Using genetics to understand the role of antihypertensive drugs modulating angiotensin‐converting enzyme in immune function and inflammation

Zhao, Jie V.; Schooling, C. Mary; Leung, Gabriel M.

AIM: Angiotensin‐converting enzyme 2 (ACE 2) is the binding domain for severe acute respiratory syndrome coronavirus (SARS‐CoV) and SARSCoV‐2. Some antihypertensive drugs affect ACE2 expression or activity (ACE inhibitors and angiotensin II receptor blockers [ARBs]), suggesting use of other hypertensives might be preferable, such as calcium channel blockers (CCBs). Given the limited evidence, the International Society of Hypertension does not support such a policy. METHODS: We used a Mendelian randomization study to obtain unconfounded associations of antihypertensives, instrumented by published genetic variants in genes regulating target proteins of these drugs, with immune (lymphocyte and neutrophil percentage) and inflammatory (tumour necrosis factor alpha [TNF‐α]) markers in the largest available genome‐wide association studies. RESULTS: Genetically predicted effects of ACE inhibitors increased lymphocyte percentage (0.78, 95% confidence interval [CI] 0.35, 1.22), decreased neutrophil percentage (−0.64, 95% CI −1.09, −0.20) and possibly lowered TNF‐α (−4.92, 95% CI −8.50, −1.33). CCBs showed a similar pattern for immune function (lymphocyte percentage 0.21, 95% CI 0.05 to 0.36; neutrophil percentage −0.23, 95% CI −0.39 to −0.08) but had no effect on TNF‐α, as did potassium‐sparing diuretics and aldosterone antagonists, and vasodilator antihypertensives. ARBs and other classes of hypertensives had no effect on immune function or TNF‐α. CONCLUSION: Varying effects of different classes of antihypertensives on immune and inflammatory markers do not suggest antihypertensive use based on their role in ACE2 expression, but instead suggest investigation of the role of antihypertensives in immune function and inflammation might reveal important information that could optimize their use in SARSCoV‐2.