Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics

KEY POINTS: 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.

BACKGROUND: 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.

METHODS: We conducted genome-wide association study analyses of plasma sodium concentration, thiazide-induced decrease in sodium concentration, and thiazide-induced 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.

RESULTS: Meta-analysis yielded 31 independent associated signals at P < 5×10−8 with plasma sodium concentrations. Subsequent tissue specificity analysis showed a significantly increased expression of sodium-associated genes in pituitary tissue (P = 4.5×10−5). No genome-wide significant loci were found for thiazide-induced 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 (P = 0.71).

CONCLUSIONS: 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.