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• W4282946972 abstract "HomeCirculation ResearchVol. 131, No. 3Genome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBGenome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus Carolina G. Downie, Heather M. Highland, Moa P. Lee, Laura M. Raffield, Michael Preuss, Eric A. Whitsel, Bruce M. Psaty, Colleen M. Sitlani, Mariaelisa Graff and Christy L. Avery Carolina G. DownieCarolina G. Downie Correspondence to: Carolina G. Downie, MPH, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 123 W Franklin St, Building C, Suite 4210, Chapel Hill, NC 27514. Email: E-mail Address: [email protected] https://orcid.org/0000-0001-6972-9981 Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Search for more papers by this author , Heather M. HighlandHeather M. Highland https://orcid.org/0000-0002-3583-8239 Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Search for more papers by this author , Moa P. LeeMoa P. Lee Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Search for more papers by this author , Laura M. RaffieldLaura M. Raffield Department of Genetics, UNC Chapel Hill (L.M.R.). Search for more papers by this author , Michael PreussMichael Preuss https://orcid.org/0000-0001-5266-8465 The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai (M.P.). Search for more papers by this author , Eric A. WhitselEric A. Whitsel https://orcid.org/0000-0003-4843-3641 Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Department of Medicine, UNC Chapel Hill (E.A.W.). Search for more papers by this author , Bruce M. PsatyBruce M. Psaty https://orcid.org/0000-0002-7278-2190 The Cardiovascular Health Research Unit, Department of Medicine (B.M.P., C.M.S.), University of Washington. Department of Epidemiology (B.M.P.), University of Washington. Department of Health Systems and Population Health (B.M.P.), University of Washington. Search for more papers by this author , Colleen M. SitlaniColleen M. Sitlani https://orcid.org/0000-0001-7656-7482 The Cardiovascular Health Research Unit, Department of Medicine (B.M.P., C.M.S.), University of Washington. Search for more papers by this author , Mariaelisa GraffMariaelisa Graff https://orcid.org/0000-0001-6380-1735 Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Search for more papers by this author and Christy L. AveryChristy L. Avery https://orcid.org/0000-0002-1044-8162 Department of Epidemiology, UNC Chapel Hill (C.G.D., H.M.H., M.P.L., E.A.W., M.G., C.L.A.). Search for more papers by this author Originally published14 Jun 2022https://doi.org/10.1161/CIRCRESAHA.122.321120Circulation Research. 2022;131:277–279is related toMeet the First AuthorsOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 15, 2022: Ahead of Print Although thiazide diuretics are common therapies for the treatment of high blood pressure, they are also associated with elevated blood lipid concentrations after initiation.1 Total cholesterol concentrations have been shown to increase by 4%, low-density lipoprotein cholesterol (LDL-C) concentrations by 10%, and triglyceride (TG) concentrations by 5% to 15%; high density lipoprotein cholesterol concentrations remain unaffected.1 Pharmacogenomics could potentially help identify mechanistic pathways underlying this observation. However, few well-powered studies examining variant-by-thiazide interactions on blood lipid concentrations have been conducted. The purpose of this study was to identify genetic variants that modify the effect of thiazide diuretics on LDL-C, total cholesterol, and TG using data from the UK Biobank (UKBB), a publicly available, longitudinal study of UK adults.Meet the First Author, see p 187Due to small sample sizes for other populations, we restricted analyses to unrelated participants of European ancestry, defined by projecting the 1000G European reference panel dataset on previously calculated ancestral principal component loadings (PCs) and applying a k-means clustering approach defined by the first 4 PCs. Medications were recorded via nurse-led interview, mapped to corresponding active ingredients, and classified using the Anatomic Therapeutic Chemical Classification system. We categorized participants as thiazide users if Anatomic Therapeutic Chemical codes at baseline visit included thiazides alone or in combination preparations; we excluded loop diuretic users. Participants taking neither thiazide nor loop diuretics were defined as unexposed. Lipid concentrations (mmol/l) were adjusted for statin use.We conducted genome wide association studies (GWAS) stratified by thiazide exposure, adjusting for age, sex, fasting status, BMI, study center, and 10 PCs using linear mixed models in SAIGE. After removing variants with minor allele frequency <0.01 and imputation quality <0.60, we computed interaction P by testing for difference between β̂thiazides and β̂unexposed according to Winkler et al,2 using R version 4.0.3. Our conservative P threshold was 1.67×10−9 (ie, 5×10−9/3 lipid traits).After exclusions, a maximum of n=391 239 participants were available (mean age=57 years; 54% female), of which 7.1% reported thiazide use. Thiazide users were older (mean age=62 versus 56 years), with higher average LDL-C (4.55 versus 3.97 mmol/l), TG (2.42 versus 1.87 mmol/l), and total cholesterol (6.67 versus 6.13 mmol/l) than nonusers. Statin use was higher among thiazide users than nonusers (44% versus 14%); however, mean LDL-C concentrations among statin users and nonstatin users were comparable across thiazide exposure strata.The thiazide-LDL-C GWAS (n=9 680 686 variants) identified one chromosome 19 locus harboring statistically significant variants with larger effect size among thiazide users than nonusers (Figure [A]). Lead variant rs2199576 (minor allele frequency=0.18) had effect estimates (SE) of 0.159 (0.013) and 0.083 (0.003) per A allele among thiazide users and nonusers respectively, yielding an interaction effect estimate of 0.076 (0.013; Pinteraction=1.62×10−9). Sensitivity analyses excluding statin users decreased statistical power to 16%, but yielded effects consistent with primary analyses, as evidenced by overlapping 95% CIs for the interaction effect estimates. No genome-wide significant loci were identified for total cholesterol or TG (Figure [B] and [C]).Download figureDownload PowerPointFigure. Manhattan plots for analysis of variant-thiazide interactions effects on low-density lipoprotein cholesterol (LDL-C), total cholesterol, and natural log-transformed triglycerides concentrations, and LocusZoom plot and functional annotation of lead significant variant-thiazide interaction on LDL-C in European-ancestry UK Biobank participants. As done in previous publications, LDL-C was adjusted by +2.7695 mmol/l, TC was adjusted by +2.8916 mmol/l, and triglyceride (TG) was adjusted by +1.0212 mmol/l among participants also using statins to account for their effect. TG concentrations were subsequently natural-log transformed. A, Manhattan plot of variant-thiazide interaction on LDL-C concentration, (B) Manhattan plot of variant-thiazide interaction on TC concentration, (C) Manhattan plot of variant-thiazide interaction on natural-log transformed TG concentration, (D) LocusZoom plot of lead significant variant-thiazide interaction effect on LDL-C on chromosome 19. Linkage disequilibrium was generated in European ancestry, (E) functional annotation of lead significant variant rs2199576 (in blue) and high LD (r2>0.80) proxies (in red) from the UCSC Genome Browser.Thiazide-LDL-C lead variant rs2199576 resides within 3.7 KB of NECTIN2, a cholesterol-responsive gene previously associated with TC3 (Figure [D]). Conditional analysis identified no genome-wide significant independent secondary signals. rs2199576 and proxies in high linkage disequilibrium (r2>0.80) are located near a H3K27Ac mark, which are often found near active regulatory elements and help enhance transcription (Figure [E]). In the GTEx database, rs2199576 and proxies have been identified as eQTLs with BCAM and NECTIN2 in lung and pancreas tissue, respectively, as well as with RP11-15A1.8 in esophagus-mucosa tissue (linkage disequilibrium proxy rs11668738).Characterizing gene-by-environment effects for complex phenotypes has lagged behind main effect GWAS, limiting the ability to inform underlying biology. We attempted to address this limitation, providing sample sizes ≈ 10× larger than previous efforts.4 Nevertheless, we only had 74% power to detect lead variant rs2199576 at genome-wide significance thresholds. This study was also limited by its cross-sectional design, inability to account for medication duration and dosage effects, and restriction to European ancestry participants. Thus, this is a hypothesis-generating study, and future well-powered prospective analyses in diverse populations are necessary to replicate NECTIN2 and more completely characterize the genetic architecture underlying lipid response to thiazide diuretics.Article InformationAcknowledgmentsThis research has been conducted using the UK Biobank Resource under Application Number 25953.Sources of FundingC.G. Downie, H.M. Highland, C.M. Sitlani, and C.L. Avery are supported by R01HL14825. M. Preuss is supported by F32HL149256. L.M. Raffield is supported by KL2TR002490. B.M. Psaty is supported by R01HL105756.Disclosures H.M. Highland is a Statistical Editor for Circulation Research. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.FootnotesThis manuscript was sent to Francisco Violi, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 279.Correspondence to: Carolina G. Downie, MPH, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 123 W Franklin St, Building C, Suite 4210, Chapel Hill, NC 27514. Email: [email protected]unc.eduReferences1. Herink M, Ito MK. Medication induced changes in lipid and lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S et al., eds. Endotext. South Dartmouth, MA; 2000.Google Scholar2. Winkler TW, Justice AE, Cupples LA, Kronenberg F, Kutalik Z, Heid IM; GIANT consortium. Approaches to detect genetic effects that differ between two strata in genome-wide meta-analyses: recommendations based on a systematic evaluation.PLoS One. 2017; 12:e0181038. doi: 10.1371/journal.pone.0181038CrossrefMedlineGoogle Scholar3. Spracklen CN, Chen P, Kim YJ, Wang X, Cai H, Li S, Long J, Wu Y, Wang YX, Takeuchi F. Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.Hum Mol Genet. 2018; 27:1122. doi: 10.1093/hmg/ddx439CrossrefMedlineGoogle Scholar4. de Las Fuentes L, Sung YJ, Sitlani CM, Avery CL, Bartz TM, Keyser C, Evans DS, Li X, Musani SK, Ruiter R, et al. Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.Pharmacogenomics J. 2020; 20:482–493. doi: 10.1038/s41397-019-0132-yCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMeet the First AuthorsCirculation Research. 2022;131:186-188 July 22, 2022Vol 131, Issue 3 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.122.321120PMID: 35701873 Originally publishedJune 14, 2022 Keywordscholesterol, LDLpharmacogeneticscholesteroltriglyceridesdiureticsthiazidesPDF download Advertisement SubjectsEpidemiologyGenetic, Association StudiesHypertension" @default.
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