Genomics and Pharmacogenomics of Hypertension

There are over 1 billion people with high blood pressure (HTN) worldwide and the World Health Organisation estimates that this will rise to 1.5 billion by 2020. In adults, there is a continuous, incremental risk of cardiovascular disease, stroke, and renal disease for example for every 20 point increase in BP, cardiovascular disease risk doubles. The high prevalence of HTN and its consequent significant adverse economic impact on the individual and population, highlights the importance of early diagnosis and effective treatment of HTN. The causation of HTN is complex with the involvement of multiple biological pathways and environmental factors. A strategy to ameliorate the burden of HTN would be through early diagnosis and targeted pharmacological or non-pharmacological interventions. This necessitates a more individualised understanding of the underlying dysfunctional pathways in a particular individual. Current strategies have focussed on identifying DNA variations primarily in the form of single nucleotide polymorphisms (SNPs) that are associated with BP regulation or HTN and thus provide the starting point for functional dissection and clinical studies.

 Genetic approaches have advanced our understanding of biological pathways underlying inter-individual variation in blood pressure (BP). So far, the most powerful approaches for finding genetic variants influencing susceptibility to complex diseases, which tend to have relatively small marginal effects, have been genome wide association studies (GWAS) between single nucleotide polymorphisms (SNPs) and disease phenotypes. We are attempting to identify genetic markers for hypertension and related cardiovascular traits using high-throughput genomics and functional dissection of these signals. We have identified a new gene for hypertension that has revealed a novel pathway for hypertension. We are also using similar strategies to identify the genetic predictors of response to antihypertensive drugs that will help target the right drug to the right patient.

Image of Biological Pathways

 

Image of Biological Pathways 2

 

 Publications:

  1. Padmanabhan S, Newton-Cheh C, Dominiczak AF. Genetic basis of blood pressure and hypertension. Trends Genet 2012; 28(8):397-408.
  2. Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, Kuznetsova T, Arima H, Hoggart C, Tichet J, Nikitin YP, Conti C, Seidlerova J, Tikhonoff V, Stolarz-Skrzypek K, Johnson T, Devos N, Zagato L, Guarrera S, Zaninello R, Calabria A, Stancanelli B, Troffa C, Thijs L, Rizzi F, Simonova G, Lupoli S, Argiolas G, Braga D, D'Alessio MC, Ortu MF, Ricceri F, Mercurio M, Descombes P, Marconi M, Chalmers J, Harrap S, Filipovsky J, Bochud M, Iacoviello L, Ellis J, Stanton AV, Laan M, Padmanabhan S, Dominiczak AF, Samani NJ, Melander O, Jeunemaitre X, Manunta P, Shabo A, Vineis P, Cappuccio FP, Caulfield MJ, Matullo G, Rivolta C, Munroe PB, Barlassina C, Staessen JA, Beckmann JS, Cusi D. Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 2012; 59(2):248-255.
  3. Johnson T, Gaunt TR, Newhouse SJ, Padmanabhan S, Tomaszewski M, Kumari M, Morris RW, Tzoulaki I, O'Brien ET, Poulter NR, Sever P, Shields DC, Thom S, Wannamethee SG, Whincup PH, Brown MJ, Connell JM, Dobson RJ, Howard PJ, Mein CA, Onipinla A, Shaw-Hawkins S, Zhang Y, Davey SG, Day IN, Lawlor DA, Goodall AH, Fowkes FG, Abecasis GR, Elliott P, Gateva V, Braund PS, Burton PR, Nelson CP, Tobin MD, van der Harst P, Glorioso N, Neuvrith H, Salvi E, Staessen JA, Stucchi A, Devos N, Jeunemaitre X, Plouin PF, Tichet J, Juhanson P, Org E, Putku M, Sober S, Veldre G, Viigimaa M, Levinsson A, Rosengren A, Thelle DS, Hastie CE, Hedner T, Lee WK, Melander O, Wahlstrand B, Hardy R, Wong A, Cooper JA, Palmen J, Chen L, Stewart AF, Wells GA, Westra HJ, Wolfs MG, Clarke R, Franzosi MG, Goel A, Hamsten A, Lathrop M, Peden JF, Seedorf U, Watkins H, Ouwehand WH, Sambrook J, Stephens J, Casas JP, Drenos F, Holmes MV, Kivimaki M, Shah S, Shah T, Talmud PJ, Whittaker J, Wallace C, Delles C, Laan M, Kuh D, Humphries SE, Nyberg F, Cusi D, Roberts R, Newton-Cheh C, Franke L, Stanton AV, Dominiczak AF, Farrall M, Hingorani AD, Samani NJ, Caulfield MJ, Munroe PB. Blood pressure loci identified with a gene-centric array. Am J Hum Genet 2011; 89(6):688-700.
  4. Shah S, Nelson CP, Gaunt TR, van der Harst P, Barnes T, Braund PS, Lawlor DA, Casas JP, Padmanabhan S, Drenos F, Kivimaki M, Talmud PJ, Humphries SE, Whittaker J, Morris RW, Whincup PH, Dominiczak A, Munroe PB, Johnson T, Goodall AH, Cambien F, Diemert P, Hengstenberg C, Ouwehand WH, Felix JF, Glazer NL, Tomaszewski M, Burton PR, Tobin MD, van Veldhuisen DJ, de Boer RA, Navis G, van Gilst WH, Mayosi BM, Thompson JR, Kumari M, MacFarlane PW, Day IN, Hingorani AD, Samani NJ. Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy. Circ Cardiovasc Genet 2011; 4(6):626-635.
  5. Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D, Hastie CE, Menni C, Monti MC, Delles C, Laing S, Corso B, Navis G, Kwakernaak AJ, van der Harst P, Bochud M, Maillard M, Burnier M, Hedner T, Kjeldsen S, Wahlstrand B, Sjogren M, Fava C, Montagnana M, Danese E, Torffvit O, Hedblad B, Snieder H, Connell JM, Brown M, Samani NJ, Farrall M, Cesana G, Mancia G, Signorini S, Grassi G, Eyheramendy S, Wichmann HE, Laan M, Strachan DP, Sever P, Shields DC, Stanton A, Vollenweider P, Teumer A, Volzke H, Rettig R, Newton-Cheh C, Arora P, Zhang F, Soranzo N, Spector TD, Lucas G, Kathiresan S, Siscovick DS, Luan J, Loos RJ, Wareham NJ, Penninx BW, Nolte IM, McBride M, Miller WH, Nicklin SA, Baker AH, Graham D, McDonald RA, Pell JP, Sattar N, Welsh P, Munroe P, Caulfield MJ, Zanchetti A, Dominiczak AF. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet 2010; 6(10):e1001177.
  6. Sotoodehnia N, Isaacs A, de Bakker PI, Dorr M, Newton-Cheh C, Nolte IM, van der Harst P, Muller M, Eijgelsheim M, Alonso A, Hicks AA, Padmanabhan S, Hayward C, Smith AV, Polasek O, Giovannone S, Fu J, Magnani JW, Marciante KD, Pfeufer A, Gharib SA, Teumer A, Li M, Bis JC, Rivadeneira F, Aspelund T, Kottgen A, Johnson T, Rice K, Sie MP, Wang YA, Klopp N, Fuchsberger C, Wild SH, Mateo L, I, Estrada K, Volker U, Wright AF, Asselbergs FW, Qu J, Chakravarti A, Sinner MF, Kors JA, Petersmann A, Harris TB, Soliman EZ, Munroe PB, Psaty BM, Oostra BA, Cupples LA, Perz S, de Boer RA, Uitterlinden AG, Volzke H, Spector TD, Liu FY, Boerwinkle E, Dominiczak AF, Rotter JI, van HG, Levy D, Wichmann HE, van Gilst WH, Witteman JC, Kroemer HK, Kao WH, Heckbert SR, Meitinger T, Hofman A, Campbell H, Folsom AR, van Veldhuisen DJ, Schwienbacher C, O'Donnell CJ, Volpato CB, Caulfield MJ, Connell JM, Launer L, Lu X, Franke L, Fehrmann RS, te MG, Groen HJ, Weersma RK, van den Berg LH, Wijmenga C, Ophoff RA, Navis G, Rudan I, Snieder H, Wilson JF, Pramstaller PP, Siscovick DS, Wang TJ, Gudnason V, van Duijn CM, Felix SB, Fishman GI, Jamshidi Y, Stricker BH, Samani NJ, Kaab S, Arking DE. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet 2010; 42(12):1068-1076.
  7. Padmanabhan S, Menni C, Lee WK, Laing S, Brambilla P, Sega R, Perego R, Grassi G, Cesana G, Delles C, Mancia G, Dominiczak AF. The effects of sex and method of blood pressure measurement on genetic associations with blood pressure in the PAMELA study. J Hypertens 2010; 28(3):465-477.
  8. Padmanabhan S. Genetic causation: the end of parsimony? J Hypertens 2009; 27(8):1521-1523.
  9. Delles C, Padmanabhan S, Lee WK, Miller WH, McBride MW, McClure JD, Brain NJ, Wallace C, Marcano AC, Schmieder RE, Brown MJ, Caulfield MJ, Munroe PB, Farrall M, Webster J, Connell JM, Dominiczak AF. Glutathione S-transferase variants and hypertension. J Hypertens 2008; 26(7):1343-1352.
  10. Padmanabhan S, Wallace C, Munroe PB, Dobson R, Brown M, Samani N, Clayton D, Farrall M, Webster J, Lathrop M, Caulfield M, Dominiczak AF, Connell JM. Chromosome 2p shows significant linkage to antihypertensive response in the British Genetics of Hypertension Study. Hypertension 2006; 47(3):603-608.