RARE VARIANT ANALYSIS OF APPARENT TREATMENT RESISTANT HYPERTENSION WITHIN THE UK BIOBANK

Objective: Primary hypertension affects over one billion people worldwide and is a leading risk factor for cardiovascular mortality, with many cases undiagnosed or inadequately controlled. Although rare coding variants (minor allele frequency <= 0.01) have been implicated in hypertension, their contribution to apparent treatment-resistant hypertension (aTRH) has not been determined. We investigated associations of rare exonic variants from whole-exome sequencing (WES) for effective blood pressure (BP) control and aTRH in individuals with primary hypertension within the UK Biobank.
Design and method: An aTRH cohort (n=26,640) was defined from participants with clinically diagnosed primary hypertension prior to their baseline assessment using linked hospital and primary care records. Controlled BP control was defined as systolic BP <140 mmHg and diastolic BP <90 mmHg. aTRH was defined as (i) use of >=3 antihypertensive classes with uncontrolled BP, or (ii) use of >=4 classes regardless of BP control. Medication use was determined from primary care prescription records. Rare variant association analyses were conducted using REGENIE v4.1 with gene-based burden tests, and gene-P omnibus tests to account for heterogeneous effect directions. Models were adjusted for age, age², sex, genotyping array, waist circumference, genomic ancestry, and population structure. Analyses were conducted in European ancestry and multi-ancestry cohorts, and included time-restricted aTRH definitions using 1-, 2-, and 3-year antihypertensive drug exposure windows.
Results: Multiple gene-level associations were identified for aTRH. After correction for multiple testing, significant associations were observed for PDE11A in European ancestry analyses (p=2.74e-5) and for DHX9 in multi-ancestry analyses (p=1.72e-5). The PDE11A signal was driven by missense variant rs6433711, and DHX9 driven by the synonymous variant rs6677840. Additional suggestive gene-level associations were observed for EEF1D, HEYL, CD48, TRH, TAF1B, RRNAD1, and C8orf74 within missense variant masks.
Conclusions: These findings represent the first rare variant analysis of aTRH, and provides evidence that rare coding variation may contribute to treatment resistance with ancestry specific signals. Larger, independent and more diverse cohorts will be required to validate these associations and clarify their clinical relevance. Future work will explore blood-based multi-omics biomarkers and functional pathways underlying aTRH within the UK Biobank.