BACKGROUND High heritability of salt sensitivity suggests an essential role for genetics in the relationship between sodium intake and blood pressure (BP). The role of glycosaminoglycan genes, which are crucial for salinity tolerance, remains to be elucidated. METHODS Interactions between 54 126 variants in 130 glycosaminoglycan genes and daily sodium excretion on BP were explored in 20 420 EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) subjects. The UK Biobank (n=414 132) and the multiethnic HELIUS study (Healthy Life in an Urban Setting; n=2239) were used for validation. Afterward, the urinary glycosaminoglycan composition was studied in HELIUS participants (n=57) stratified by genotype and upon dietary sodium loading in a time-controlled crossover intervention study (n=12). RESULTS rs2892799 in NDST3 (heparan sulfate N-deacetylase/N-sulfotransferase 3) showed the strongest interaction with sodium on mean arterial pressure (false discovery rate 0.03), with higher mean arterial pressure for the C allele in high sodium conditions. Also, rs9654628 in HS3ST5 (heparan sulfate-glucosamine 3-sulfotransferase 5) showed an interaction with sodium on systolic BP (false discovery rate 0.03). These interactions were multiethnically validated. Stratifying for the rs2892799 genotype showed higher urinary expression of N-sulfated heparan sulfate epitope D0S0 for the T allele. Conversely, upon dietary sodium loading, urinary D0S0 expression was higher in participants with stable BP after sodium loading, and sodium-induced effects on this epitope were opposite in individuals with and without BP response to sodium. CONCLUSIONS The C allele of rs2892799 in NDST3 exhibits higher BP in high sodium conditions when compared with low sodium conditions, whereas no differences were detected for the T allele. Concomitantly, both alleles demonstrate distinct expressions of D0S0, which, in turn, correlates with sodium-mediated BP elevation. These findings underscore the potential significance of genetic glycosaminoglycan variation in human BP regulation.

中文翻译：

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乙酰肝素硫酸化的遗传变异与盐敏感性有关。


背景盐敏感性的高遗传性表明遗传学在钠摄入量与血压（BP）之间的关系中发挥着重要作用。糖胺聚糖基因对于耐盐性至关重要，其作用仍有待阐明。方法 在 20 420 名 EPIC-Norfolk（欧洲诺福克癌症前瞻性调查）受试者中探讨了 130 个糖胺聚糖基因的 54 126 个变异与血压每日钠排泄之间的相互作用。英国生物银行 (n=414 132) 和多种族 HELIUS 研究（城市环境中的健康生活；n=2239）用于验证。随后，在时间控制交叉干预研究（n=12）中，根据基因型和膳食钠负荷分层，研究了 HELIUS 参与者（n=57）的尿糖胺聚糖组成。结果 NDST3（硫酸乙酰肝素 N-脱乙酰酶/N-磺基转移酶 3）中的 rs2892799 显示出与钠对平均动脉压的最强相互作用（错误发现率 0.03），在高钠条件下，C 等位基因的平均动脉压较高。此外，HS3ST5（硫酸乙酰肝素-葡萄糖胺 3-磺基转移酶 5）中的 rs9654628 显示出与钠对收缩压的相互作用（错误发现率 0.03）。这些相互作用得到了多种族的验证。 rs2892799 基因型分层显示 T 等位基因的 N-硫酸化硫酸乙酰肝素表位 D0S0 的尿表达较高。相反，在饮食钠负荷后，钠负荷稳定后血压稳定的参与者的尿液 D0S0 表达较高，并且钠对该表位的诱导作用在对钠有或没有血压反应的个体中是相反的。 结论 与低钠条件相比，NDST3 中 rs2892799 的 C 等位基因在高钠条件下表现出更高的血压，而 T 等位基因未检测到差异。同时，两个等位基因都表现出 D0S0 的不同表达，这反过来又与钠介导的血压升高相关。这些发现强调了遗传糖胺聚糖变异在人类血压调节中的潜在重要性。