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Researchers Identify Variant that Seems to Offer Protection from Cervical Artery Dissection

NEW YORK (GenomeWeb) – A variant of the PHACTR1 gene appears to protect young adults from cervical artery dissection, an international team of researchers led by INSERM's Jean Dallongeville reported in Nature Genetics today.

While uncommon in the general population, cervical artery dissection — a rip in an artery leading to the brain — is a major cause of stroke among young adults.

Dallongeville and her colleagues with the Cervical Artery Dissections and Ischemic Stroke Patients group performed a genome-wide association study of nearly 1,400 people with cervical artery dissection and more than 14,000 controls. From this, they homed in on a number of loci associated with cervical artery dissection, including one in PHACTR1.

"Further genetic analyses and worldwide collaborations of this kind provide hope of pinpointing the underlying mechanisms that cause stroke," co-author Pankaj Sharma, from Royal Holloway, University of London, said in a statement.

For the discovery phase of their GWAS, the team collected DNA samples from 1,393 CeAD cases and 14,416 controls of European ancestry for genotyping on Illumina's Human610-Quad or Human660W-Quad BeadChip. The average age of the cohort was 44 years.

From this, they uncovered two SNPs at two loci that reached genome-wide significance: rs9349379 in intron 2 of PHACTR1 and rs11172113 in intron 1 of LRP1. A handful of other SNPs, including ones in LRP1 and LNX, also reached significance, but at lower levels.

Additionally, through imputation, they found significant SNPs in CCDC102B on chromosome 18q22.1 and on chromosome 17q21.1, though the latter was estimated to have a low minor allele frequency.

To validate these associations, Dallongeville and her colleagues genotyped an additional 659 CeAD cases and nearly 2,650 controls. For this, they particularly focused on SNPs associated with PHACTR1, LRP1, FGGY, LNX1, or ZNF804A, as well as two SNPs near 18q22.1, among others.

The strongest association in this follow-up work was at rs9349379 in PHACTR, the researchers reported. A meta-analysis of the discovery and validation cohorts also found a strong association between rs9349379 and cervical artery dissection. The G allele appears to be protective.

Another strong association was at rs6820391 in LNX1, but it, unlike the one in PHACTR, had a high approximate Bayes factor, indicating only a suggestive association, the researchers said.

PHACTR1 falls in a highly conserved region, Dallongeville and her colleagues noted, which indicates that its protein has an important, though unclear biological role. It has, they added, been linked to vascular tube formation and actin polymerization, suggesting that it plays a part in angiogenesis.

The PHACTR1 SNP they identified — rs9349379 — has also been linked with heart attacks, and it and rs11172113 at LRP1 have also been implicated in migraine susceptibility.

Migraines, the researchers said, are more common in people with cervical artery dissection than in the wider population, but the G allele of the rs9349379 loci is associated with lower risk of migraine, though increased risk of heart attack.

For CeAD, the researchers also reported that the rs9349379[G] allele at PHACTR1 was linked to a lower risk of disease, both in the discovery and validation cohorts, with an odds ratio of 0.77 in their overall meta-analysis of the discovery and validation cohorts.

"Our findings provide us with a greater understanding of how this region of the genome appears to influence key vascular functions, which could have major implications for the treatment of these severe and disabling conditions," Sharma added.