scholarly journals Pharmacogenomics in Hypertension: Where We Stand Today

2019 ◽  
Author(s):  
Patrick N. Cunningham ◽  
Arlene B. Chapman
Keyword(s):  
Blood Pressure ◽  
Genetic Variants ◽  
Association Studies ◽  
Pressure Control ◽  
Medical Problem ◽  
Large Individual ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Improve Blood Pressure Control ◽  
Antihypertensive Response

Hypertension is a common and growing medical problem that leads to enormous cardiovascular and kidney disease worldwide. While many drugs exist to treat hypertension, there is large individual variation in how a given individual responds to different agents, which contributes to dismal rates of hypertension control. While demographic factors predict which drugs may work better in certain individuals, a great degree of this variation has a genetic basis. In recent years, genome wide association studies have begun to identify specific gene variants that predict drug response to particular agents. This review identifies the major genetic variants influencing antihypertensive response that have emerged from this growing body of work. For novel genetic variants without a previously known biologic basis in blood pressure, it is crucial to validate initial findings in subsequent studies. This information may eventually lead to a more personalized approach to hypertension management that will improve blood pressure control and patient outcomes. The integration of this large amount of data and its real world application will be highly challenging, but strategies to accomplish this are discussed.

scholarly journals Association of Established Blood Pressure Loci With 10‐Year Change in Blood Pressure and Their Ability to Predict Incident Hypertension

2020 ◽  
Vol 9 (16) ◽  
Author(s):  
Alaitz Poveda ◽  
Naeimeh Atabaki‐Pasdar ◽  
Shafqat Ahmad ◽  
Göran Hallmans ◽  
Frida Renström ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Genetic Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Swedish Population ◽  
Long Term Changes ◽  
Traditional Risk Factors

Background Genome‐wide association studies have identified >1000 genetic variants cross‐sectionally associated with blood pressure variation and prevalent hypertension. These discoveries might aid the early identification of subpopulations at risk of developing hypertension or provide targets for drug development, amongst other applications. The aim of the present study was to analyze the association of blood pressure‐associated variants with long‐term changes (10 years) in blood pressure and also to assess their ability to predict hypertension incidence compared with traditional risk variables in a Swedish population. Methods and Results We constructed 6 genetic risk scores (GRSs) by summing the dosage of the effect allele at each locus of genetic variants previously associated with blood pressure traits (systolic blood pressure GRS (GRS SBP ): 554 variants; diastolic blood pressure GRS (GRS DBP ): 481 variants; mean arterial pressure GRS (GRS MAP ): 20 variants; pulse pressure GRS (GRS PP ): 478 variants; hypertension GRS (GRS HTN ): 22 variants; combined GRS (GRS com b ): 1152 variants). Each GRS was longitudinally associated with its corresponding blood pressure trait, with estimated effects per GRS SD unit of 0.50 to 1.21 mm Hg for quantitative traits and odds ratios (ORs) of 1.10 to 1.35 for hypertension incidence traits. The GRS comb was also significantly associated with hypertension incidence defined according to European guidelines (OR, 1.22 per SD; 95% CI, 1.10‒1.35) but not US guidelines (OR, 1.11 per SD; 95% CI, 0.99‒1.25) while controlling for traditional risk factors. The addition of GRS comb to a model containing traditional risk factors only marginally improved discrimination (Δarea under the ROC curve = 0.001–0.002). Conclusions GRSs based on discovered blood pressure‐associated variants are associated with long‐term changes in blood pressure traits and hypertension incidence, but the inclusion of genetic factors in a model composed of conventional hypertension risk factors did not yield a material increase in predictive ability.

scholarly journals Bivariate genome-wide association study (GWAS) of body mass index and blood pressure phenotypes in northern Chinese twins

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246436
Author(s):  
Zhaoying Li ◽  
Weijing Wang ◽  
Xiaocao Tian ◽  
Haiping Duan ◽  
Chunsheng Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Body Mass ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Northern Chinese

Recently, new loci related to body mass index (BMI) or blood pressure (BP) have been identified respectively in genome-wide association studies (GWAS). However, limited studies focused on jointly associated genetic variance between systolic pressure (SBP), diastolic pressure (DBP) and BMI. Therefore, a bivariate twin study was performed to explore the genetic variants associated with BMI-SBP, BMI-DBP and SBP-DBP. A total of 380 twin pairs (137 dizygotic pairs and 243 monozygotic pairs) recruited from Qingdao Twin Registry system were used to access the genetic correlations (0.2108 for BMI-SBP, 0.2345 for BMI-DBP, and 0.6942 for SBP-DBP, respectively) by bivariate Cholesky decomposition model. Bivariate GWAS in 137 dizygotic pairs nominated 27 single identified 27 quantitative trait nucleotides (QTNs) for BMI and SBP, 27 QTNs for BMI and DBP, and 25 QTNs for SBP and DBP with the suggestive P-value threshold of 1×10−5. After imputation, we found eight SNPs, one for both BMI-SBP and SBP-DBP, and eight for SBP-DBP, exceed significant statistic level. Expression quantitative trait loci analysis identified rs4794029 as new significant eQTL in tissues related to BMI and SBP. Also, we found 6 new significant eQTLs (rs4400367, rs10113750, rs11776003, rs3739327, rs55978930, and rs4794029) in tissues were related to SBP and DBP. Gene-based analysis identified nominally associated genes (P < 0.05) with BMI-SBP, BMI-DBP, and SBP-DBP, respectively, such as PHOSPHO1, GNGT2, KEAP1, and S1PR5. In the pathway analysis, we found some pathways associated with BMI-SBP, BMI-DBP and SBP-DBP, such as prion diseases, IL5 pathway, cyclin E associated events during G1/S transition, TGF beta signaling pathway, G βγ signaling through PI3Kγ, prolactin receptor signaling etc. These findings may enrich the results of genetic variants related to BMI and BP traits, and provide some evidences to future study the pathogenesis of hypertension and obesity in the northern Chinese population.

A Hypertension Gene: Are We There Yet?

2011 ◽  
Vol 14 (4) ◽  
pp. 295-304 ◽  
Author(s):  
Samantha J. Lupton ◽  
Christine L. Chiu ◽  
Joanne M. Lind
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Diseases ◽  
Association Studies ◽  
Single Gene ◽  
Pressure Control ◽  
Genome Wide Association Studies ◽  
Candidate Gene Association ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Treatment Of Hypertension

Cardiovascular diseases are the leading cause of death worldwide. Essential hypertension is a major risk factor for the development of other cardiovascular diseases and is caused by a combination of environmental and genetic factors, with up to 50% of blood pressure variance currently attributed to an individual's genetic makeup. By studying genes that cause monogenic forms of hypertension and pathways relevant to blood pressure control, a number of polymorphisms have been identified that increase an individual's risk of developing high blood pressure. We report on candidate gene association studies and genome-wide association studies that have been performed to date in the field of hypertension research. It is becoming clear that for the majority of people there is no single gene polymorphism that causes hypertension, but rather a number of common genetic variants, each having a small effect. Using pharmacogenomics to personalize the treatment of hypertension holds promise for achieving and sustaining normotensive pressures quickly, while minimizing the risk of adverse reactions and unwanted side-effects. This will decrease the risk of stroke and myocardial infarction in individuals and lead to a reduced burden of disease upon society as a whole.

scholarly journals FUNCTIONAL IN SILICO ANALYSIS OF GENETIC VARIANTS FROM GENOME-WIDE ASSOCIATION STUDIES OF BLOOD PRESSURE AND HYPERTENSION

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e260-e261
Author(s):  
Sanjeev Pramanik ◽  
Xiao Jiang ◽  
James Eales ◽  
Xiaoguang Xu ◽  
Sushant Saluja ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genetic Variants ◽  
In Silico ◽  
Association Studies ◽  
In Silico Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Silico Analysis

Abstract MP60: Investigation of Blood Pressure Genetic Loci in African Americans using the Metabochip

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Cara L Carty ◽  
Lucia A Hindorff ◽  
Steven Buyske ◽  
Jeff Haessler ◽  
Megan D Fesinmeyer ◽  
...  
Keyword(s):  
Blood Pressure ◽  
African Americans ◽  
Genetic Variants ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
European Descent ◽  
Gwas Snps ◽  
Significance Threshold ◽  
Original Gwas

Introduction. African Americans (AA) have a higher burden of hypertension than European descent individuals, thus motivating research on blood pressure (BP) risk factors in AA, including genetic variants. Yet to date, few genome-wide association studies (GWAS) of BP have been conducted in AA and it is unclear whether genetic variants identified in mainly European descent populations are also associated with BP in AA. Furthermore, investigation of established BP loci in diverse race/ethnicity groups such as AA, who tend to have higher levels of genetic diversity, provides opportunities to narrow loci for identifying potential causal variants. Methods. We examined whether systolic BP (SBP) and diastolic BP (DBP) loci on the Illumina Metabochip array were associated with BP traits in 18,832 AA from the PAGE, HyperGen and GenNet studies. Only SNPs with minor allele frequency≥0.001 and passing stringent QC were tested. Using p-value<0.05 as a significance threshold for replication of GWAS SNPs in our AA population, we investigated the original GWAS SNP and all SNPs ±500 kilobases in modest linkage disequilibrium with it (r 2 ≥0.3). To test SNPs in the 16 SBP and 14 DBP loci, we used a Bonferroni corrected p-value of 0.05/total SNPs per locus (the number SNPs at each BP locus ranges from 104 to 2,337). Results. In models adjusted for sex, age, body mass index and global ancestry, 5 prior GWAS SNPs were associated (p<0.05) with DBP: rs13107325/ SLC39A8 (non-synonymous), rs1165196/ SLC17A1 (non-synonymous), rs6495122/ CPLX3 , rs1327235/intergenic and rs6015450/intergenic. At several loci, we identified finely-mapped SNPs more strongly associated with DBP in AA than the original GWAS SNPs. Notably, we identified rs56153133 in the gene-rich 1p26 region harboring the chloride channel-voltage-sensitive-6 ( CLCN6 ) gene, p=6.9E-5. This SNP is highly correlated with the GWAS SNP rs17367504/ MTHFR in European-descent individuals (r 2 =0.98) and less so in AA (r 2 =0.64). For SBP, we replicated two GWAS SNPs: rs16998073/intergenic and rs2681472/ ATP2B1 and at many loci (10q24, 1p26, 15q26 et al .), we identified SNPs more strongly associated with SBP in AA than the original GWAS SNPs. Conclusions. Overall, several BP loci originally reported in individuals of European and East Asian ancestry also generalize to AA, which confirms the relevance of specific BP susceptibility loci across diverse populations. In addition, we identified SNPs more strongly associated with BP traits in AA than the original GWAS SNPs, underlying the importance of leveraging differences in nucleotide diversity and LD patterns among populations to narrow GWAS signal boundaries. Future work will include conditional analysis to further refine GWAS loci, and to identify additional signals and population-specific variation.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

scholarly journals Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323906
Author(s):  
Jue-Sheng Ong ◽  
Jiyuan An ◽  
Xikun Han ◽  
Matthew H Law ◽  
Priyanka Nandakumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Testing ◽  
Association Studies ◽  
Barrett’S Oesophagus ◽  
Oesophageal Reflux ◽  
Oesophageal Adenocarcinoma ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Disease Heterogeneity ◽  
Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

scholarly journals Case–Parent Trio Studies in Cleft Lip and Palate

2020 ◽  
Vol 07 (03) ◽  
pp. 075-079
Author(s):  
Mahamad Irfanulla Khan ◽  
Prashanth CS
Keyword(s):  
Genetic Variants ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Geographical Location ◽  
Genetic Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Family Based ◽  
Study Designs

AbstractCleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans involving various genetic and environmental risk factors. The prevalence of CL/P varies according to geographical location, ethnicity, race, gender, and socioeconomic status, affecting approximately 1 in 800 live births worldwide. Genetic studies aim to understand the mechanisms contributory to a phenotype by measuring the association between genetic variants and also between genetic variants and phenotype population. Genome-wide association studies are standard tools used to discover genetic loci related to a trait of interest. Genetic association studies are generally divided into two main design types: population-based studies and family-based studies. The epidemiological population-based studies comprise unrelated individuals that directly compare the frequency of genetic variants between (usually independent) cases and controls. The alternative to population-based studies (case–control designs) includes various family-based study designs that comprise related individuals. An example of such a study is a case–parent trio design study, which is commonly employed in genetics to identify the variants underlying complex human disease where transmission of alleles from parents to offspring is studied. This article describes the fundamentals of case–parent trio study, trio design and its significances, statistical methods, and limitations of the trio studies.

scholarly journals Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shuquan Rao ◽  
Yao Yao ◽  
Daniel E. Bauer
Keyword(s):  
Genome Editing ◽  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Functional Genetics ◽  
Genome Wide ◽  
Causal Variants ◽  
Experimental Approaches

AbstractGenome-wide association studies (GWAS) have uncovered thousands of genetic variants that influence risk for human diseases and traits. Yet understanding the mechanisms by which these genetic variants, mainly noncoding, have an impact on associated diseases and traits remains a significant hurdle. In this review, we discuss emerging experimental approaches that are being applied for functional studies of causal variants and translational advances from GWAS findings to disease prevention and treatment. We highlight the use of genome editing technologies in GWAS functional studies to modify genomic sequences, with proof-of-principle examples. We discuss the challenges in interrogating causal variants, points for consideration in experimental design and interpretation of GWAS locus mechanisms, and the potential for novel therapeutic opportunities. With the accumulation of knowledge of functional genetics, therapeutic genome editing based on GWAS discoveries will become increasingly feasible.

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

Sign in / Sign up

Export Citation Format

Share Document