Genome-wide association analysis of common genetic variants of resistant hypertension

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy—GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10⁻⁴ were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2–1.8), p = 7.3 × 10⁻⁵) and replicated in SPS3 (OR = 2.0 (1.4–2.8), p = 4.3 × 10⁻⁵), with genome-wide significance in meta-analysis (OR = 1.60 (1.3–1.9), p = 3.8 × 10⁻⁸). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4–2.5), p = 1.1 × 10⁻⁵) and SPS3 (OR = 1.70 (1.2–2.5), p = 4 × 10⁻³). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3–2.0), p = 3.4 × 10⁻⁵) and replicated in SPS3 (OR = 1.60 (1.1–2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10⁻¹⁵). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.