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Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Abstract

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans1,2,3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10−8 to P = 2.3 × 10−13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

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Figure 1: Regional association plots of the eight SNPs at seven loci showing genome-wide significant association (P < 5 × 10−8) with pulse pressure (PP) and/or mean arterial pressure (MAP).
Figure 2: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) effect sizes (β coefficients) for all blood pressure SNPs identified in the present study and a concurrent study1 obtained from follow-up samples only.

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References

  1. Ehret, G. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature advance online publication, doi: 10.1038/nature10405 (11 September 2011).

  2. Levy, D. et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677–687 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Lawes, C.M. et al. Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden. J. Hypertens. 24, 423–430 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Rose, G. Strategies of prevention: the individual and the population. in Coronary Heart Disease Epidemiology: from Aetiology to Public Health (ed. Marmot M, E.P.) 631–41 (Oxford University Press, Oxford, UK, 2005).

    Chapter  Google Scholar 

  6. Domanski, M.J. et al. Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction. J. Am. Coll. Cardiol. 33, 951–958 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Domanski, M. et al. Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). J. Am. Med. Assoc. 287, 2677–2683 (2002).

    Article  Google Scholar 

  8. Franklin, S.S. et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation 119, 243–250 (2009).

    Article  PubMed  Google Scholar 

  9. Lewington, S., Clarke, R., Qizilbash, N., Peto, R. & Collins, R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

    Article  PubMed  Google Scholar 

  10. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Kato, N. et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat. Genet. 43, 531–538 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Sesso, H.D. et al. Systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure as predictors of cardiovascular disease risk in men. Hypertension 36, 801–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Darne, B., Girerd, X., Safar, M., Cambien, F. & Guize, L. Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 13, 392–400 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Blacher, J. & Safar, M.E. Large-artery stiffness, hypertension and cardiovascular risk in older patients. Nat. Clin. Pract. Cardiovasc. Med. 2, 450–455 (2005).

    Article  PubMed  Google Scholar 

  15. Dart, A.M. & Kingwell, B.A. Pulse pressure–a review of mechanisms and clinical relevance. J. Am. Coll. Cardiol. 37, 975–984 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Johnson, A.D. et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat. Genet. 42, 608–613 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Soranzo, N. et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood 113, 3831–3837 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Soranzo, N. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182–1190 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Oudit, G.Y. et al. Phosphoinositide 3-kinase γ-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108, 2147–2152 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Perrino, C. et al. Dynamic regulation of phosphoinositide 3-kinase-γ activity and β-adrenergic receptor trafficking in end-stage human heart failure. Circulation 116, 2571–2579 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Wågsäter, D. et al. ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 196, 514–522 (2008).

    Article  PubMed  Google Scholar 

  22. Ellis, P.D., Chen, Q., Barker, P.J., Metcalfe, J.C. & Kemp, P.R. Nov gene encodes adhesion factor for vascular smooth muscle cells and is dynamically regulated in response to vascular injury. Arterioscler. Thromb. Vasc. Biol. 20, 1912–1919 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Shimoyama, T. et al. CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration. Arterioscler. Thromb. Vasc. Biol. 30, 675–682 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Heath, E. et al. Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC Dev. Biol. 8, 18 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  25. Cools, J. et al. Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood 94, 1820–1824 (1999).

    CAS  PubMed  Google Scholar 

  26. Kamatani, Y. et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat. Genet. 42, 210–215 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Dorn, G.W. II. Adrenergic signaling polymorphisms and their impact on cardiovascular disease. Physiol. Rev. 90, 1013–1062 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Kitsios, G.D. & Zintzaras, E. Synopsis and data synthesis of genetic association studies in hypertension for the adrenergic receptor family genes: the CUMAGAS-HYPERT database. Am. J. Hypertens. 23, 305–313 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Rohrer, D.K., Chruscinski, A., Schauble, E.H., Bernstein, D. & Kobilka, B.K. Cardiovascular and metabolic alterations in mice lacking both β1- and β2-adrenergic receptors. J. Biol. Chem. 274, 16701–16708 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Cheng, G., Qiao, F., Gallien, T.N., Kuppuswamy, D. & Cooper, G. IV. Inhibition of β-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules. Am. J. Physiol. Heart Circ. Physiol. 288, H1193–H1202 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Li, Y. & Abecasis, G.R. Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  32. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Servin, B. & Stephens, M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

A number of the participating studies and authors are members of the CHARGE and Global BPgen consortia. Many funding mechanisms by the US National Institutes of Health and National Heart, Lung, and Blood Institute, European and private funding agencies contributed to this work, and a full list of acknowledgements is provided in the Supplementary Note.

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Authors and Affiliations

Authors

Consortia

Contributions

ICBP-GWAS PP and MAP Working and Writing Sub-Group (alphabetical order): M.J.C., P.E. (co-chair), T.J., P.B.M., P.F.O., M.D.T. (co-chair), C.M.v.D. (co-chair), G.C.V., L.V.W. ICBP-GWAS Steering Committee (alphabetical order): G.R.A., M. Bochud, M. Boehnke, M.J.C. (co-chair), A.C., G.B.E., P.E., T.B.H., M.-R.J., A.D.J., T.J., M.G.L., L.L., D.L. (co-chair), P.B.M.(co-chair), C.N.-C. (co-chair), B.M.P., K.M.R., A.V.S., M.D.T., C.M.v.D., G.C.V. Analysis: L.V.W., G.C.V., P.F.O., T.J. Expression analyses: V.E., P.H., A.D.J., D.L., J.H.L., C.P.N., A. Plump, P.A.C.'t H., K.W.v.D. Cohort contributions (alphabetical order): Study concept/design: AGES: T.A., V.G., T.B.H., L.L., A.V.S. AortaGen Consortium: G.F.M. ARIC: E.B., A.C., S.K.G. ASPS: H. Schmidt, R.S. BLSA: L.F. B58C-T1DGC: D.P.S. B58C-WTCCC: D.P.S. BHS: L.J.P. CARDIoGRAM Consortium: N.J.S. C4D Consortium: R. Clarke, CHS: J.C.B., N.L.G., B.M.P., K.M.R., K.D.T. CHARGE Consortium Heart Failure Working Group: N.L.S. CoLaus: V.M., P. Vollenweider, G. Waeber CROATIA-Korcula: C.H. CROATIA-Split: M. Boban, I.R. CROATIA-Vis: A.F.W. DeCode Genetics: H.H., K.S., G.T., U.T. DGI controls: D.A., L.G., C.N.-C. ENGAGE: J.E., I.R.K. EGCUT: H.A., A.M. EPIC: K.-T.K. ERF: B.A.O. Fenland: N.J.W. FUSION: M. Boehnke, F.S.C., R.N.B., J.T. INGI CARL: A.P.d'A., P. Gasparini INGI-FVG: A.P.d'A., P. Gasparini INCHIANTI: S. Bandinelli., Y.M. KORA S3: C.G., M. Laan, E.O. KORA F4: T.M., H.-E.W. LifeLines: R.P.S., M.M.v.d.K. LOLIPOP: J.C.C., P.E., J.S.K. LBC1921/LBC1936: I.J.D., J.M.S. MICROS: A. Pfeufer MESA: G.L.B., X.G., W.P. MIGen controls: O.M., C.J.O., V.S., D. Siscovick NESDA: B.W.P., H. Snieder NEURO-CHARGE Consortium: M. Breteler, M. Fornage NFBC1966: M.-R.J., P.Z. NSPHS: U.B.G. NTR: D.I.B., E.J.C.d.G. ORCADES: H.C., J.F.W. PROCARDIS controls: M. Farrall, A. Hamsten, J.F.P., H.W. PROSPER/PHASE: B.B., J.W.J., D. Stott RSI/RSII/RSIII: A. Hofman, C.M.v.D., J.C.M.W. SardiNIA: G.R.A., M.U. SHIP: M.D., H.K.K., R.R., U.V., H.V. SUVIMAX: P. Galan, S. Hercberg, P.M. TwinsUK: T.D.S. WGHS: P.M.R. YFS: M.K., T.L., O.T.R., J.V. Phenotype data acquisition and quality control: AGES: T.A., V.G., T.B.H., L.L. ARIC: A.C., S.K.G., A.C.M., D.C.R. ASPS: M. Loitfelder, R.S. BLSA: S.S.N. B58C-T1DGC: D.P.S. B58C-WTCCC: D.P.S. BHS: J.P.B., J.H. C4D Consortium: R. Clarke, J.C.H. CHS: B.M.P. CoLaus: M. Bochud, V.M., P. Vollenweider CROATIA-Korcula: C.H., O.P. CROATIA-Split: M. Boban, I.R. DGI controls: L.G., C.N.-C. EGCUT: H.A., A.K., A.M., M.-L.T. EPIC: N.J.W. Fenland: N.J.W. FHS: S.-J.H., M.G.L., D.L., R.S.V., T.J.W. FUSION: J.T. INGI CARL: A.F., F.F., P. Gasparini, S.U. INGI FVG: A.F., F.F., P. Gasparini, S.U. INGI-Val Borbera: C. Masciullo, C.S., D.T. INCHIANTI: A.M.C. KORA S3: C.G. KORA F4: A.D. LifeLines: M.M.v.d.K. LOLIPOP: J.C.C., J.S.K., J.S. LBC1921/LBC1936: I.J.D., L.M.L., J.M.S. MICROS: M. Facheris, A. Pfeufer MESA: G.L.B., X.G., W.P. MIGen controls: G.L., O.M., C.J.O., V.S., D. Siscovick NESDA: X. Lu, I.M.N., B.W.P., H. Snieder NEURO-CHARGE Consortium: M. Breteler, S.D., A.L.D., M. Fornage NFBC1966: P.E., M.-R.J., J. Laitinen, A. Pouta, P.Z. NSPHS: U.B.G. NTR: D.I.B., E.J.C.d.G., G. Willemsen ORCADES: S.H.W., J.F.W. PROCARDIS controls: J.F.P. PROSPER/PHASE: D. Stott, S.T. RSI/RSII/RSIII: F.U.S.M.-R., E.J.G.S., C.M.v.D., G.C.V., J.C.M.W. SardiNIA: M.O., M.U. SHIP: M.D., R.R., H.V. SUVIMAX: P. Galan, M. Lathrop TwinsUK: T.D.S. WGHS: P.M.R. YFS: M.K., T.L., O.T.R., J.V. Genotype data acquisition and quality control: AGES: A.V.S. ARIC: A.C., G.B.E., S.K.G., A.C.M., D.C.R., G.S. ASPS: P. Gider, H. Schmidt, M.Z. BLSA: D. Hernandez B58C-T1DGC: S. Heath, W.L.M. B58C-WTCCC: W.L.M. BHS: J.P.B., R.J.W. C4D Consortium: J.C.H., H.O. CHS: J.C.B., N.L.G., K.D.T. CoLaus: V.M., P. Vollenweider CROATIA-Korcula: C.H., O.P. CROATIA-Split: I.R. CROATIA-Vis: V.V. DGI controls: D.A., B.F.V. EGCUT: T.E., T.H. EPIC: N.J.W. Fenland: R.J.F.L., J. Luan, N.J.W. FHS: S.-J.H., M.G.L. FUSION: F.S.C. INGI CARL: A.P.d'A. INGI FVG: A.P.d'A. INGI Val Borbera: C. Masciullo, C.S., D.T. INCHIANTI: A.S. KORA S3: C.G., M. Laan, E.O. KORA F4: T.M., H.-E.W. LifeLines: B.Z.A. LOLIPOP: J.C.C., J.S.K., J.S., W.Z. LBC1921/LBC1936: G.D., I.J.D. MICROS: I.P. MESA: G.L.B., Y.-D.I.C., X.G. MIGen controls: G.L., O.M., C.J.O., V.S., D.S. NESDA: J.F., X. Lu, I.M.N., B.W.P., H. Snieder NFBC1966: P.E., M.-R.J., J. Laitinen, P.Z. NTR: D.I.B., E.J.C.d.G., J.-J.H., G. Willemsen ORCADES: H.C., J.F.W. PROCARDIS controls: A.G., J.F.P. PROSPER/PHASE: S.T. RSI/RSII/RSIII: F.R., A.G.U. SardiNIA: G.R.A. SHIP: H.K.K., U.V., H.V. SUVIMAX: S. Heath, M. Lathrop TwinsUK: M.M., S.-Y.S., N.S., F.Z. WGHS: D.I.C., A.N.P. YFS: T.L., O.T.R. Data analysis: AGES: T.A., A.V.S. ARIC: A.C., G.B.E., A.C.M., V.P., D.C.R., G.S. ASPS: P. Gider, H. Schmidt, M.Z. BLSA: T.T. B58C-T1DGC: D.P.S. B58C-WTCCC: D. Hadley, D.P.S. BHS: A.W.M., L.J.P., R.J.W. C4D Consortium: J.C.H., H.O., CHS: J.C.B., N.L.G., K.M.R. CoLaus: J.S.B., S. Bergmann, M. Bochud, T.J. CROATIA-Korcula: C.H., O.P. CROATIA-Split: C.H. CROATIA-Vis: V.V. DGI controls: P.A., C.N.-C., B.F.V. EchoGen Consortium: J.F.F. EGCUT: T.E., T.H. ENGAGE: M.P. EPIC: I.B., R.J.F.L., N.J.W., J.H.Z. ERF: A.C.J.W.J., Y.A. Fenland: R.J.F.L., J. Luan FHS: S.-J.H., M.G.L. FUSION: A.U.J. INGI CARL: N.P. INGI FVG: N.P. INGI Val Borbera: T.C., G.P., C.S., D.T. KORA S3: S.E., S.S. KORA F4: B.K. LifeLines: B.Z.A. LOLIPOP: J.C.C., J.S.K., X. Li, J.S., W.Z. LBC1921/LBC1936: L.M.L. MICROS: F.D.G.M. MESA: Y-D.I.C., X.G., W.P. MIGen controls: G.L. NESDA: J.F., X. Lu NEURO-CHARGE Consortium: S.D., A.L.D., M. Fornage NFBC1966: P.F.O. NSPHS:W.I. NTR: J.-J.H. ORCADES: P.N., S.H.W., J.F.W. PROCARDIS controls: M. Farrall, A.G., J.F.P. PROSPER/PHASE: J.W.J., S.T. RSI/RSII/RSIII: N.A., S.K., C.M.v.D., G.C.V. SardiNIA: J.L.B.-G. SHIP: U.V. SUVIMAX: T.J., P.M. TwinsUK: N.S., F.Z. WGHS: D.I.C., L.M.R., YFS: T.L., O.T.R.

Corresponding authors

Correspondence to Martin D Tobin, Paul Elliott or Cornelia M van Duijn.

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Competing interests

A.C. is managed by Johns Hopkins Medicine. I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. A.N.P. is an employee of Amgen. G.F.M. is owner of Cardiovascular Engineering, Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical studies that evaluate the effects of diseases and interventions on vascular stiffness. V.M. is an employee of GlaxoSmithKline plc. A. Plump is an employee of Merck and Co, Inc.

Additional information

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Figures 1–4, Supplementary Tables 1–3 and Supplementary Note. (PDF 3579 kb)

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Wain, L., Verwoert, G., O'Reilly, P. et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43, 1005–1011 (2011). https://doi.org/10.1038/ng.922

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