Obesity-associated hypertension is ameliorated in patients with TLR4 single nucleotide polymorphism (SNP) rs4986790.
ABSTRACT: BACKGROUND:Obesity is strongly associated with hypertension. Despite numerous mechanistic links the association is not fully understood. Western diet increases uptake of Toll-Like receptor 4 (TLR4) ligands such as free fatty acids or endotoxin. We recently demonstrated that TLR4 ligands are involved in the development of hypertension. We hypothesized that TLR4 ligands are involved in obesity-associated hypertension and investigated the TLR4 single nucleotide polymorphism (SNP rs 498790). This SNP is frequent, associated with cardiovascular disease and characterized by blunted response upon exposure to TLR4 ligands. METHODS:We investigated 3657 patients undergoing coronary angiography. Blood pressure was determined in standardized manner prior angiography. The diagnosis of hypertension was based on record data. Patients were characterized for TLR4 single nucleotide polymorphism (SNP) rs4986790. Patients were stratified according to quartiles of Body mass index (BMI) and according to the polymorphism. The association between the TLR4 polymorphism and blood pressure in obese patients (BMI?>?30 kg/m(2)) was investigated by multivariate regression analysis. RESULTS:Out of 3657 patients 3017 patients fulfilled inclusion criteria. In the whole cohort a significant increase of SBP, pulse pressure and diagnosis of hypertension was observed across BMI quartiles. By contrast, no significant increase of SBP, pulse pressure or diagnosis of hypertension was observed in the 319 cases with TLR4 SNP rs4986790 across BMI quartiles. These obese cases had significantly lower SBP, lower pulse pressure (7.0 and 7.6 mmHg) and less diagnosis of hypertension as controls. In obesity the TLR4 SNP rs4986790 was an independent predictor of SBP. CONCLUSION:Systolic blood pressure increase with obesity was blunted in cases with TLR4 SNP rs4986790.
Project description:BACKGROUND:Systolic blood pressure (SBP) increases steadily with age and bears an independent continuous relationship with the incidence of cardiovascular events. Low-grade inflammation is a suspected pathomechanism causing vascular aging and promote coronary artery disease (CAD). Recent animal studies give evidence that Toll-like receptor 4 (TLR4) modulate inflammation and contribute to age-dependent SBP increase. However, there are no data about TLR4 and age-dependent blood pressure increase in human. METHODS AND RESULTS:We therefor investigate a human cohort of 2679 patients with CAD aged between 50-80 years. Genotypes were determined for the TLR4 single nucleotide polymorphism rs4986790 (TLR4 896A/G). Patients were stratified according to tertiles of age and the upper tertile was compared to lower tertiles. In this cohort we show that older patients with the TLR4 896 G allele had significantly lower SBP (TLR4 G allele carriers: 148.2?±?30.4 mmHg versus A/A allele carrier: 154.9?±?27.2 mmHg; P?<?0.05) and lower pulse pressure (TLR4 G allele carriers: 69.1?±?29.7 mmHg versus A/A allele carrier: 75.5?±?26.4 mmHg; P?<?0.05) as compared to TLR4 896A/A allele carrier. CONCLUSION:We demonstrate an association between the TLR4 SNP rs4986790 genotype and age-dependant blood pressure increase in patients with coronary artery disease.
Project description:<h4>Background</h4>Recent studies have reported that height is inversely associated with blood pressure and hypertension. However, there is lack of comprehensive findings from Bangladesh in this regard.<h4>Objective</h4>The purpose of this study was to explore the association between height and blood pressure in a Bangladeshi population.<h4>Setting</h4>Rural and urban sites from seven divisions of Bangladesh.<h4>Participants</h4>Participants were 7932 males and females (aged ?35 years) evaluated in the 2011 Bangladesh Demographic Health Survey. Participants (n = 7647) who had complete height, weight, systolic and diastolic blood pressure (SBP and DBP) measurements and non-missing medication history, were included in the analysis.<h4>Methods</h4>Hypertension was defined as an SBP over 140 mmHg or/and a DBP over 90 mmHg, or current use of antihypertensive medication. Difference between SBP and DBP was calculated to get pulse pressure (PP). Multivariate linear and logistic regression models were used.<h4>Results</h4>PP decreased linearly with increasing height among males (-0.11, P < 0.05) and females (-0.19, P < 0.05) after adjusting for age, BMI, living region, type of occupation, wealth index, and highest level of education. SBP decreased linearly with increasing height among only females (-0.14, P < 0.05), after adjusting for age, BMI, living region, type of occupation, wealth index, and highest level of education. No association was found between quartiles of height and prevalence of hypertension.<h4>Conclusions</h4>Height was found to be inversely associated with pulse pressure in both sexes. Studies with longitudinal design are needed to investigate the association between shortness with blood pressure and hypertension.
Project description:The study of genetic polymorphisms and body mass index (BMI) among African women in Africa and in the United States contributes to our understanding of the genetic and environmental risk factors for hypertension. African American women have the highest prevalence of hypertension and obesity compared to other ethnic groups in the United States. Using a cross-sectional research design, we examined the effects of genetic and environmental risks of single nucleotide polymorphisms (SNPs) and BMI on blood pressure (BP) among three generations of West African Dogon women (N = 199). We genotyped six SNPs located in the candidate genes known to be related to hypertension. We tested the associations between these SNPs and systolic BP (SBP) and diastolic BP (DBP) with Fisher's exact tests, chi-square tests for independence, and multivariable linear mixed models. The SNP rs8179526 (SLC4A5) was significantly associated with SBP adjusted for age, age(2), and BMI (p = .02). The "C" allele variant of rs8179526 (allele frequency of 0.445) was associated with higher SBP. This SNP did not deviate from the Hardy-Weinberg equilibrium (HWE) with p value of .772. The SNP × BMI interaction effects associated with SBP and DBP were not significant. rs8179526 is located on the SLC4A5 gene on chromosome 2. SLC4A5 encodes a protein that transports sodium and bicarbonate across cell membranes while regulating cellular pH and contains several SNPs linked to elevated BP. Knowledge of the SNP's effect on hypertension among West African women can help health practitioners educate their patients about genetic risks of developing hypertension.
Project description:BACKGROUND: Toll-like-receptor 4 (TLR) is discussed to provide a molecular link between obesity, inflammation and insulin resistance. Genetic studies with replications in non-diabetic individuals in regard to their fat distribution or insulin resistance according to their carrier status of a common toll-like receptor 4 (TLR4) variant (TLR4(D299G/T399I)) are still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional analysis in individuals phenotyped for prediabetic traits as body fat composition (including magnetic resonance imaging), blood glucose levels and insulin resistance (oral glucose tolerance testing, euglycemic hyperinsulinemic clamp), according to TLR4 genotype determined by candidate SNP analyses (rs4986790). We analyzed N?=?1482 non-diabetic individuals from the TÜF/TULIP cohort (South Germany, aged 39±13 y, BMI 28.5±7.9, mean±SD) and N?=?5327 non-diabetic participants of the METSIM study (Finland, males aged 58±6 y, BMI 26.8±3.8) for replication purposes. German TLR4(D299G/T399I) carriers had a significantly increased body fat (XG in rs4986790: +6.98%, p?=?0.03, dominant model, adjusted for age, gender) and decreased insulin sensitivity (XG: -15.3%, Matsuda model, p?=?0.04; XG: -20.6%, p?=?0.016, clamp; both dominant models adjusted for age, gender, body fat). In addition, both liver fat (AG: +49.7%; p?=?0.002) and visceral adipose tissue (AG: +8.2%; p?=?0.047, both adjusted for age, gender, body fat) were significantly increased in rs4986790 minor allele carriers, and the effect on liver fat remained significant also after additional adjustment for visceral fat (p?=?0.014). The analysis in METSIM confirmed increased body fat content in association with the rare G allele in rs4986790 (AG: +1.26%, GG: +11.0%; p?=?0.010, additive model, adjusted for age) and showed a non-significant trend towards decreased insulin sensitivity (AG: -0.99%, GG: -10.62%). CONCLUSIONS/SIGNIFICANCE: TLR4(D299G/T399I) associates with increased total body fat, visceral fat, liver fat and decreased insulin sensitivity in non-diabetic Caucasians and may contribute to diabetes risk. This finding supports the role of TLR4 as a molecular link between obesity and insulin resistance.
Project description:African American women have the highest prevalence of hypertension and obesity of any group in the United States. African American girls have the highest incidence of obesity of any groups of children in the nation, and diagnoses of hypertension have been rising among this group. Because both genetic heredity and body mass index (BMI) are important risk factors for hypertension, this study examined the gene-BMI interaction for hypertension across the lifespan in two generations of African American women. Participants comprised of 868 African American women in the parent cohort and 322 in the offspring cohort from the Hypertension Genetic Epidemiology Network (HyperGEN) study, part of the Family Blood Pressure Program (FBPP). A total of 115 single-nucleotide polymorphisms (SNPs) were evaluated among the parent cohort and 491 among the offspring cohort for tests of SNP-BMI interaction using methods of false discovery rate (FDR; <.20) and examination of minor allele frequency (MAF; >.05) and Hardy-Weinberg equilibrium (>.10). One SNP (located in the CAPN 13 gene, rs1879282) passed adjustments for the multiple testing mentioned above and had a significant (p < .01) gene-BMI interaction on both systolic blood pressure (SBP) and diastolic blood pressure (DBP) among African American female offspring. The rs1879282 SNP is located on chromosome 2 on the calpain (CAPN) 13 gene, which is part of a family of cytosolic calcium-activated proteases involved in apoptosis, cell division, modulation of integrin-cytoskeletal interactions, and synaptic plasticity. This SNP was not available for testing in the African American parent cohort.
Project description:Genetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure (BP), BMI, and high-density lipoprotein cholesterol (HDL-C).This study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, wherein ancestry association evidence for hypertension, BMI, or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1733 unrelated African-Americans from the National Heart, Lung and Blood Institute's Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, SBP, DBP, BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age, sex, local marker ancestry, and BMI, as applicable. An individual's African ancestry estimated from 2507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.CXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (P?<?0.0006). F2RL1 (rs631465) on chromosome 5 was associated with BMI (P?=?0.0005). Local ancestry in these regions was associated with the respective traits as well.This study suggests that CXADR and F2RL1 likely play important roles in BP and obesity variation, respectively; and these findings are consistent with those of other studies, so replication and functional analyses are necessary.
Project description:OBJECTIVE:Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African-Americans. METHODS:We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African-Americans and performed a case-control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components). RESULTS:A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P?=?9.3?×?10). For SBP, rs3917420 in the SELE gene (P?=?9.0?×?10) and rs4657251 in the RGS5 gene (P?=?9.7?×?10) were the top hits. Effect size for each of these variants was approximately 2-3?mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P?<?0.01). CONCLUSION:These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.
Project description:OBJECTIVE:Coiled-coil-helix-coiled-coil-helix domain containing 5 (CHCHD5), a mitochondrial protein, is involved in the oxidative folding process in the mitochondrial intermembrane space. A previous study identified a hypertension-related single nucleotide polymorphism (SNP), rs3748024, in CHCHD5 in adults, but there are no reports regarding the association between CHCHD5 and obesity, which is a known risk factor for hypertension. The aim of the present study is to investigate the associations of the SNP rs3748024 with hypertension and obesity. DESIGN:Cohort study. SETTING:Institute of Pediatrics in China. PARTICIPANTS:We genotyped the SNP rs3748024 in the Beijing Child and Adolescent Metabolic Syndrome study. A total of 3503 children participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES:Genotyping of rs3748024 was conducted using the TaqMan Allelic Discrimination Assay. Lipids and glucose were analysed by an automatic biochemical analyser using a kit assay. The levels of adipocytokines (leptin, adiponectin and resistin) were measured by ELISA techniques. RESULTS:There was a statistically significant association between rs3748024 and systolic blood pressure (SBP) (?=-0.853, 95% CI -1.482 to -0.024, p=0.044) under an additive model adjusted for age, gender and body mass index (BMI) after correction for multiple testing. The SNP was also significantly associated with BMI (?=-0.286, 95% CI -0.551 to -0.021, p=0.043), obesity (OR=0.828, 95% CI 0.723 to 0.949, p=0.018) and triglycerides (?=-0.039, 95% CI -0.070 to -0.007, p=0.044) after correction for multiple testing. CONCLUSIONS:We demonstrate for the first time that the SNP rs3748024 in CHCHD5 is associated with SBP, BMI, obesity and triglycerides in Chinese children. Our study identifies a new risk locus for hypertension and obesity in a child population. The function of CHCHD5 remains to be further studied to help elucidate the pathogenic role of CHCHD5 in hypertension and obesity.
Project description:It is a well established fact that age, ethnicity, weight, and lifestyle behaviors can affect blood pressure (BP). Co-morbid conditions such as HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), pre-eclampsia, and previous hypertension diagnosis might also be risks for chronic hypertension among women who have had children. Although parity has been linked to changes in blood pressure in White women, these findings have not been replicated among African-American women. The purpose of this study was to determine if the number of pregnancies urban African-American women have effects BMI and blood pressure readings later in life. Results indicated that women with a previous diagnosis of hypertension had higher SBP and DBP, and a slightly higher BMI than women who had never been diagnosed. Additionally, women with a prior history of hypertension had more children than those without a diagnosis of hypertension. As parity increased, SBP increased. However, DBP decreased after 3 to 4 children, even with increases in BMI. This study shows that parity may increase African-American women's risk for hypertension in terms of increased SBP and BMI with increased parity. However, increased parity and BMI may also serve as protective factors in lowering DBP. Further studies, with larger samples followed throughout their pregnancies, is needed before more definitive statements may be drawn about the effects of parity on BMI and blood pressure readings among African-American women can be made.
Project description:Background: Essential hypertension (EH) is a chronic disease of universal high prevalence and a well-established independent risk factor for cardiovascular and cerebrovascular events. The regulation of blood pressure is crucial for improving life quality and prognoses in patients with EH. Therefore, it is of important clinical significance to develop prediction models to recognize individuals with high risk for EH. Methods: In total, 965 subjects were recruited. Clinical parameters and genetic information, namely EH related SNPs were collected for each individual. Traditional statistic methods such as t-test, chi-square test and multi-variable logistic regression were applied to analyze baseline information. A machine learning method, mainly support vector machine (SVM), was adopted for the development of the present prediction models for EH. Results: Two models were constructed for prediction of systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. The model for SBP consists of 6 environmental factors (age, BMI, waist circumference, exercise [times per week], parental history of hypertension [either or both]) and 1 SNP (rs7305099); model for DBP consists of 6 environmental factors (weight, drinking, exercise [times per week], TG, parental history of hypertension [either and both]) and 3 SNPs (rs5193, rs7305099, rs3889728). AUC are 0.673 and 0.817 for SBP and DBP model, respectively. Conclusions: The present study identified environmental and genetic risk factors for EH in northern Han Chinese population and constructed prediction models for SBP and DBP.