title: Pharmacogenetic effects of 'candidate gene complexes' on stroke in the GenHAT study.
abstract: OBJECTIVE
  The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril.
  
  
  METHODS
  A population of 436 African Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein-protein interactions. To assess the statistical significance of the observed test statistic, we derived an empirical P-value by simulating data under the null hypothesis.
  
  
  RESULTS
  We found that, in patients who have experienced stroke, there is a significant genetic difference between hypertension drug treatment groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene complexes tested showed significance.
  
  
  CONCLUSIONS
  On the basis of the genetic differences between drug treatment groups, we conclude that there may be an interaction between certain genotypes and antihypertensive treatment in stroke patients. This needs to be replicated in other studies.
authors.affiliation: Departments of aBiostatistics bEpidemiology, University of Alabama at Birmingham, Birmingham, Alabama cDepartment of Biostatistics dDepartment of Epidemiology, Human Genetics & Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, Texas eDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA fDepartment of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Denmark.
authors.forename: Izel F
authors.initials: IF
authors.lastname: Sørensen
authors.forename: Ana I
authors.initials: AI
authors.lastname: Vazquez
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Peter
authors.initials: P
authors.lastname: Sørensen
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.forename: Charles E
authors.initials: CE
authors.lastname: Ford
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000368:Aged; D017311:Amlodipine / Q000627:therapeutic use; D002752:Chlorthalidone / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D017706:Lisinopril / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000188:drug therapy / Q000235:genetics*
chemical_list: D017311:Amlodipine; D017706:Lisinopril; D002752:Chlorthalidone