@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} } @article {9007, title = {Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 12}, pages = {e003460}, abstract = {

BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.

METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.

RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in and 3 previously reported loci at , , and . One known locus at was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6\% increase in hs-cTnT levels (minor allele frequency, 0.18; =2.80{\texttimes}10). We observed pleiotropic loci located at and . The proportions of variances explained by single-nucleotide polymorphisms were 10.15\% and 7.74\% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with expression in heart tissues and hs-cTnT and with expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95\% CI, 1.25-1.54] for hs-cTnT and 1.21 [95\% CI, 1.06-1.37] for hs-cTnI).

CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.121.003460}, author = {Yang, Yunju and Bartz, Traci M and Brown, Michael R and Guo, Xiuqing and Zilh{\~a}o, Nuno R and Trompet, Stella and Weiss, Stefan and Yao, Jie and Brody, Jennifer A and deFilippi, Christopher R and Hoogeveen, Ron C and Lin, Henry J and Gudnason, Vilmundur and Ballantyne, Christie M and D{\"o}rr, Marcus and Jukema, J Wouter and Petersmann, Astrid and Psaty, Bruce M and Rotter, Jerome I and Boerwinkle, Eric and Fornage, Myriam and Jun, Goo and Yu, Bing} } @article {9501, title = {Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Oct}, pages = {1651-1664}, abstract = {

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

}, issn = {1546-1718}, doi = {10.1038/s41588-023-01518-4}, author = {Kavousi, Maryam and Bos, Maxime M and Barnes, Hanna J and Lino Cardenas, Christian L and Wong, Doris and Lu, Haojie and Hodonsky, Chani J and Landsmeer, Lennart P L and Turner, Adam W and Kho, Minjung and Hasbani, Natalie R and de Vries, Paul S and Bowden, Donald W and Chopade, Sandesh and Deelen, Joris and Benavente, Ernest Diez and Guo, Xiuqing and Hofer, Edith and Hwang, Shih-Jen and Lutz, Sharon M and Lyytik{\"a}inen, Leo-Pekka and Slenders, Lotte and Smith, Albert V and Stanislawski, Maggie A and van Setten, Jessica and Wong, Quenna and Yanek, Lisa R and Becker, Diane M and Beekman, Marian and Budoff, Matthew J and Feitosa, Mary F and Finan, Chris and Hilliard, Austin T and Kardia, Sharon L R and Kovacic, Jason C and Kral, Brian G and Langefeld, Carl D and Launer, Lenore J and Malik, Shaista and Hoesein, Firdaus A A Mohamed and Mokry, Michal and Schmidt, Reinhold and Smith, Jennifer A and Taylor, Kent D and Terry, James G and van der Grond, Jeroen and van Meurs, Joyce and Vliegenthart, Rozemarijn and Xu, Jianzhao and Young, Kendra A and Zilh{\~a}o, Nuno R and Zweiker, Robert and Assimes, Themistocles L and Becker, Lewis C and Bos, Daniel and Carr, J Jeffrey and Cupples, L Adrienne and de Kleijn, Dominique P V and de Winther, Menno and den Ruijter, Hester M and Fornage, Myriam and Freedman, Barry I and Gudnason, Vilmundur and Hingorani, Aroon D and Hokanson, John E and Ikram, M Arfan and I{\v s}gum, Ivana and Jacobs, David R and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lehtim{\"a}ki, Terho and Pasterkamp, Gerard and Raitakari, Olli T and Schmidt, Helena and Slagboom, P Eline and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Bis, Joshua C and Franceschini, Nora and Psaty, Bruce M and Post, Wendy S and Rotter, Jerome I and Bj{\"o}rkegren, Johan L M and O{\textquoteright}Donnell, Christopher J and Bielak, Lawrence F and Peyser, Patricia A and Malhotra, Rajeev and van der Laan, Sander W and Miller, Clint L} }