Expressive

rs10102164 (RP1): Blood Clotting Factor VIII Variant

Key takeaways

  • This variant in the SOX17/RP1 region is linked to plasma Factor VIII levels, a protein central to blood clotting, in more than 46,000 people across four ancestry groups.
  • The finding comes from a trans-ethnic GWAS meta-analysis covering European, African, East Asian, and Hispanic participants.
  • Mendelian randomization in the same study found statistical evidence that higher Factor VIII levels may causally raise the risk of venous thrombosis and coronary artery disease.
  • In skin tissue, this variant is associated with increased RP1 gene expression in both sun-exposed and non-sun-exposed skin, according to GTEx eQTL data.

Key takeaways

  • This variant in the SOX17/RP1 region is linked to plasma Factor VIII levels, a protein central to blood clotting, in more than 46,000 people across four ancestry groups.
  • The finding comes from a trans-ethnic GWAS meta-analysis covering European, African, East Asian, and Hispanic participants.
  • Mendelian randomization in the same study found statistical evidence that higher Factor VIII levels may causally raise the risk of venous thrombosis and coronary artery disease.
  • In skin tissue, this variant is associated with increased RP1 gene expression in both sun-exposed and non-sun-exposed skin, according to GTEx eQTL data.

What the research says A trans-ethnic genome-wide association meta-analysis of 46,354 individuals identified the SOX17/RP1 locus (the genomic region containing rs10102164, also annotated as TRMT112P7 - RP1) as one of seven novel genome-wide significant (P<=2.5x10^-8) associations with plasma Factor VIII (FVIII) activity; FVIII is a protein required for normal blood clotting, and severe deficiency causes the bleeding disorder hemophilia A PMID 30586006. Thirteen novel loci were identified in total across both FVIII and von Willebrand factor (VWF, another clotting protein) phenotypes; this locus was specific to FVIII and was not among the 11 novel VWF loci in the same study PMID 30586006. Two-sample Mendelian randomization (a statistical approach using genetic variants as instruments to assess whether an exposure may causally influence an outcome) found evidence for causal effects of plasma FVIII activity on venous thrombosis and coronary artery disease risk, and of VWF levels on ischemic stroke risk PMID 30586006.

Reported associations

  • Plasma Factor VIII (FVIII) levels: The locus reached genome-wide significance (P<=2.5x10^-8) in a 46,354-individual trans-ethnic meta-analysis and was one of seven loci newly linked to FVIII levels; no per-allele effect size for rs10102164 was reported in the available study text PMID 30586006.

Evidence quality The FVIII association was identified in a well-powered trans-ethnic meta-analysis of 46,354 individuals from 20 contributing studies, surpassing the study genome-wide significance threshold of P<=2.5x10^-8 PMID 30586006. The study spanned European, African, East Asian, and Hispanic ancestry groups, and in vitro gene silencing in cultured endothelial cells was performed to functionally evaluate candidate genes; 10 of the 13 novel loci were functionally supported, though the available text does not specify whether this locus was among those 10 PMID 30586006. No per-allele effect size for rs10102164 is provided in the available excerpts, and independent replication of this specific locus in a separate cohort is not described in the provided material; the locus-specific evidence should be interpreted with appropriate caution pending further replication.

Tissue-specific expression effects

  • RP1: The alternative allele at rs10102164 is associated with increased expression of RP1 in sun-exposed lower leg skin (p=2.4x10^-16) and in non-sun-exposed suprapubic skin (p=2.7x10^-10), representing a cis-eQTL effect (meaning the variant influences the expression level of a nearby gene in the same chromosomal region) GTEx Portal. RP1 encodes a photoreceptor-specific structural protein; how elevated RP1 expression in skin relates to the FVIII association at this locus is not established in the provided studies.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10102164 associated with?

rs10102164 is in the SOX17/RP1 region on chromosome 8 and has been linked to plasma Factor VIII levels in a multi-ancestry genome-wide association study of 46,354 individuals. It also shows a cis-expression QTL effect on the RP1 gene in skin tissue.

What does the RP1 gene do?

RP1 encodes a structural protein found in photoreceptor cells of the eye. GTEx eQTL data show that rs10102164 increases RP1 expression in skin tissue, though the functional significance of that skin expression in relation to blood clotting is not established in available studies.

What is Factor VIII and why does it matter genetically?

Factor VIII is a protein in the blood coagulation cascade that helps blood clot after injury. Very low Factor VIII levels cause hemophilia A, a bleeding disorder. Genome-wide association studies have found that genetic variants influencing circulating Factor VIII levels are statistically connected to venous thrombosis and coronary artery disease risk through Mendelian randomization analysis.

Is rs10102164 linked to thrombosis or heart disease?

The SOX17/RP1 region is associated with plasma Factor VIII levels, and Mendelian randomization in the same study found evidence that higher Factor VIII levels may causally influence venous thrombosis and coronary artery disease risk. This is an indirect connection, not a direct association between rs10102164 and clinical disease.

What populations were included in the research on rs10102164?

The main GWAS meta-analysis identifying the SOX17/RP1 region included 46,354 individuals from 20 studies with European, African, East Asian, and Hispanic ancestry participants, conducted under the CHARGE Consortium Hemostasis Working Group.