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August 19, 2025

CYP4A11 Gene Variants and Cardiovascular Disease Risk

CYP4A11 encodes an enzyme that regulates vascular tone and sodium handling in the kidney. Variants in this gene increase risk for hypertension and cardiovascular disease. CardiaX testing helps personalize prevention and treatment.

CYP4A11 Gene Variants and Cardiovascular Disease Risk

CYP4A11: A Genetic Driver of Hypertension and Cardiovascular Risk

Introduction

The CYP4A11 gene encodes a cytochrome P450 enzyme that metabolizes arachidonic acid into 20-hydroxyeicosatetraenoic acid (20-HETE). This lipid mediator plays a crucial role in vascular tone, sodium excretion, and kidney function.

Variants in CYP4A11 alter 20-HETE synthesis, predisposing individuals to salt-sensitive hypertension, vascular dysfunction, and increased cardiovascular disease (CVD) risk. The CardiaX test evaluates CYP4A11 polymorphisms to help clinicians design precision-based strategies for prevention and intervention.

Biological Role of CYP4A11

  • 20-HETE production: Regulates renal sodium transport and vascular smooth muscle tone.

  • Blood pressure control: Balances vasoconstriction and sodium handling; disruptions lead to salt-sensitive hypertension.

  • Endothelial health: Modulates nitric oxide signaling and vascular reactivity.

  • Renal physiology: Critical for kidney microcirculation and tubular sodium reabsorption.

Key CYP4A11 Variants

rs1126742 (T8590C, Ile198Val)

  • Most studied CYP4A11 polymorphism.

  • Associated with reduced enzyme activity and impaired 20-HETE synthesis.

  • Carriers of the C allele have increased risk of hypertension, stroke, and cardiovascular disease, particularly in the context of high-salt intake.

Other rare variants

  • Less common coding changes may alter enzymatic efficiency and further modify blood pressure regulation.

How CYP4A11 Variants Elevate Cardiovascular Risk

  1. Salt-sensitive hypertension — Reduced 20-HETE leads to impaired sodium excretion, raising blood pressure.

  2. Vascular dysfunction — Deficiency in 20-HETE disrupts endothelial NO signaling and promotes vasoconstriction.

  3. Kidney injury — Altered renal hemodynamics can worsen CKD progression, compounding CVD risk.

  4. Atherosclerosis and stroke — Hypertension plus endothelial dysfunction accelerates plaque formation and cerebrovascular risk.

Factors That Exacerbate CYP4A11-Related Risk

  • High dietary sodium intake

  • Obesity and insulin resistance

  • Chronic kidney disease (CKD)

  • Sedentary lifestyle

  • Smoking and oxidative stress

  • High alcohol intake

Strategies to Mitigate Risk

1. Lifestyle Modifications

  • Nutrition:

    • Limit sodium to <2,000 mg/day (especially important for carriers of the risk allele).

    • Adopt a DASH or Mediterranean diet: rich in vegetables, fruits, whole grains, nuts, legumes, and fish.

    • Reduce processed foods and excess sugar to improve insulin sensitivity.

    • Ensure adequate potassium and magnesium (leafy greens, nuts, seeds, legumes) for blood pressure control.

  • Exercise:

    • 150+ minutes/week of aerobic exercise plus resistance training.

    • Improves vascular function and lowers blood pressure.

  • Weight optimization:

    • Even modest 5–10% reductions in body weight can normalize blood pressure in salt-sensitive individuals.

2. Nutraceuticals

  • Omega-3 fatty acids — Omega 1300: Improve endothelial function and lower blood pressure.

  • CoQ10 Omega — CoQ10 Omega: Supports mitochondrial and vascular health.

  • Magnesium glycinate: Natural vasodilator, helps reduce blood pressure.

  • Curcumin Complex — Curcumin Complex: Anti-inflammatory, reduces endothelial dysfunction.

  • Vitamin D/K2: Supports cardiovascular and renal health.

  • N-acetylcysteine (NAC): Boosts antioxidant defense and reduces oxidative stress in vasculature.

3. Peptides

  • MOTS-c: Improves insulin sensitivity and vascular health.

  • BPC-157: Promotes vascular repair and protects microcirculation.

  • KPV: Anti-inflammatory peptide that reduces vascular and systemic inflammation.

4. Medications

  • First-line antihypertensives:

    • ACE inhibitors or ARBs: Reduce vasoconstriction, protect kidneys.

    • Thiazide diuretics: Particularly effective for salt-sensitive hypertension.

    • Calcium channel blockers: Improve vasodilation and reduce vascular resistance.

  • Add-on therapy:

    • Mineralocorticoid receptor antagonists (spironolactone, eplerenone): For resistant hypertension.

  • CKD management: Tight BP control slows progression of renal damage.

Case Example

Patient: 55-year-old woman with hypertension despite moderate lifestyle efforts. CardiaX shows CYP4A11 rs1126742 risk allele (C carrier). BP averages 148/92 mmHg, sodium intake high from processed foods, family history of stroke.

Plan:

  • Lifestyle: Sodium reduction, Mediterranean diet, structured aerobic training.

  • Supplements: Omega 1300, CoQ10 Omega, Curcumin Complex, magnesium.

  • Peptide: MOTS-c for metabolic health and KPV for vascular inflammation.

  • Medications: Initiated ARB plus low-dose thiazide diuretic.

  • 6-month follow-up: BP 122/78 mmHg, improved energy, hs-CRP reduced, PULS markers improved.

The Bottom Line

CYP4A11 variants, particularly the rs1126742 C allele, predispose to salt-sensitive hypertension and cardiovascular disease. By identifying these variants with CardiaX testing, clinicians can take a precision-based approach to optimize nutrition, lifestyle, supplements, peptides, and medications—dramatically reducing cardiovascular risk.

References

  1. Gainer JV, et al. Functional variant of CYP4A11 associated with essential hypertension. Hypertension.

  2. Ward NC, et al. Cytochrome P450 metabolites of arachidonic acid and cardiovascular disease. Pharmacol Ther.

  3. Laffer CL, et al. Genetic variation in CYP4A11 and blood pressure regulation. J Hypertens.

  4. Zordoky BN, et al. CYP enzymes, hypertension, and cardiovascular risk. Pharmacol Rev.