rs11589889 (CYP4A43P): Treatment-Resistant Hypertension

Key takeaways

• Over 29,000 participants had their genomes sequenced to find genetic factors behind blood pressure that resists three or more medications, and this locus was among those analyzed
• GTEx data link this variant to reduced CYP4A22 expression in brain cerebellar tissue and increased CYP4A11 expression in subcutaneous fat tissue
• No specific p-value or odds ratio for rs11589889 is reported as a primary finding; the evidence for this locus is preliminary
• The study's leading single-variant result was rs12476527 in KCNK3 (odds ratio 0.80, 95% CI 0.74-0.88), replicated in over 35,000 additional participants; this locus was not the primary reported finding

What the research says The CYP4A43P - CYP4A27P locus was analyzed within a large whole-genome sequencing study of apparent treatment-resistant hypertension (aTRH) - a condition defined as blood pressure remaining above target while taking three antihypertensive drug classes, or requiring four or more classes to achieve control. The analysis drew on 12 Trans-Omics for Precision Medicine (TOPMed) cohorts comprising 1,705 aTRH cases, 22,079 normotensive controls, and 5,424 treatment-responsive controls, with logistic regression adjusted for kinship, age, sex, and genetic ancestry across pooled multi-ethnic and race/ethnicity-stratified samples. GTEx v11 eQTL (expression quantitative trait locus) data from 953 donors (FDR < 0.05) independently associate this variant with expression changes in two nearby CYP4A-family genes across distinct tissue types GTEx Portal.

Reported associations

• Apparent treatment-resistant hypertension (aTRH): This locus was analyzed in a WGS study of 29,208 TOPMed participants (1,705 aTRH cases versus 27,503 controls across two groups); the variant's specific effect size and significance level are not reported in the available study text.

Evidence quality The associated aTRH study is among the larger genetic investigations of treatment-resistant hypertension, enrolling over 29,000 participants from 12 diverse TOPMed cohorts using whole-genome sequencing and including both normotensive and treatment-responsive control groups. Analyses were run in a pooled multi-ethnic stratum and in self-reported European and African American strata separately. The study's top single-variant finding was rs12476527 in KCNK3 (OR 0.80, 95% CI 0.74-0.88, p = 8.23×10^-7), replicated in the Vanderbilt University BioVU repository (>35,000 participants), and aggregate gene-based signals were reported for AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. No specific p-value or effect estimate for rs11589889 appears in the available study text, indicating it was not among the primary reported results. The study authors noted that additional work validating findings in larger, more diverse populations is warranted. GTEx eQTL data (v11, 953 donors, FDR < 0.05) provide independent functional context by associating the variant with expression differences in CYP4A11 and CYP4A22; however, eQTL associations reflect gene-expression mechanisms and do not establish disease causation GTEx Portal.

Tissue-specific expression effects

• CYP4A22: Reduced expression in brain cerebellar hemisphere tissue GTEx Portal
• CYP4A11: Increased expression in subcutaneous adipose (fat) tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.