rs3865418 — NEDD4L

Intronic NEDD4L variant

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NEDD4L — The Kidney's Sodium Channel Gatekeeper

Every heartbeat depends on the right amount of sodium in the blood. The kidneys are the master regulators of that balance, and NEDD4L is one of their most critical molecular gatekeepers. This gene encodes an E3 ubiquitin ligase11 E3 ubiquitin ligase
an enzyme that tags specific proteins for degradation by attaching ubiquitin chains to them. Its primary target in the kidney collecting duct is the epithelial sodium channel (ENaC)22 epithelial sodium channel (ENaC)
the principal channel through which sodium is reclaimed from urine back into the bloodstream. By ubiquitinating ENaC subunits, NEDD4L controls how many active channels are present at the cell surface — and therefore how much sodium the kidney retains.

The Mechanism

NEDD4L recognizes ENaC through its WW domains, which bind PY motifs on the β- and γ-ENaC subunits33 WW domains, which bind PY motifs on the β- and γ-ENaC subunits
creating a molecular handshake that initiates ubiquitin transfer and channel endocytosis. Once ubiquitinated, ENaC is internalized and degraded, reducing sodium reabsorption. This process is under tight hormonal control: aldosterone and the kinase SGK1 phosphorylate NEDD4L, causing it to bind 14-3-3 proteins44 aldosterone and the kinase SGK1 phosphorylate NEDD4L, causing it to bind 14-3-3 proteins
sequestering it away from ENaC and temporarily allowing greater sodium reabsorption in response to volume depletion. NEDD4L also regulates NCC (the distal tubule Na⁺-Cl⁻ cotransporter)55 NCC (the distal tubule Na⁺-Cl⁻ cotransporter)
another major renal sodium transporter whose overactivity compounds ENaC-mediated hypertension, and knockout studies confirm that renal NEDD4L loss alone causes salt-sensitive hypertension in animal models.

The Evidence

Direct evidence for rs3865418 in humans comes from several Asian population studies. Wen et al. 200866 Wen et al. 2008
Two polymorphisms in NEDD4L gene and essential hypertension in Chinese Hans. Clin Exp Hypertens 2008 conducted a population-based case-control study in Chinese Han individuals and found that the T allele at rs3865418 was associated with significantly higher diastolic blood pressure under a dominant model (p=0.009). The sex-stratified analysis by Liang et al. 201477 Liang et al. 2014
Gender difference in association of NEDD4L gene variants among southern Han Chinese with essential hypertension. Clin Exp Hypertens 2014 in 1,898 participants found rs3865418 associated with hypertension in men (OR=0.71, p=0.009), revealing a gene-by-sex interaction. A review of NEDD4L in cardiovascular disease by Li et al. 202288 Li et al. 2022
Research progress of Nedd4L in cardiovascular diseases. Cell Death Discovery 2022 further confirmed rs3865418 association with hypertension in American and Greek white populations.

In the broader NEDD4L context, a large Korean cohort study of 8,842 individuals99 large Korean cohort study of 8,842 individuals
Jin et al. Kidney Blood Press Res 2010 identified 13 SNPs in SCNN1B, SCNN1G, and NEDD4L genes linked to hypertension in case-control analysis, supporting the entire ENaC-NEDD4L regulatory axis as a polygenic determinant of blood pressure.

Nutrient Interactions

sodium altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal ENaC Regulation Normal

Normal NEDD4L activity toward the epithelial sodium channel

You carry two copies of the C allele at rs3865418. About 24% of people globally share this genotype, though it is more common in East Asian populations (roughly 44%).

CT Mildly Impaired ENaC Regulation Intermediate

One copy of the T allele moderately reduces NEDD4L activity toward the sodium channel

Wen et al. 2008 (PMID 18293164) found that even single-copy T allele carriers showed elevated diastolic blood pressure relative to CC homozygotes in Chinese Hans. Monitoring blood pressure is warranted, especially if you have other cardiovascular risk factors.

TT Significantly Impaired ENaC Regulation High Risk

Two copies of the T allele substantially reduce NEDD4L-ENaC ubiquitination and confer marked salt-sensitive hypertension risk

Wen et al. 2008 (PMID 18293164) found T-allele carriers (dominant model including TT) had significantly higher diastolic blood pressure (p=0.009). The Russian cardiovascular cohort (PMC4610169) found rs3865418 associated with ischemic heart disease risk in a Mendelian sense, consistent with the downstream consequences of chronically elevated blood pressure. Li et al. 2022 confirmed rs3865418 association with hypertension in multiple ethnic populations.