title: Association of polymorphisms in the aldosterone-regulated sodium reabsorption pathway with blood pressure among Hispanics.
abstract: BACKGROUND
  Whereas genome-wide association study (GWAS) has proven to be an important tool for discovery of variants influencing many human diseases and traits, unfortunately its performance has not been much of all-around success for some complex conditions, for example, hypertension. Because some of the existing effective pharmacotherapeutic agents act by targeting known biological pathways, pathway-based analytical approaches could lead to more success in discovery of disease-associated variants. The objective of the present study was to identify functional variants associated with blood pressure in the aldosterone-regulated sodium reabsorption pathway using the simulated and real blood pressure phenotypes provided for Genetic Analysis Workshop 19.
  
  
  METHODS
  The present analysis included 1942 samples with exome sequencing data and for whom blood pressure phenotypes were available. Because only odd-numbered autosomes were available, we restricted analysis to 127 quality-controlled single-nucleotide polymorphisms from the aldosterone-regulated sodium reabsorption pathway. We performed pathway-based association analysis using appropriate regression models for single variant, haplotype and epistasis association analyses. To account for multiple comparisons, statistical significance was empirically derived by permutation procedure and Bonferroni correction.
  
  
  RESULTS
  The topmost pathway-based association signals were observed inPRKCAgene for diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) in both real and simulated data. The associations remained significant (P<0.05) after multiple testing corrections for the number of genes. Similarly, the pathway-based 2-locus epistasis analysis indicated significant interactions betweenINSRandPRKCGfor SBP and MAP;INSandPIK3R2for DBP;PIK3CDandATP1B2for hypertension in the real data set. We also observed significant within-gene interactions inINSRfor SBP, DBP, and hypertension in the simulated data set.
  
  
  CONCLUSIONS
  The findings from this study show that pathway-based analytical approach targeting known biological pathways can be useful in identification of disease-associated variants that are otherwise undetectable by GWAS. The approach takes advantage of the assumption of nonindependence of variants within and across pathway genes which leads to reduced penalty of multiple testing and thus less-stringent statistical significance threshold.
authors.affiliation: Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153 USA.
authors.forename: Bamidele O
authors.initials: BO
authors.lastname: Tayo
authors.affiliation: Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153 USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153 USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper