Expressive

rs11585710 (CROCC): Carotid Artery Wall Thickness

Key takeaways

  • rs11585710 at the CROCC locus has been linked to carotid intima-media thickness (cIMT), an ultrasound measure of artery wall thickness used as a proxy for atherosclerosis risk
  • Evidence comes from a 2022 GWAS of 7,894 adults from Burkina Faso, Ghana, Kenya, and South Africa, addressing a long-standing gap in African-ancestry cardiovascular genetics
  • GTEx data shows the alternate allele is associated with reduced CROCC expression in skeletal muscle, stomach, brain, esophagus, and skin
  • Known GWAS loci for cIMT collectively explain only about 1.1% of its variance despite family and twin study heritability estimates of 20-65%
  • Sex-stratified analysis found distinct male-specific and female-specific cIMT loci, with female signals enriched for estrogen-response genes

Key takeaways

  • rs11585710 sits at the CROCC (Ciliary Rootlet Coiled-Coil) locus and has been investigated in relation to carotid intima-media thickness (cIMT), an ultrasound measure of artery wall thickness used as a proxy for atherosclerosis risk
  • Evidence comes from a 2022 genome-wide association study of 7,894 adults from four sub-Saharan African countries, a population historically underrepresented in cardiovascular genetics research
  • GTEx expression data shows the alternate allele is associated with reduced CROCC expression in skeletal muscle, stomach, brain, esophagus, and skin
  • Two nearby genes (ENSG00000290122 and ENSG00000291072) show increased expression in tibial nerve, subcutaneous fat, and whole blood with the alternate allele
  • Known GWAS loci for cIMT together explain only about 1.1% of its variance despite heritability estimates of 20-65%, indicating substantial undiscovered genetic architecture

What the research says A genome-wide association study of cIMT in 7,894 unrelated adults (3,963 women and 3,931 men, ages 40-60) from Burkina Faso, Ghana, Kenya, and South Africa, genotyped on the H3Africa SNP Array, identified two new African-specific genome-wide significant loci (SIRPA, p=4.7E-08; FBXL17, p=2.5E-08) and replicated prior cIMT associations originally identified in European populations using different lead SNPs in linkage disequilibrium (LD, meaning the SNPs are co-inherited more often than expected by chance). Sex-stratified analysis revealed distinct male-specific (SNX29, p=6.3E-09) and female-specific (LARP6, p=2.4E-09; PROK1, p=1.0E-08) loci, with female-specific signals significantly enriched for genes involved in estrogen response. Heritability of cIMT is estimated at 20-65% from family and twin studies, yet all identified GWAS loci collectively account for only about 1.1% of cIMT variance.

Reported associations

  • Carotid intima-media thickness (cIMT): The CROCC locus was examined in a 2022 GWAS of mean-max cIMT in 7,894 sub-Saharan African adults (ages 40-60), as part of a study that replicated prior cIMT associations first identified predominantly in European-ancestry populations using different lead SNPs in LD with the index SNP
  • Atherosclerosis (surrogate measure): cIMT is a widely accepted surrogate marker for generalized atherosclerosis; prior genome-wide work catalogues 136 SNPs from 98 independent loci associated with cIMT, the majority from European-ancestry cohorts

Evidence quality The primary evidence derives from a single GWAS (n=7,894 adults) across four sub-Saharan African sites, genotyped on the H3Africa SNP Array. The association at the CROCC locus represents replication of a prior European-population signal rather than a novel discovery; specific effect sizes (beta coefficients or odds ratios) for rs11585710 are not reported in the provided study text. No independent replication specific to this SNP within an African-ancestry cohort is described in the available data. Sex-stratified analyses were conducted, revealing dimorphic effects not apparent in combined-sex models. African populations have shorter average haplotype blocks (approximately 8.8 kb vs. approximately 20.7 kb in Europeans), which may help localize causal variants but also means LD patterns differ from those underlying prior European GWAS signals. The study provides important representation for a population historically absent from cardiovascular genetics research.

Tissue-specific expression effects

  • CROCC: The alternate allele is associated with reduced CROCC expression across multiple tissues, with the strongest reduction in skeletal muscle, followed by esophagus mucosa, skin (sun-exposed lower leg), stomach, and brain cerebellar hemisphere GTEx Portal
  • ENSG00000290122: The alternate allele is associated with increased expression of this gene in tibial nerve and subcutaneous adipose (fat) tissue GTEx Portal
  • ENSG00000291072: The alternate allele is associated with increased expression of this gene in whole blood GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What does the CROCC gene do?

CROCC encodes the Ciliary Rootlet Coiled-Coil protein, which provides structural support for cilia, the hair-like projections found on many cell types. GTEx data shows the rs11585710 alternate allele is associated with reduced CROCC expression in skeletal muscle, brain, stomach, esophagus, and skin.

Is rs11585710 linked to heart disease?

rs11585710 has been studied in relation to carotid intima-media thickness (cIMT), an ultrasound measure of artery wall thickness used as a proxy for atherosclerosis, which underlies many cardiovascular diseases. The available evidence comes from one GWAS in sub-Saharan African adults and should be considered preliminary, with no direct clinical outcome data reported.

What is carotid intima-media thickness and why does it matter genetically?

Carotid intima-media thickness (cIMT) is the combined thickness of the two innermost layers of the carotid artery wall, measured by ultrasound. It is widely used as a surrogate marker for generalized atherosclerosis. Family and twin studies estimate cIMT heritability at 20-65%, though identified genetic variants together explain only about 1.1% of its variance.

Why is studying this variant in African populations important?

Most GWAS data on cIMT comes from European-ancestry populations. African populations have shorter haplotype blocks (on average about 8.8 kb vs. 20.7 kb in Europeans) and greater genetic diversity, which can help localize causal variants more precisely. Research in African cohorts also uncovers population-specific and sex-specific genetic signals absent from European studies.

Does rs11585710 affect gene expression?

Yes. GTEx eQTL (expression quantitative trait loci) data shows the alternate allele is associated with reduced CROCC expression in skeletal muscle, brain, stomach, esophagus, and skin, and with increased expression of two nearby genes (ENSG00000290122 and ENSG00000291072) in tibial nerve, fat tissue, and whole blood. These are molecular associations and do not directly indicate clinical outcomes.