Effects Of NADPH Oxidase-related Genes On Blood Pressure And Salt Sensitivity And Long-term Changes In Blood Pressure In Chinese Han Population

Background and objectiveEssential hypertension is a major risk factor of cardiovascular disease and mortality and has become a serious public health problem.An excess of dietary salt is one of the established environmental risk factors of hypertension.Blood pressure(BP)response to dietary sodium intake varies considerably among individuals,termed as salt sensitivity of BP(SSBP).The Genetic Epidemiology Network of Salt Sensitivity(GenSalt)study indicates that the heritability of SSBP ranges from 20%to 33%among people from northern rural area in China.However,the genomic mechanisms of SSBP remain to be elucidated.Previous studies have indicated that reactive oxygen species(ROS)produced by nicotinamide adenine dinucleotide phosphate(NADPH)are important risk factors of hypertension.The aim of this study was to comprehensively test the associations of genetic variants of NADPH oxidase related genes with BP responses to dietary sodium intervention,longitudinal BP changes and the risk of incident hypertension(HT)in a family study of Chinese population.Subjects and MethodsWe conducted a 7-day low-sodium intervention followed by a 7-day high-sodium intervention among 1,906 participants in rural China from the GenSalt study from 2003 to 2005.Two follow-up examinations that were conducted in 2008-2009 and 2011-2012,respectively.BP measurements were obtained at baseline,each dietary intervention and two follow-up visits using a random-zero sphygmomanometer.Linear or generalized linear mixed-effect models were used to assess the additive associations of 63 tag single nucleotide polymorphisms(SNPs)in 11 NADPH oxidase related genes with BP responses to dietary sodium intervention,longitudinal BP changes and the risk of incident HT.The false discovery rate(FDR)was calculated for single SNP-based analyses to adjust for multiple testing.Gene-based analyses were conducted using the truncated product method(TPM)and Versatile Gene-based Association Study(VEGAS).The Bonferroni method was used to adjust for multiple testing in gene-based analyses.ResultsSystolic BP(SBP)response to high-sodium intervention significantly decreased with the number of minor T allele of marker rs6967221 in RAC1(P =4.51× 10-4,Q = 0.03).SBP responses(95%confidence interval)for genotypes CC,CT,and TT were 5.03(4.71,5.36),4.20(3.54,4.85),and 0.56(-1.08,2.20)mmHg,respectively,during the high-sodium intervention.NCF2 SNPs rs12094228 and rs12086699 were significantly associated with longitudinal change in SBP(Pinteraction = 1.13 × 10-3 and 1.23 × 10-3,respectively;Q = 0.04 and 0.04).Gene-based analyses revealed that RAC1 was significantly associated with SBP response to high-sodium intervention(PTPM = 1.00 × 10-6,PVEGAS = 4.92 × 10-3),NCF2 was significantly associated with longitudinal SBP(PTPM = 3.00 × 10-6,PVEGAS = 1.00 × 10-4)and DBP changes(PTPM = 8.25 × 10-4,PVEGAS = 1.02 × 10-3).ConclusionThese findings suggested that genetic variants of NADPH oxidase related genes may contribute to the variation of BP responses to sodium intervention and BP changes over time in Chinese population.However,replications of these results in other populations with different genetic background and further functional studies are warranted.