Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels

PMCID: PMC3480949This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Dietary Patterns and Practices and Leucocyte Telomere Length: Findings from the UK Biobank

BACKGROUND: Shorter telomere length (TL) is associated with risk of several age-related diseases and decreased life span, but the extent to which dietary patterns and practices associate with TL is uncertain. OBJECTIVE: This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL). DESIGN: This was a cross-sectional study. PARTICIPANTS AND SETTING: Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010. MAIN OUTCOME MEASURES: LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardized (z-LTL). STATISTICAL ANALYSES PERFORMED: Adherence a priori to a Mediterranean-style diet was assessed through the MedDietScore. Principal component analysis was used to a posteriori extract the "Meat" and "Prudent" dietary patterns. Additional dietary practices considered were the self-reported adherence to "Vegetarian" diet, "Eating 5-a-day of fruit and vegetables" and "Abstaining from eggs/dairy/wheat/sugar." Associations between quintiles of dietary patterns or adherence to dietary practices with z-LTL were investigated through multivariable linear regression models (adjusted for demographic, lifestyle, and clinical characteristics). RESULTS: Adherence to the "Mediterranean" and the "Prudent" patterns, was positively associated with LTL, with an effect magnitude in z-LTL of 0.020 SD and 0.014 SD, respectively, for the highest vs the lowest quintile of adherence to the pattern (both P values < 0.05). Conversely, a reversed association between quintile of the "Meat" pattern and LTL was observed, with z-LTL being on average shorter by 0.025 SD (P = 6.12×10-05) for participants in the highest quintile of the pattern compared with the lowest quintile. For adherents to "5-a-day" z-LTL was on average longer by 0.027 SD (P = 5.36×10-09), and for "abstainers," LTL was shorter by 0.016 SD (P = 2.51×10-04). The association of LTL with a vegetarian diet was nonsignificant after adjustment for demographic, lifestyle, and clinical characteristics. CONCLUSIONS: Several dietary patterns and practices associated with beneficial health effects are significantly associated with longer LTL. However, the magnitude of the association was small, and any clinical relevance is uncertain

Genome-Wide Association Analysis of Incident Coronary Heart Disease (CHD) in African Americans: A Short Report

African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10−08), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans

Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

OBJECTIVE: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. RESEARCH DESIGN AND METHODS: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment. RESULTS: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17–1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs. CONCLUSIONS: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes

The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Case-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.</p> <p>Methods</p> <p>Extensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.</p> <p>Results</p> <p>Only Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.</p> <p>Conclusion</p> <p>We conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.</p

Evaluation of the uptake and delivery of the NHS Health Check programme in England, using primary care data from 9.5 million people: a cross-sectional study.

OBJECTIVES: To describe the uptake and outputs of the National Health Service Health Check (NHSHC) programme in England. DESIGN: Observational study. SETTING: National primary care data extracted directly by NHS Digital from 90% of general practices (GP) in England. PARTICIPANTS: Individuals aged 40-74 years, invited to or completing a NHSHC between 2012 and 2017, defined using primary care Read codes. INTERVENTION: The NHSHC, a structured assessment of non-communicable disease risk factors and 10-year cardiovascular disease (CVD) risk, with recommendations for behavioural change support and therapeutic interventions. RESULTS: During the 5-year cycle, 9 694 979 individuals were offered an NHSHC and 5 102 758 (52.6%) took up the offer. There was geographical variation in uptake between local authorities across England ranging from 25.1% to 84.7%. Invitation methods changed over time to incorporate greater digitalisation, opportunistic delivery and delivery by third-party providers.The population offered an NHSHC resembled the English population in ethnicity and deprivation characteristics. Attendees were more likely to be older and women, but were similar in terms of ethnicity and deprivation, compared with non-attendees. Among attendees, risk factor prevalence reflected population survey estimates for England. Where a CVD risk score was documented, 25.9% had a 10-year CVD risk ≥10%, of which 20.3% were prescribed a statin. Advice, information and referrals were coded as delivered to over 2.5 million individuals identified to have risk factors. CONCLUSION: This national analysis of the NHSHC programme, using primary care data from over 9.5 million individuals offered a check, reveals an uptake rate of over 50% and no significant evidence of inequity by ethnicity or deprivation. To maximise the anticipated value of the NHSHC, we suggest continued action is needed to invite more eligible people for a check, reduce geographical variation in uptake, prioritise engagement with non-attendees and promote greater use of evidence-based interventions especially where risk is identified

The narrow-sense and common single nucleotide polymorphism heritability of early repolarization.

BACKGROUND: Early repolarization (ER) is a risk marker for sudden cardiac death. Higher risk is associated with horizontal/descending ST-segment ER in the inferior or inferolateral ECG leads. Studies in family cohorts have demonstrated substantial heritability for the ER pattern, but genome-wide association studies (GWAS) have failed to identify statistically significant and replicable genetic signals. METHODS AND RESULTS: We assessed the narrow-sense and common single nucleotide polymorphism (SNP) heritability of ER and ER subtypes using ECG data from 5829 individuals (TwinsUK, BRIGHT and GRAPHIC cohorts). ER prevalence was 8.3%. In 455 monozygous vs 808 dizygous twin pairs, concordances and twin correlations for ER subtypes (except horizontal/descending ST-segment ER) were higher and familial resemblance (except notched ER) was significant. Narrow-sense heritability estimates derived from 1263 female twin pairs using the structural equation program Mx ranged from 0.00-0.47 and common SNP heritability estimates derived from 4009 unrelated individuals of both sexes using Genome-wide Restricted Maximum Likelihood (GREML) ranged from 0.00-0.36, but none were statistically significant. CONCLUSION: From our data, ER shows limited genetic predisposition. There appears to be significant environmental influence and these modest narrow-sense and common SNP heritability estimates may explain why previous GWAS have been unsuccessful

A Preclinical Ultrasound Method for the Assessment of Vascular Disease Progression in Murine Models

INTRODUCTION: The efficacy of preclinical ultrasound at providing a quantitative assessment of mouse models of vascular disease is relatively unknown. In this study, preclinical ultrasound was used in combination with a semi-automatic image processing method to track arterial distension alterations in mouse models of abdominal aortic aneurysm and atherosclerosis. METHODS: Longitudinal B-mode ultrasound images of the abdominal aorta were acquired using a preclinical ultrasound scanner. Arterial distension was assessed using a semi-automatic image processing algorithm to track vessel wall motion over the cardiac cycle. A standard, manual analysis method was applied for comparison. RESULTS: Mean arterial distension was significantly lower in abdominal aortic aneurysm mice between day 0 and day 7 post-onset of disease (p < 0.01) and between day 0 and day 14 (p < 0.001), while no difference was observed in sham control mice. Manual analysis detected a significant decrease (p < 0.05) between day 0 and day 14 only. Atherosclerotic mice showed alterations in arterial distension relating to genetic modification and diet. Arterial distension was significantly lower (p < 0.05) in Ldlr−/−(++/−−) mice fed high-fat western diet when compared with both wild type (++/++) mice and Ldlr−/−(++/−−) mice fed chow diet. The manual method did not detect a significant difference between these groups. CONCLUSIONS: Arterial distension can be used as an early marker for the detection of arterial disease in murine models. The semi-automatic analysis method provided increased sensitivity to differences between experimental groups when compared to the manual analysis method