sleep duration and antihypertensive agent non-use for PWV (p<0.05). Especially, in the group without calcium channel blockers (CCBs), long sleep duration was significantly associated with PWV (p<0.01), while a marginal significant synergetic relationship was observed between long sleep duration and log hs-CRP for PWV (p=0.07). On the other hand, there were no significant interactions between long sleep duration and angiotensin receptor blockers non-use. Conclusions: Long sleep duration and hs-CRP were significant indicators of increased PVW in the high-risk Japanese population. In those without CCBs, long sleep duration served as a strong determinant for arterial stiffness, marginally interacted by low-grade inflammation. CCBs use might be important not to aggravate artery remodeling caused by long sleep duration.

Download Full-text