Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage-1) followed by replication study of up to 28,783 participants (stage-2). For novel loci, statistical significance was determined by a P<5.0×10−8 in joint analysis of stage-1 and stage-2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of trans-ethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10−3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for trans-ethnic replication including rs17249754 at ATP2B1 (P=7.5×10−15), rs2681492 at ATP2B1 (P=3.4×10−7), rs11191593 at NT5C2 (1.1×10−6), rs3824755 at CYP17A1 (P=1.2×10−6), and rs13149993 at FGF5 (P=2.4×10−4). Two additional variants showed suggestive evidence of trans-ethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10−5) and rs11191593 at NT5C2 (P=1.1×10−3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10−3) and rs2681492 at ATP2B1 (P=9.0×10−3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mmHg for mean arterial pressure and from 0.03 to 0.21 mmHg for pulse pressure. In conclusion, we present the first evidence of trans-ethnic replication of several mean arterial and pulse pressure loci in an East Asian population

Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure

Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 &times; 10-11 to 5.0 &times; 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 &times; 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation

Mixed Cerebrovascular Disease and the Future of Stroke Prevention

Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed “mixed cerebrovascular disease”, offers a conceptual framework that appears useful for stroke prevention strategies. Mixed cerebrovascular disease incorporates clinical and subclinical syndromes, including ischemic stroke, subclinical infarct, white matter disease of aging (leukoaraiosis), intracerebral hemorrhage, and cerebral microbleeds. Reliance on mixed cerebrovascular disease as a diagnostic entity may assist in stratifying risk of hemorrhagic stroke associated with platelet therapy and anticoagulants. Animal models of hemorrhagic cerebrovascular disease, particularly models of cerebral amyloid angiopathy and hypertension, offer novel means for identifying underlying mechanisms and developing focused therapy. Phosphodiesterase (PDE) inhibitors represent a class of agents that, by targeting both platelets and vessel wall, provide the kind of dual actions necessary for stroke prevention, given the spectrum of disorders that characterizes mixed cerebrovascular disease

Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels

Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5-1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05-0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between -1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The -1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the -1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05-0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05-0.01).The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe