Abstract
Genome-wide association studies suggest that there is a significant genetic susceptibility to salt sensitivity of blood pressure (SSBP), but it still needs to be verified in varied and large sample populations. We attempted to verify the associations between single-nucleotide polymorphisms (SNPs) in candidate genes and SSBP and to estimate their interaction with potential risk factors. A total of 29 candidate SNPs were genotyped in the 2,057 northern Han Chinese population from the Systems Epidemiology Study on Salt Sensitivity. A modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) was used to identify SSBP. A generalized linear model was conducted to analyze the association between SNPs and SSBP, and Bonferroni correction was used for multiple testing. Mediation analysis was utilized to explore the mediation effect of risk factors. Eleven SNPs in eight genes (PRKG1, CYBA, BCAT1, SLC8A1, AGTR1, SELE, CYP4A11, and VSNL1) were identified to be significantly associated with one or more SSBP phenotypes (P < 0.05). Four SNPs (PRKG1/rs1904694 and rs7897633, CYP4A11/rs1126742, and CYBA/rs4673) were still significantly associated after Bonferroni correction (P < 0.0007) adjusted for age, sex, fasting blood glucose, total cholesterol, salt-eating habit, physical activity, and hypertension. Stratified analysis showed that CYBA/rs4673 was significantly associated with SSBP in hypertensive subjects (P < 0.0015) and CYP4A11/rs1126742 was significantly associated with SSBP in normotensive subjects (P < 0.0015). Subjects carrying both CYBA/rs4673-AA and AGTR1/rs2638360-GG alleles have a higher genetic predisposition to salt sensitivity due to the potential gene co-expression interaction. Expression quantitative trait loci analysis (eQTL) suggested that the above positive four SNPs showed cis-eQTL effects on the gene expression levels. Mediation analysis suggested that several risk factors were mediators of the relation between SNP and SSBP. This study suggests that the genetic variants in eight genes might contribute to the susceptibility to SSBP, and other risk factors may be the mediators.
Highlights
Salt sensitivity of blood pressure (SSBP) is defined as a quantitative trait in which the BP of some members of the population displays changes that are parallel to changes in sodium ingestion (Elijovich et al, 2016)
The genome-wide association studies (GWAS) conducted by Lorena Citterio on Caucasians with mild hypertension found that single-nucleotide polymorphisms (SNPs) located in the cGMP-dependent protein kinase 1 (PRKG1) gene are associated with changes in the diastolic BP (DBP), whereas SLC24A3 and SLC8A1 are associated with changes in the systolic BP (SBP), which focuses on acute salt loading but that study is limited by modest sample sizes (n = 329), and the results may not apply to other racial groups (Citterio et al, 2011)
We reviewed the literature to select candidate genes based on the biological knowledge of relevant pathways involved in SSBP and sought to validate the role of polymorphisms in 23 candidate genes involved in seven potential pathways in explaining the genetic mechanism of SSBP in the Han Chinese population
Summary
Salt sensitivity of blood pressure (SSBP) is defined as a quantitative trait in which the BP of some members of the population displays changes that are parallel to changes in sodium ingestion (Elijovich et al, 2016). Several genome-wide association studies (GWAS) and candidate gene studies have been conducted for SSBP, and the results were reviewed (Liu et al, 2020). Several candidate studies have indicated that genomic variations are associated with SSBP; these results are inconsistent and limited considering that there are only a handful of SNPs in one gene or are limited by their statistical power. Such an association study is unable to explain the biological complexity of SSBP, a multifactorial disease with several components involved in its pathological mechanism, including numerous environmental, and genetic risk factors
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