Andersson Niklas Worm, Wu Xiaoping, Geller Frank, Wohlfahrt Jan, Melbye Mads, Hviid Anders, Schwinn Michael, Mikkelsen Christina, Dowsett Joseph, Bruun Mie Topholm, Aagaard Bitten, Ullum Henrik, Erikstrup Christian, Gudbjartsson Daniel Fannar, Stefánsson Kári, Ghouse Jonas, Pedersen Ole Birger, Sørensen Erik, Ostrowski Sisse Rye, Bundgaard Henning, Lund Marie, Feenstra Bjarke
Department of Epidemiology Research, Statens Serums Institut, Copenhagen, Denmark.
Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
J Am Soc Nephrol. 2025 Jun 1;36(6):1014-1027. doi: 10.1681/ASN.0000000622. Epub 2025 Jan 31.
This large-scale genetic study identified 31 loci associated with plasma sodium concentrations in individuals of European ancestry. Tissue specificity analysis showed a significantly increased expression of sodium-associated genes in the pituitary gland. No genetic association signals were found for the risk of hyponatremia after thiazide exposure.
Abnormal plasma sodium concentration represents an imbalance of total body water relative to electrolyte content. Hyponatremia is a common and potentially severe adverse event, and thiazide diuretics constitute a leading cause of drug-induced hyponatremia.
We conducted genome-wide association study analyses of plasma sodium concentration, thiazideinduced decrease in sodium concentration, and thiazideinduced hyponatremia in a total of 188,461 individuals of European ancestry. In addition, we tested for gene–environment interaction between a polygenic score developed for plasma sodium concentration and thiazide exposure on sodium concentration and hyponatremia risk.
Meta-analysis yielded 31 independent associated signals at < 5×10 with plasma sodium concentrations. Subsequent tissue specificity analysis showed a significantly increased expression of sodium-associated genes in pituitary tissue ( = 4.5×10). No genome-wide significant loci were found for thiazideinduced sodium concentration decrease or thiazide-induced hyponatremia. A polygenic score for plasma sodium concentration was associated with 0.43 (95% confidence interval, 0.39 to 0.46) mmol/L lower plasma sodium per SD decrease, and thiazide use was associated with 0.80 (95% confidence interval, 0.72 to 0.88) mmol/L lower plasma sodium, but we observed no gene–environment interaction effect ( = 0.71).
These results underline the role of genetic variation in regulating plasma sodium concentration and highlight the importance of pathways involving the pituitary gland while finding no evidence of genetic predisposition for the plasma sodium–lowering effect of thiazides.
这项大规模基因研究在欧洲血统个体中确定了31个与血浆钠浓度相关的基因座。组织特异性分析显示垂体中钠相关基因的表达显著增加。噻嗪类药物暴露后低钠血症风险未发现遗传关联信号。
血浆钠浓度异常代表总体水与电解质含量失衡。低钠血症是一种常见且可能严重的不良事件，噻嗪类利尿剂是药物性低钠血症的主要原因。
我们对总共188461名欧洲血统个体的血浆钠浓度、噻嗪类药物引起的钠浓度降低和噻嗪类药物引起的低钠血症进行了全基因组关联研究分析。此外，我们测试了为血浆钠浓度开发的多基因评分与噻嗪类药物暴露之间在钠浓度和低钠血症风险方面的基因-环境相互作用。
荟萃分析在血浆钠浓度<5×10时产生了31个独立的关联信号。随后的组织特异性分析显示垂体组织中钠相关基因的表达显著增加（=4.5×10）。未发现全基因组显著的基因座与噻嗪类药物引起的钠浓度降低或噻嗪类药物引起的低钠血症有关。血浆钠浓度的多基因评分每降低一个标准差，血浆钠降低0.43（95%置信区间，0.39至0.46）mmol/L，使用噻嗪类药物与血浆钠降低0.80（95%置信区间，0.72至0.88）mmol/L有关，但我们未观察到基因-环境相互作用效应（= 0.71）。
这些结果强调了遗传变异在调节血浆钠浓度中的作用，突出了涉及垂体的途径的重要性，同时未发现噻嗪类药物降低血浆钠作用存在遗传易感性的证据。
