@article {6591, title = {Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Oct 28}, pages = {5068}, abstract = {

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

}, keywords = {Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6068}, author = {Postmus, Iris and Trompet, Stella and Deshmukh, Harshal A and Barnes, Michael R and Li, Xiaohui and Warren, Helen R and Chasman, Daniel I and Zhou, Kaixin and Arsenault, Benoit J and Donnelly, Louise A and Wiggins, Kerri L and Avery, Christy L and Griffin, Paula and Feng, QiPing and Taylor, Kent D and Li, Guo and Evans, Daniel S and Smith, Albert V and de Keyser, Catherine E and Johnson, Andrew D and de Craen, Anton J M and Stott, David J and Buckley, Brendan M and Ford, Ian and Westendorp, Rudi G J and Slagboom, P Eline and Sattar, Naveed and Munroe, Patricia B and Sever, Peter and Poulter, Neil and Stanton, Alice and Shields, Denis C and O{\textquoteright}Brien, Eoin and Shaw-Hawkins, Sue and Chen, Y-D Ida and Nickerson, Deborah A and Smith, Joshua D and Dub{\'e}, Marie Pierre and Boekholdt, S Matthijs and Hovingh, G Kees and Kastelein, John J P and McKeigue, Paul M and Betteridge, John and Neil, Andrew and Durrington, Paul N and Doney, Alex and Carr, Fiona and Morris, Andrew and McCarthy, Mark I and Groop, Leif and Ahlqvist, Emma and Bis, Joshua C and Rice, Kenneth and Smith, Nicholas L and Lumley, Thomas and Whitsel, Eric A and St{\"u}rmer, Til and Boerwinkle, Eric and Ngwa, Julius S and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and Wei, Wei-Qi and Wilke, Russell A and Liu, Ching-Ti and Sun, Fangui and Guo, Xiuqing and Heckbert, Susan R and Post, Wendy and Sotoodehnia, Nona and Arnold, Alice M and Stafford, Jeanette M and Ding, Jingzhong and Herrington, David M and Kritchevsky, Stephen B and Eiriksdottir, Gudny and Launer, Leonore J and Harris, Tamara B and Chu, Audrey Y and Giulianini, Franco and MacFadyen, Jean G and Barratt, Bryan J and Nyberg, Fredrik and Stricker, Bruno H and Uitterlinden, Andr{\'e} G and Hofman, Albert and Rivadeneira, Fernando and Emilsson, Valur and Franco, Oscar H and Ridker, Paul M and Gudnason, Vilmundur and Liu, Yongmei and Denny, Joshua C and Ballantyne, Christie M and Rotter, Jerome I and Adrienne Cupples, L and Psaty, Bruce M and Palmer, Colin N A and Tardif, Jean-Claude and Colhoun, Helen M and Hitman, Graham and Krauss, Ronald M and Wouter Jukema, J and Caulfield, Mark J} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0{\texttimes}10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} } @article {7358, title = {Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Dec}, pages = {835-845}, abstract = {

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1{\texttimes}10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5{\texttimes}10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103966}, author = {Postmus, Iris and Warren, Helen R and Trompet, Stella and Arsenault, Benoit J and Avery, Christy L and Bis, Joshua C and Chasman, Daniel I and de Keyser, Catherine E and Deshmukh, Harshal A and Evans, Daniel S and Feng, QiPing and Li, Xiaohui and Smit, Roelof A J and Smith, Albert V and Sun, Fangui and Taylor, Kent D and Arnold, Alice M and Barnes, Michael R and Barratt, Bryan J and Betteridge, John and Boekholdt, S Matthijs and Boerwinkle, Eric and Buckley, Brendan M and Chen, Y-D Ida and de Craen, Anton J M and Cummings, Steven R and Denny, Joshua C and Dub{\'e}, Marie Pierre and Durrington, Paul N and Eiriksdottir, Gudny and Ford, Ian and Guo, Xiuqing and Harris, Tamara B and Heckbert, Susan R and Hofman, Albert and Hovingh, G Kees and Kastelein, John J P and Launer, Leonore J and Liu, Ching-Ti and Liu, Yongmei and Lumley, Thomas and McKeigue, Paul M and Munroe, Patricia B and Neil, Andrew and Nickerson, Deborah A and Nyberg, Fredrik and O{\textquoteright}Brien, Eoin and O{\textquoteright}Donnell, Christopher J and Post, Wendy and Poulter, Neil and Vasan, Ramachandran S and Rice, Kenneth and Rich, Stephen S and Rivadeneira, Fernando and Sattar, Naveed and Sever, Peter and Shaw-Hawkins, Sue and Shields, Denis C and Slagboom, P Eline and Smith, Nicholas L and Smith, Joshua D and Sotoodehnia, Nona and Stanton, Alice and Stott, David J and Stricker, Bruno H and St{\"u}rmer, Til and Uitterlinden, Andr{\'e} G and Wei, Wei-Qi and Westendorp, Rudi G J and Whitsel, Eric A and Wiggins, Kerri L and Wilke, Russell A and Ballantyne, Christie M and Colhoun, Helen M and Cupples, L Adrienne and Franco, Oscar H and Gudnason, Vilmundur and Hitman, Graham and Palmer, Colin N A and Psaty, Bruce M and Ridker, Paul M and Stafford, Jeanette M and Stein, Charles M and Tardif, Jean-Claude and Caulfield, Mark J and Jukema, J Wouter and Rotter, Jerome I and Krauss, Ronald M} } @article {7353, title = {A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 May}, pages = {313-323}, abstract = {

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104112}, author = {Noordam, Raymond and Sitlani, Colleen M and Avery, Christy L and Stewart, James D and Gogarten, Stephanie M and Wiggins, Kerri L and Trompet, Stella and Warren, Helen R and Sun, Fangui and Evans, Daniel S and Li, Xiaohui and Li, Jin and Smith, Albert V and Bis, Joshua C and Brody, Jennifer A and Busch, Evan L and Caulfield, Mark J and Chen, Yii-der I and Cummings, Steven R and Cupples, L Adrienne and Duan, Qing and Franco, Oscar H and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Harris, Tamara B and Heckbert, Susan R and van Heemst, Diana and Hofman, Albert and Floyd, James S and Kors, Jan A and Launer, Lenore J and Li, Yun and Li-Gao, Ruifang and Lange, Leslie A and Lin, Henry J and de Mutsert, Ren{\'e}e and Napier, Melanie D and Newton-Cheh, Christopher and Poulter, Neil and Reiner, Alexander P and Rice, Kenneth M and Roach, Jeffrey and Rodriguez, Carlos J and Rosendaal, Frits R and Sattar, Naveed and Sever, Peter and Seyerle, Amanda A and Slagboom, P Eline and Soliman, Elsayed Z and Sotoodehnia, Nona and Stott, David J and St{\"u}rmer, Til and Taylor, Kent D and Thornton, Timothy A and Uitterlinden, Andr{\'e} G and Wilhelmsen, Kirk C and Wilson, James G and Gudnason, Vilmundur and Jukema, J Wouter and Laurie, Cathy C and Liu, Yongmei and Mook-Kanamori, Dennis O and Munroe, Patricia B and Rotter, Jerome I and Vasan, Ramachandran S and Psaty, Bruce M and Stricker, Bruno H and Whitsel, Eric A} } @article {7448, title = {PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, pages = {e001632}, abstract = {

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3\%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1\%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95\% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95\% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95\% CI, 0.28-0.92) in blacks and 0.82 (95\% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95\% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95\% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001632}, author = {Kent, Shia T and Rosenson, Robert S and Avery, Christy L and Chen, Yii-der I and Correa, Adolfo and Cummings, Steven R and Cupples, L Adrienne and Cushman, Mary and Evans, Daniel S and Gudnason, Vilmundur and Harris, Tamara B and Howard, George and Irvin, Marguerite R and Judd, Suzanne E and Jukema, J Wouter and Lange, Leslie and Levitan, Emily B and Li, Xiaohui and Liu, Yongmei and Post, Wendy S and Postmus, Iris and Psaty, Bruce M and Rotter, Jerome I and Safford, Monika M and Sitlani, Colleen M and Smith, Albert V and Stewart, James D and Trompet, Stella and Sun, Fangui and Vasan, Ramachandran S and Woolley, J Michael and Whitsel, Eric A and Wiggins, Kerri L and Wilson, James G and Muntner, Paul} } @article {7775, title = {Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.}, journal = {Br J Nutr}, year = {2018}, month = {2018 Sep 12}, pages = {1-12}, abstract = {

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1{\textperiodcentered}1 ml in EA (95 \% CI 0{\textperiodcentered}9, 1{\textperiodcentered}3; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}8 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}5; P<0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}06), and forced vital capacity (FVC) was higher by 1{\textperiodcentered}3 ml in EA (95 \% CI 1{\textperiodcentered}0, 1{\textperiodcentered}6; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}5 ml (95 \% CI 0{\textperiodcentered}8, 2{\textperiodcentered}3; P=0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}3) for current smokers and 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}2, 2{\textperiodcentered}1) for former smokers, compared with 0{\textperiodcentered}8 ml (95 \% CI 0{\textperiodcentered}4, 1{\textperiodcentered}2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

}, issn = {1475-2662}, doi = {10.1017/S0007114518002180}, author = {Xu, Jiayi and Bartz, Traci M and Chittoor, Geetha and Eiriksdottir, Gudny and Manichaikul, Ani W and Sun, Fangui and Terzikhan, Natalie and Zhou, Xia and Booth, Sarah L and Brusselle, Guy G and de Boer, Ian H and Fornage, Myriam and Frazier-Wood, Alexis C and Graff, Mariaelisa and Gudnason, Vilmundur and Harris, Tamara B and Hofman, Albert and Hou, Ruixue and Houston, Denise K and Jacobs, David R and Kritchevsky, Stephen B and Latourelle, Jeanne and Lemaitre, Rozenn N and Lutsey, Pamela L and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Pankow, James S and Psaty, Bruce M and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Smith, Lewis J and Stricker, Bruno H and Voruganti, V Saroja and Wang, Thomas J and Zillikens, M Carola and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Lahousse, Lies and London, Stephanie J and North, Kari E and Smith, Albert V and Steffen, Lyn M and Hancock, Dana B and Cassano, Patricia A} } @article {7776, title = {Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.}, journal = {Am J Respir Crit Care Med}, year = {2018}, month = {2018 Sep 10}, abstract = {

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4{\texttimes}10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80\%) was associated with lower FVC (P=2.1{\texttimes}10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1{\texttimes}10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

}, issn = {1535-4970}, doi = {10.1164/rccm.201802-0304OC}, author = {Xu, Jiayi and Gaddis, Nathan C and Bartz, Traci M and Hou, Ruixue and Manichaikul, Ani W and Pankratz, Nathan and Smith, Albert V and Sun, Fangui and Terzikhan, Natalie and Markunas, Christina A and Patchen, Bonnie K and Schu, Matthew and Beydoun, May A and Brusselle, Guy G and Eiriksdottir, Gudny and Zhou, Xia and Wood, Alexis C and Graff, Mariaelisa and Harris, Tamara B and Ikram, M Arfan and Jacobs, David R and Launer, Lenore J and Lemaitre, Rozenn N and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Psaty, Bruce M and Ramachandran, Vasan S and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Smith, Lewis J and Tiemeier, Henning and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and Voruganti, V Saroja and Xu, Hanfei and Zilh{\~a}o, Nuno R and Fornage, Myriam and Zillikens, M Carola and London, Stephanie J and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Gudnason, Vilmundur and Lahousse, Lies and North, Kari E and Steffen, Lyn M and Cassano, Patricia A and Hancock, Dana B} } @article {9372, title = {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.}, journal = {Am J Hypertens}, volume = {32}, year = {2019}, month = {2019 Nov 15}, pages = {1146-1153}, abstract = {

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 {\texttimes} 10-8) and in the race-combined analysis (P = 1.5 {\texttimes} 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95\% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

}, keywords = {Aged, Antihypertensive Agents, Black or African American, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States, White People}, issn = {1941-7225}, doi = {10.1093/ajh/hpz150}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Floyd, James S and Psaty, Bruce M and Bis, Joshua C and Wiggins, Kerri L and Whitsel, Eric A and St{\"u}rmer, Til and Stewart, James and Raffield, Laura and Sun, Fangui and Liu, Ching-Ti and Xu, Hanfei and Cupples, Adrienne L and Tanner, Rikki M and Rossing, Peter and Smith, Albert and Zilh{\~a}o, Nuno R and Launer, Lenore J and Noordam, Raymond and Rotter, Jerome I and Yao, Jie and Li, Xiaohui and Guo, Xiuqing and Limdi, Nita and Sundaresan, Aishwarya and Lange, Leslie and Correa, Adolfo and Stott, David J and Ford, Ian and Jukema, J Wouter and Gudnason, Vilmundur and Mook-Kanamori, Dennis O and Trompet, Stella and Palmas, Walter and Warren, Helen R and Hellwege, Jacklyn N and Giri, Ayush and O{\textquoteright}donnell, Christopher and Hung, Adriana M and Edwards, Todd L and Ahluwalia, Tarunveer S and Arnett, Donna K and Avery, Christy L} }