Abstract
Despite recent success with genome-wide association studies (GWAS), identifying hypertension (HTN)-susceptibility loci in the general population remains difficult. Here, we present a novel strategy to address this challenge by studying salinity adaptation in the threespine stickleback, a fish species with diverse salt-handling ecotypes. We acclimated native freshwater (FW) and anadromous saltwater (SW) threespine sticklebacks to fresh, brackish, and sea water for 30 days, and applied RNA sequencing to determine the gene expression in fish kidneys. We identified 1844 salt-responsive genes that were differentially expressed between FW sticklebacks acclimated to different salinities and/or between SW and FW sticklebacks acclimated to full-strength sea water. Significant overlap between stickleback salt-responsive genes and human genes implicated in HTN was detected (P < 10−7, hypergeometric test), suggesting a possible similarity in genetic mechanisms of salt handling between threespine sticklebacks and humans. The overlapping genes included a newly discovered HTN gene—MAP3K15, whose expression in FW stickleback kidneys decreases with salinity. These also included genes located in the GWAS loci such as AGTRAP-PLOD1 and CYP1A1-ULK3, which contain multiple potentially causative genes contributing to HTN susceptibility that need to be prioritized for study. Taken together, we show that stickleback salt-responsive genes provide valuable information facilitating the identification of human HTN genes. Thus, threespine sticklebacks may be used as a model, complementary to existing animal models, in human HTN research.
Highlights
Hypertension (HTN), or the chronic elevation of blood pressure (BP), is a major human health problem
SIGNIFICANT OVERLAP BETWEEN SALT-RESPONSIVE GENES AND HTN and/or BP-regulating (HTN/BP) GENES To examine the overlap between stickleback salt-responsive genes and human HTN/BP genes, we compiled the list of HTN/BP genes including 560 identified using non-Genome-wide association studies (GWAS) approaches (Supplementary Table 4) and 108 identified using GWAS approach (Supplementary Table 5) (Levy et al, 2009; Newton-Cheh et al, 2009; Ho et al, 2011; International Consortium for Blood Pressure Genome-Wide Association Studies, 2011; Kato et al, 2011; Wain et al, 2011)
We adopt the idea of using threespine sticklebacks as a GxE animal model to facilitate the search of genes underlying human susceptibility to HTN and BP regulation
Summary
Hypertension (HTN), or the chronic elevation of blood pressure (BP), is a major human health problem. Identifying genetic loci associated with HTN or BP regulation in the general population has proved to be challenging (Dominiczak and Munroe, 2010; Hastie et al, 2010; Padmanabhan et al, 2012). Chronic excess salt intake results in the development of HTN in the general human population (Kotchen et al, 2013). Clinical, and experimental studies have shown that a reduction in dietary salt intake lowers BP (Luft and Weinberger, 1982; Haddy and Pamnani, 1995; Frisoli et al, 2012; Kotchen et al, 2013). In some populations with very low salt intake, such as Papua New Guineans and Yanomamo Indians in the Amazon region, HTN and age-related increases in BP are virtually absent (Denton, 1982)
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