About this item:

280 Views | 268 Downloads

Author Notes:

Correspondence: juliod@uic.edu Center for Pharmacogenomics and Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL 32610, USA

JDD participated in the study design, participated in genotyping, performed statistical analyses and drafted the manuscript.

IZ participated in the design of the study and helped to draft the manuscript. BB participated in sample processing and genotyping and helped to draft the manuscript.

KRB assisted with statistical analysis, STT and ALB participated in study coordination and helped to draft the manuscript.

YG, TYL, ABC, EB, JGG, RMC, RBF participated in study coordination.

BCK conceived the study, participated in its design, and helped to draft the manuscript.

JAJ conceived the study, participated in its design, and helped to draft the manuscript.

All authors read and approved the final manuscript.

While Dr. Zineh is an employee of the FDA, no official FDA endorsement of this manuscript is intended nor should be inferred.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

GERA: This work was supported by NIH grants HL74735, HL53335, and the Mayo Foundation.

PEAR: This work is supported by a grant from the National Institutes of Health (Bethesda, MD), grant U01 GM074492, funded as part of the Pharmacogenetics Research Network.

This work is also supported by the following grants from the NIH National Center for Research Resources: grant M01 RR00082 and UL1 RR029890 to the University of Florida, grants UL1 RR025008 and M01 RR00039 to Emory University, and UL1 RR024150 to Mayo Clinic.

This research was also supported by NIH grants R01 DK075065 (B.C.K.), R01 HL064691 (J.A.J.), R01 NS42754 (R.L.F.), K23 HL091120 (A.L.B.), and T32 DK007518 (J.D.D.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • Pharmacogenomics
  • Pharmacogenetics
  • hydrochlorothiazide
  • hypertension
  • blood pressure
  • DOT1L
  • SIRT1
  • MLLT3
  • SGK1
  • histone methylation
  • SINGLE-NUCLEOTIDE POLYMORPHISMS
  • ANTIHYPERTENSIVE RESPONSE
  • ENAC-ALPHA
  • REPRESSION
  • CHANNEL
  • HOME
  • TRANSCRIPTION
  • HYPERTENSION
  • HOMEOSTASIS
  • ATENOLOL

Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide

Show all authors Show less authors

Journal Title:

Journal of Translational Medicine

Volume:

Volume 10, Number 1

Publisher:

, Pages 56-56

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.Methods: We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant.Results: In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.Conclusions: Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.

Copyright information:

© 2012 Duarte et al; licensee BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

Creative Commons License

Export to EndNote