Leveraging a Genetic Proxy to Investigate the Effects of Lifelong Adrenergic Receptor Blockade

Objective: The sympathetic nervous system plays a key role in blood pressure regulation and hypertension pathophysiology. We investigated a genetic variant that we found to act like a natural lifelong adrenergic receptor blockade. Design and method: DBH encodes the enzyme dopamine beta-hydroxylase, which is crucial for converting dopamine to norepinephrine. We studied the impact of the Finnish-enriched DBH missense variant (rs77273740) on biochemical markers and on the risk of hypertension and cardiovascular disease in 520,210 participants from the FinnGen cohort. We used Cox models to investigate the association between variant carrier status and disease outcomes, and linear models for the association with laboratory measurements. Results: We identified 1342 homozygotes (5.0% of the study sample) and 49,176 heterozygotes. rs77273740 conveyed protection from hypertension (HR, 0.64; 95% CI 0.57-0.72; p < 0.001 for homozygotes and HR, 0.89; 95% CI 0.88-0.91; p < 0.001 for heterozygotes; Figure) and cardiovascular disease (HR, 0.83; 95% CI 0.76-0.89; p < 0.001 for homozygotes and HR, 0.96; 95% CI 0.94-0.97; p < 0.001 for heterozygotes. Compared to wild-type carriers, homozygotes and heterozygotes had significantly lower platelet (p = 9.6e-25) and normetanephrine (p = 8.4e-6) levels.Conclusions: The missense variant of rs77273740 in DBH gene was enriched by more than 50-fold in Finland compared to other populations. Our data offers a rare chance to study partial DBH deficiency, and lifelong adrenergic receptor blockade, in relation to blood pressure and cardiovascular disease. The studied gene variant was associated with reduced risk of hypertension and had a protective effect against cardiovascular disease. This study lays the groundwork for additional research into developing dopamine beta-hydroxylase (translation) inhibitors as a new class of hypertension therapeutics.