rs11693319 (CCDC141): Blood Pressure Salt Sensitivity

Key takeaways

• This variant, near CCDC141 (coiled-coil domain containing 141), has been studied in relation to how blood pressure responds to changes in dietary sodium and potassium.
• A genome-wide association study of 1,881 Han Chinese participants, replicated in 698 individuals, identified genetic loci predicting blood pressure responses to controlled dietary interventions and a cold-stress test.
• Carrying more risk alleles across the study's identified loci was associated with up to 1.84-fold higher odds of developing hypertension over 7.5 years.
• In skeletal muscle, the alternate allele of this variant is linked to increased expression of this gene according to large-scale tissue expression data.

What the research says

A genome-wide association study (GWAS) of blood pressure (BP) responses to a 3-week dietary protocol - a 7-day low-sodium period (51.3 mmol sodium/day), a 7-day high-sodium period (307.8 mmol sodium/day), and a 7-day high-sodium-plus-potassium period (60 mmol potassium/day), plus a cold pressor test (CPT, brief ice-water hand immersion assessing sympathetic nervous system reactivity) - enrolled 1,881 Han Chinese participants with de novo replication in 698 individuals. Eight loci reached genome-wide significance for BP response phenotypes, and cumulative risk-allele count across those loci predicted new-onset hypertension over 7.5 years with an odds ratio of 1.84 (95% CI 1.29-2.62) for the highest versus lowest risk-allele quartile (P=0.0003 for trend). Separately, the alternate allele of rs11693319 is associated with increased expression of this gene in skeletal muscle (slope +0.19, p=3.7×10^-¹², GTEx v11, n=953 donors) GTEx Portal.

Reported associations

• Blood pressure response to low-sodium diet: A Han Chinese dietary-intervention GWAS found genetic loci associated with BP changes during a controlled 51.3 mmol sodium/day period (n≈1,850 completers).
• Blood pressure response to high-sodium diet: BP responses during a 307.8 mmol sodium/day period were captured as a distinct genetically-associated phenotype in the same cohort.
• Blood pressure response to potassium supplementation: Changes in BP during a high-sodium-plus-potassium regimen (60 mmol potassium/day) were assessed as a separate intervention phenotype.
• Blood pressure response to cold pressor test: Sympathetic reactivity, indexed by BP rise during a 1-minute ice-water hand immersion, was examined as a genetic association phenotype in the same study.
• 7.5-year hypertension incidence: Cumulative risk-allele count across the eight GWAS-identified loci predicted new-onset hypertension in initially normotensive participants, with odds ratios of 1.39 (95% CI 0.97-1.99), 1.72 (95% CI 1.19-2.47), and 1.84 (95% CI 1.29-2.62) for the second, third, and fourth risk-allele quartiles versus the first (P=0.0003 for trend).
• Skeletal muscle gene expression (eQTL): The alternate allele of rs11693319 is associated with increased expression of this gene in skeletal muscle GTEx Portal.

Evidence quality

The GWAS was conducted in a Han Chinese dietary-intervention cohort (initial n=1,881; replication n=698), with dietary compliance verified through timed 24-hour urinary sodium and potassium excretion. The study reports that the identified loci have larger effect sizes on BP response phenotypes than those from prior GWAS of resting BP, though the per-allele BP effect for this specific locus is not separately reported in the available text. Both cohorts were drawn from the same ancestral group in rural north China, so generalizability to other populations is unknown. The eQTL signal in skeletal muscle is statistically robust (p=3.7×10^-¹², FDR<0.05, GTEx v11, n=953 donors) GTEx Portal, but whether altered expression of this gene in muscle is mechanistically related to BP responses has not been examined. Evidence should be considered preliminary pending multi-ancestry replication and functional characterization.

Tissue-specific expression effects

• CCDC141: The alternate allele is associated with increased expression in skeletal muscle GTEx Portal.

Lifestyle considerations

• Dietary sodium (nutrition, mixed, low): Genetic variants at this locus were identified through a study specifically designed to measure blood pressure sensitivity to controlled high- and low-sodium diets, suggesting the region may interact with sodium intake; the direction of effect for this specific allele has not been separately quantified.
• Dietary potassium (nutrition, include, low): Potassium supplementation was a primary intervention arm in the source study, and the identified loci collectively predicted blood pressure responses during that condition; the specific effect of this allele on potassium sensitivity is not independently characterized.