Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

Mohamed H Shahin, Yan Gong, Reginald F Frye, Daniel M Rotroff, Amber L Beitelshees, Rebecca A Baillie, Arlene B Chapman, John G Gums, Stephen T Turner, Eric Boerwinkle, Alison Motsinger-Reif, Oliver Fiehn, Rhonda M Cooper-DeHoff, Xianlin Han, Rima Kaddurah-Daouk, Julie A Johnson, Mohamed H Shahin, Yan Gong, Reginald F Frye, Daniel M Rotroff, Amber L Beitelshees, Rebecca A Baillie, Arlene B Chapman, John G Gums, Stephen T Turner, Eric Boerwinkle, Alison Motsinger-Reif, Oliver Fiehn, Rhonda M Cooper-DeHoff, Xianlin Han, Rima Kaddurah-Daouk, Julie A Johnson

Abstract

Background: Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response.

Methods and results: First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (∆SBP/∆DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ∆SBP P=6.7E-04; ∆DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r=-0.42; P=7E-03) and SBP-response (r=-0.36; P=2E-02).

Conclusions: This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.

Keywords: blood pressure; lipid metabolites; metabolomics; pharmacogenetics; thiazide diuretics.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Overall framework analyses. BP indicates blood pressure; GERA, Genetic Epidemiology of Responses to Antihypertensives; HCTZ, hydrochlorothiazide; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses; SNPs, single‐nucleotide polymorphisms.
Figure 2
Figure 2
The effect of rs6078905 polymorphism on the blood pressure response of whites and blacks treated with hydrochlorothiazide in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. Blood pressure responses were adjusted for baseline blood pressure, age, sex, and population substructure, and P values represented are for contrast of adjusted means between different genotype groups. Error bars represent SEM. DBP indicates diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure; SPTLC3, serine palmitoyltransferase, long chain base subunit 3 (A) Diastolic blood pressure response in PEAR white participants, (B) Systolic blood pressure response in PEAR white participants, (C) Diastolic blood pressure response in PEAR black participants, (D) Systolic blood pressure response in PEAR black participants.
Figure 3
Figure 3
The effect of rs6078905 polymorphism on sphingomyelin concentrations of SM N24:2, SM N24:3, SM N16:1, and SM N22:1 in whites treated with hydrochlorothiazide in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. P values were generated using a linear regression model adjusted for age. SM indicates sphingomyelin; SPTLC3, serine palmitoyltransferase, long chain base subunit 3.
Figure 4
Figure 4
The correlation between Sphingomyelin N24:2 and hydrochlorothiazide blood pressure response (A) Systolic blood pressure response, (B) Diastolic blood pressure response. P values and r values were generated using partial correlation with adjustment for age and baseline blood pressure. DBP indicates diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure; SM, sphingomyelin.

References

    1. Global, regional, and national age‐sex specific all‐cause and cause‐specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171.
    1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322.
    1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–223.
    1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta‐analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
    1. Thoenes M, Neuberger HR, Volpe M, Khan BV, Kirch W, Bohm M. Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens. 2010;24:336–344.
    1. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, Flack JM, Carter BL, Materson BJ, Ram CV, Cohen DL, Cadet JC, Jean‐Charles RR, Taler S, Kountz D, Townsend R, Chalmers J, Ramirez AJ, Bakris GL, Wang J, Schutte AE, Bisognano JD, Touyz RM, Sica D, Harrap SB. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens. 2014;32:3–15.
    1. Shahin MH, Johnson JA. Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response. Curr Opin Pharmacol. 2016;27:31–37.
    1. Materson BJ. Variability in response to antihypertensive drugs. Am J Med. 2007;120:S10–S20.
    1. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J. Single‐drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328:914–921.
    1. Turner ST, Boerwinkle E, O'Connell JR, Bailey KR, Gong Y, Chapman AB, McDonough CW, Beitelshees AL, Schwartz GL, Gums JG, Padmanabhan S, Hiltunen TP, Citterio L, Donner KM, Hedner T, Lanzani C, Melander O, Saarela J, Ripatti S, Wahlstrand B, Manunta P, Kontula K, Dominiczak AF, Cooper‐DeHoff RM, Johnson JA. Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension. 2013;62:391–397.
    1. Shahin MH, Sa AC, Webb A, Gong Y, Langaee T, McDonough CW, Riva A, Beitleshees AL, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Scherer SE, Sadee W, Cooper‐DeHoff RM, Johnson JA. Genome‐wide prioritization and transcriptomics reveal novel signatures associated with thiazide diuretics blood pressure response. Circ Cardiovasc Genet. 2017;10:e001404.
    1. Cooper‐Dehoff RM, Hou W, Weng L, Baillie RA, Beitelshees AL, Gong Y, Shahin MH, Turner ST, Chapman A, Gums JG, Boyle SH, Zhu H, Wikoff WR, Boerwinkle E, Fiehn O, Frye RF, Kaddurah‐Daouk R, Johnson JA. Is diabetes mellitus‐linked amino acid signature associated with beta‐blocker‐induced impaired fasting glucose? Circ Cardiovasc Genet. 2014;7:199–205.
    1. de Oliveira FA, Shahin MH, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, Boerwinkle E, Turner ST, Frye RF, Fiehn O, Kaddurah‐Daouk R, Johnson JA, Cooper‐DeHoff RM. Novel plasma biomarker of atenolol‐induced hyperglycemia identified through a metabolomics‐genomics integrative approach. Metabolomics (Los Angel). 2016;12:129.
    1. Kaddurah‐Daouk R, Weinshilboum R. Metabolomic signatures for drug response phenotypes: pharmacometabolomics enables precision medicine. Clin Pharmacol Ther. 2015;98:71–75.
    1. Shahin MH, Gong Y, McDonough CW, Rotroff DM, Beitelshees AL, Garrett TJ, Gums JG, Motsinger‐Reif A, Chapman AB, Turner ST, Boerwinkle E, Frye RF, Fiehn O, Cooper‐DeHoff RM, Kaddurah‐Daouk R, Johnson JA. A genetic response score for hydrochlorothiazide use: insights from genomics and metabolomics integration. Hypertension. 2016;68:621–629.
    1. Kaddurah‐Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, Watkins SM, Krauss RM. Lipidomic analysis of variation in response to simvastatin in the cholesterol and pharmacogenetics study. Metabolomics. 2010;6:191–201.
    1. Hu C, Kong H, Qu F, Li Y, Yu Z, Gao P, Peng S, Xu G. Application of plasma lipidomics in studying the response of patients with essential hypertension to antihypertensive drug therapy. Mol Biosyst. 2011;7:3271–3279.
    1. Ji Y, Hebbring S, Zhu H, Jenkins GD, Biernacka J, Snyder K, Drews M, Fiehn O, Zeng Z, Schaid D, Mrazek DA, Kaddurah‐Daouk R, Weinshilboum RM. Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics‐informed pharmacogenomics. Clin Pharmacol Ther. 2011;89:97–104.
    1. Song IS, Lee do Y, Shin MH, Kim H, Ahn YG, Park I, Kim KH, Kind T, Shin JG, Fiehn O, Liu KH. Pharmacogenetics meets metabolomics: discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition. PLoS One. 2012;7:e36637.
    1. Johnson JA, Boerwinkle E, Zineh I, Chapman AB, Bailey K, Cooper‐DeHoff RM, Gums J, Curry RW, Gong Y, Beitelshees AL, Schwartz G, Turner ST. Pharmacogenomics of antihypertensive drugs: rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Am Heart J. 2009;157:442–449.
    1. Chapman AB, Schwartz GL, Boerwinkle E, Turner ST. Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension. Kidney Int. 2002;61:1047–1055.
    1. Turner ST, Schwartz GL, Chapman AB, Beitelshees AL, Gums JG, Cooper‐Dehoff RM, Boerwinkle E, Johnson JA, Bailey KR. Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response. J Transl Med. 2012;10:47.
    1. Merrill AH Jr, Wang E, Innis WS, Mullins R. Increases in serum sphingomyelin by 17 beta‐estradiol. Lipids. 1985;20:252–254.
    1. Nikkila J, Sysi‐Aho M, Ermolov A, Seppanen‐Laakso T, Simell O, Kaski S, Oresic M. Gender‐dependent progression of systemic metabolic states in early childhood. Mol Syst Biol. 2008;4:197.
    1. Li F, Xu Y, Shang D, Yang H, Liu W, Han J, Sun Z, Yao Q, Zhang C, Ma J, Su F, Feng L, Shi X, Zhang Y, Li J, Gu Q, Li X, Li C. MPINet: metabolite pathway identification via coupling of global metabolite network structure and metabolomic profile. Biomed Res Int. 2014;2014:325697.
    1. Sobota RS, Shriner D, Kodaman N, Goodloe R, Zheng W, Gao YT, Edwards TL, Amos CI, Williams SM. Addressing population‐specific multiple testing burdens in genetic association studies. Ann Hum Genet. 2015;79:136–147.
    1. Burkhardt R, Kirsten H, Beutner F, Holdt LM, Gross A, Teren A, Tonjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, Scholz M. Integration of genome‐wide SNP data and gene‐expression profiles reveals six novel loci and regulatory mechanisms for amino acids and acylcarnitines in whole blood. PLoS Genet. 2015;11:e1005510.
    1. Purcell S, Neale B, Todd‐Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole‐genome association and population‐based linkage analyses. Am J Hum Genet. 2007;81:559–575.
    1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta‐analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191.
    1. Demirkan A, van Duijn CM, Ugocsai P, Isaacs A, Pramstaller PP, Liebisch G, Wilson JF, Johansson A, Rudan I, Aulchenko YS, Kirichenko AV, Janssens AC, Jansen RC, Gnewuch C, Domingues FS, Pattaro C, Wild SH, Jonasson I, Polasek O, Zorkoltseva IV, Hofman A, Karssen LC, Struchalin M, Floyd J, Igl W, Biloglav Z, Broer L, Pfeufer A, Pichler I, Campbell S, Zaboli G, Kolcic I, Rivadeneira F, Huffman J, Hastie ND, Uitterlinden A, Franke L, Franklin CS, Vitart V, Nelson CP, Preuss M, Bis JC, O'Donnell CJ, Franceschini N, Witteman JC, Axenovich T, Oostra BA, Meitinger T, Hicks AA, Hayward C, Wright AF, Gyllensten U, Campbell H, Schmitz G. Genome‐wide association study identifies novel loci associated with circulating phospho‐ and sphingolipid concentrations. PLoS Genet. 2012;8:e1002490.
    1. Li H, Junk P, Huwiler A, Burkhardt C, Wallerath T, Pfeilschifter J, Forstermann U. Dual effect of ceramide on human endothelial cells: induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase. Circulation. 2002;106:2250–2256.
    1. Ohmori T, Yatomi Y, Osada M, Kazama F, Takafuta T, Ikeda H, Ozaki Y. Sphingosine 1‐phosphate induces contraction of coronary artery smooth muscle cells via S1P2. Cardiovasc Res. 2003;58:170–177.
    1. Fenger M, Linneberg A, Jorgensen T, Madsbad S, Sobye K, Eugen‐Olsen J, Jeppesen J. Genetics of the ceramide/sphingosine‐1‐phosphate rheostat in blood pressure regulation and hypertension. BMC Genet. 2011;12:44.
    1. Spijkers LJ, van den Akker RF, Janssen BJ, Debets JJ, De Mey JG, Stroes ES, van den Born BJ, Wijesinghe DS, Chalfant CE, MacAleese L, Eijkel GB, Heeren RM, Alewijnse AE, Peters SL. Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide. PLoS One. 2011;6:e21817.
    1. Fenger M, Linneberg A, Jeppesen J. Network‐based analysis of the sphingolipid metabolism in hypertension. Front Genet. 2015;6:84.
    1. Rutherford PA, Thomas TH, Laker MF, Wilkinson R. Plasma lipids affect maximum velocity not sodium affinity of human sodium‐lithium countertransport: distinction from essential hypertension. Eur J Clin Invest. 1992;22:719–724.
    1. Chi Y, Mota de Freitas D, Sikora M, Bansal VK. Correlations of Na+‐Li+ exchange activity with Na+ and Li+ binding and phospholipid composition in erythrocyte membranes of white hypertensive and normotensive individuals: a nuclear magnetic resonance investigation. Hypertension. 1996;27:456–464.
    1. Zicha J, Kunes J, Devynck MA. Abnormalities of membrane function and lipid metabolism in hypertension: a review. Am J Hypertens. 1999;12:315–331.
    1. Bischoff A, Czyborra P, Meyer Zu Heringdorf D, Jakobs KH, Michel MC. Sphingosine‐1‐phosphate reduces rat renal and mesenteric blood flow in vivo in a pertussis toxin‐sensitive manner. Br J Pharmacol. 2000;130:1878–1883.
    1. Coussin F, Scott RH, Nixon GF. Sphingosine 1‐phosphate induces CREB activation in rat cerebral artery via a protein kinase C‐mediated inhibition of voltage‐gated K+ channels. Biochem Pharmacol. 2003;66:1861–1870.
    1. Guan Z, Singletary ST, Cook AK, Hobbs JL, Pollock JS, Inscho EW. Sphingosine‐1‐phosphate evokes unique segment‐specific vasoconstriction of the renal microvasculature. J Am Soc Nephrol. 2014;25:1774–1785.
    1. Spiegel S, Milstien S. Sphingosine‐1‐phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4:397–407.
    1. Zhu Q, Xia M, Wang Z, Li PL, Li N. A novel lipid natriuretic factor in the renal medulla: sphingosine‐1‐phosphate. Am J Physiol Renal Physiol. 2011;301:F35–F41.
    1. Himmel HM, Meyer Zu Heringdorf D, Graf E, Dobrev D, Kortner A, Schuler S, Jakobs KH, Ravens U. Evidence for Edg‐3 receptor‐mediated activation of I(K.ACh) by sphingosine‐1‐phosphate in human atrial cardiomyocytes. Mol Pharmacol. 2000;58:449–454.
    1. Xu SZ, Muraki K, Zeng F, Li J, Sukumar P, Shah S, Dedman AM, Flemming PK, McHugh D, Naylor J, Cheong A, Bateson AN, Munsch CM, Porter KE, Beech DJ. A sphingosine‐1‐phosphate‐activated calcium channel controlling vascular smooth muscle cell motility. Circ Res. 2006;98:1381–1389.
    1. Kim MY, Liang GH, Kim JA, Kim YJ, Oh S, Suh SH. Sphingosine‐1‐phosphate activates BKCa channels independently of G protein‐coupled receptor in human endothelial cells. Am J Physiol Cell Physiol. 2006;290:C1000–C1008.
    1. Calder JA, Schachter M, Sever PS. Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries. J Cardiovasc Pharmacol. 1994;24:158–164.
    1. Pickkers P, Hughes AD, Russel FG, Thien T, Smits P. Thiazide‐induced vasodilation in humans is mediated by potassium channel activation. Hypertension. 1998;32:1071–1076.
    1. Birchwood CJ, Saba JD, Dickson RC, Cunningham KW. Calcium influx and signaling in yeast stimulated by intracellular sphingosine 1‐phosphate accumulation. J Biol Chem. 2001;276:11712–11718.
    1. Mattie M, Brooker G, Spiegel S. Sphingosine‐1‐phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol trisphosphate‐independent pathway. J Biol Chem. 1994;269:3181–3188.
    1. Ishizawa S, Takahashi‐Fujigasaki J, Kanazawa Y, Matoba K, Kawanami D, Yokota T, Iwamoto T, Tajima N, Manome Y, Utsunomiya K. Sphingosine‐1‐phosphate induces differentiation of cultured renal tubular epithelial cells under Rho kinase activation via the S1P2 receptor. Clin Exp Nephrol. 2014;18:844–852.
    1. Wirth A. Rho kinase and hypertension. Biochim Biophys Acta. 2010;1802:1276–1284.
    1. Do e Z, Fukumoto Y, Sugimura K, Miura Y, Tatebe S, Yamamoto S, Aoki T, Nochioka K, Nergui S, Yaoita N, Satoh K, Kondo M, Nakano M, Wakayama Y, Fukuda K, Nihei T, Kikuchi Y, Takahashi J, Shimokawa H. Rho‐kinase activation in patients with heart failure. Circ J. 2013;77:2542–2550.
    1. Satoh K, Fukumoto Y, Shimokawa H. Rho‐kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol. 2011;301:H287–H296.
    1. Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M. Thiazide‐like diuretics attenuate agonist‐induced vasoconstriction by calcium desensitization linked to Rho kinase. Hypertension. 2005;45:233–239.
    1. Cooper‐DeHoff RM, Wen S, Beitelshees AL, Zineh I, Gums JG, Turner ST, Gong Y, Hall K, Parekh V, Chapman AB, Boerwinkle E, Johnson JA. Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications. Hypertension. 2010;55:61–68.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다