title: Two further blood pressure loci identified in ion channel genes with a gene-centric approach.
abstract: BACKGROUND
  Blood pressure (BP) is highly heritable, but our understanding of the genetic causes underlying variations in BP is incomplete. In this study, we explored whether novel loci associated with BP could be identified using a genecentric approach in 3 community-based cohorts with accurate BP measurements.
  
  
  RESULTS
  Genotyping of 1857 single nucleotide polymorphisms (SNPs) in 91 ion channel genes was performed in a discovery cohort (n=358). Thirty-four SNPs associated with BP traits (P≤0.01) were followed up in an independent population (n=387); significant SNPs from this analysis were looked up in another independent population (n=1010) and meta-analyzed. Repeated clinic and ambulatory measurements were available for all but the discovery cohort (clinic only). Association analyses were performed, with systolic, diastolic, and pulse pressures as quantitative traits, adjusting for age and sex. Quantile-quantile plots indicated that the genecentric approach resulted in an inflation of association signals. Of the 29 SNPs taken forward from the discovery cohort, 2 SNPs were associated with BP phenotypes with the same direction of effect, with experiment-wide significance, in follow-up cohort I. These were rs2228291, in the chloride channel gene CLCN2, and rs10513488, in the potassium channel gene KCNAB1. Both associations were subsequently replicated in follow-up cohort II.
  
  
  CONCLUSIONS
  Using a genecentric design and 3 well-phenotyped populations, this study identified 2 previously unreported, biologically plausible, genetic associations with BP. These results suggest that dense genotyping of genes, in pathways known to influence BP, could add to candidate-gene and Genome Wide Association studies in further explaining BP heritability.
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Nina S
authors.initials: NS
authors.lastname: McCarthy
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Ciara
authors.initials: C
authors.lastname: Vangjeli
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Praveen
authors.initials: P
authors.lastname: Surendran
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Eoin
authors.initials: E
authors.lastname: O'Brien
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Masca
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.).
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: From the Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (N.S.M., C.V., G.L.C., N.D., P.S., A.V.S.); Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Australia (N.S.M.); Blood Pressure Unit and Department of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland (N.D., A.V.S.); Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, NC (K.V.S.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (P.S., E.O.B.); Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, and Barts NIHR Biomedical Research Unit, London (P.B.M.); and Department of Cardiovascular Sciences, University of Leicester, and Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (N.M., M.T., N.J.S.). astanton@rcsi.ie.
authors.forename: Alice V
authors.initials: AV
authors.lastname: Stanton
mesh_terms: D000328:Adult; D000483:Alleles; D001794:Blood Pressure / Q000235:genetics*; D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D051664:Kv1.3 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D007473:Ion Channels; C097044:KCNAB1 protein, human; D051664:Kv1.3 Potassium Channel
keywords: ambulatory blood pressure monitoring; association studies; blood pressure; genetics; ion channel