AUTHOR=Chen Yu , Han Yuqing , Wu Yiyi , Hui Rutai , Yang Yunyun , Zhong Yixuan , Zhang Shuyuan , Zhang Weili 

TITLE=Pharmacogenetic association of the NR1H3 promoter variant with antihypertensive response among patients with hypertension: A longitudinal study

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1083134

DOI=10.3389/fphar.2023.1083134

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> The genetic factors in assessing therapeutic efficacy and predicting antihypertensive drug response are unclear. Therefore, this study aims to identify the associations between variants and antihypertensive drug response.</p><p><bold>Methods:</bold> A longitudinal study including 1837 hypertensive patients was conducted in Northern China and followed up for a median 2.24 years. The associations of 11 candidate variants with blood pressure changes in response to antihypertensive drugs and with the risk of cardiovascular events during the follow-up were examined. The dual-luciferase assay was carried out to assess the effect of genetic variants on gene transcriptional activity.</p><p><bold>Results:</bold> The variant rs11039149A&gt;G in the promoter of nuclear receptor subfamily 1 group H member 3 (<italic>NR1H3</italic>) was associated with the change in systolic blood pressure (ΔSBP) in response to calcium channel blockers (CCBs) monotherapy. Patients carrying rs11039149AG genotype showed a significant increase of systolic blood pressure (SBP) at follow-up compared with AA carriers, and the difference of ΔSBP between AG and AA carriers was 5.94 mm Hg (95%CI: 2.09–9.78, <italic>p</italic> = 0.002). In 1,184 patients with CCBs therapy, SBP levels decreased in AA carriers, but increased in AG carriers, the difference of ΔSBP between AG and AA carriers was 8.04 mm Hg (95%CI: 3.28–12.81, <italic>p</italic> = 0.001). Further analysis in 359 patients with CCBs monotherapy, the difference of ΔSBP between AG and AA carriers was 15.25 mm Hg (95%CI: 6.48–24.02, <italic>p</italic> = 0.001). However, there was no significant difference in ΔSBP between AG and AA carriers with CCBs multitherapy. The rs11039149A&gt;G was not associated with the cardiovascular events incidence during the follow-up. Additionally, transcriptional factor forkhead box C1 (<italic>FOXC1</italic>) bound to the <italic>NR1H3</italic> promoter containing rs11039149A and significantly increased the transcriptional activity, while rs11039149 A to G change led to a loss-of-function and disabled <italic>FOXC1</italic> binding. For the other 10 variants, associations with blood pressure changes or risk of cardiovascular events were not observed.</p><p><bold>Conclusion:</bold> Hypertensive patients with rs11039149AG genotype in the <italic>NR1H3</italic> gene have a significant worse SBP control in response to CCBs monotherapy compared with AA carriers. Our findings suggest that the <italic>NR1H3</italic> gene might act as a promising genetic factor to affect individual sensitivity to antihypertensive drugs.</p>