Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same locus, prompting us to adopt an alternative approach to testing multiple GWAS genes empirically. We used gene targeting in a disease-susceptible rat model of genetic hypertension to test all six genes at the Agtrap-Plod1 locus (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) for blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (five out of six) can impact hypertension by modifying BP and renal phenotypes. Mutations of Nppa, Plod1, and Mthfr increased disease susceptibility, whereas Agtrap and Clcn6 mutations decreased hypertension risk. Reanalysis of the human AGTRAP-PLOD1 locus also implied that disease-associated haplotype blocks with polygenic effects were not only possible, but rather were highly plausible. Combined, these data demonstrate for the first time that multiple modifiers of hypertension can cosegregate at a single GWAS locus.
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PMID:Identifying multiple causative genes at a single GWAS locus. 2400 81

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.
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PMID:Gene expression responses of threespine stickleback to salinity: implications for salt-sensitive hypertension. 2530 74

In candidate gene era, dozens of single-nucleotide polymorphisms (SNPs) within renin-angiotensin-aldosterone system (RAAS) have been reported to be significantly associated with hypertension. However, the unbiased genome-wide association studies (GWAS) rarely identified the SNPs within RAAS were associated with hypertension or blood pressure (BP) traits. In order to figure out whether genetic polymorphisms of RAAS are really associated with hypertension, we systemically searched the GWAS Catalogue and identified all the known RAAS genes and relevant diseases/traits. After data processing, we found that polymorphisms within REN, AGT, ACE2, CYP11B2, ATP6AP2 and HSD11B2 were not associated with any disease or trait. SNPs within ACE, AGTR1, AGTR2, MAS1, RENBP and NR3C2 were associated with other diseases or traits, but showed no direct connection with hypertension. The only SNP associated with a BP trait, systolic BP was rs17367504. However, it is located in the intronic region of MTHFR near many plausible candidate genes, including CLCN6, NPPA, NPPB and AGTRAP. Therefore, the effect of RAAS polymorphisms may have been overestimated during the 'candidate gene era'. In the time of 'precision medicine', the power of RAAS variants needs to be reconsidered when evaluating one's susceptibility of hypertension.
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PMID:Are genetic polymorphisms in the renin-angiotensin-aldosterone system associated with essential hypertension? Evidence from genome-wide association studies. 2842 37