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Candidate Genes for Condition Limiting Blood Flow to Extremities Identified by GWAS

NEW YORK – A team led by investigators in the UK and Germany has tracked down two genes with apparent ties to Raynaud's phenomenon (RP), a vasospastic condition marked by blood flow restrictions after exposure to triggers such as stress or cold, leading to altered finger or toe coloring.

The condition "can severely affect an individual's quality of life by causing pain or even ulcers," Maik Pietzner, a computational medicine researcher at Charité-Universitätsmedizin Berlin's Berlin Institute of Health, and his colleagues wrote in Nature Communications on Thursday.

Because RP is relatively common — affecting an estimated 2 percent to 5 percent of the population — and showed pronounced heritability in prior studies, the researchers reasoned that a genome-wide association study involving RP cases and controls from UK Biobank project might unearth previously unappreciated genetic contributors to the condition.

Using electronic health record and array-based genetic data for 5,147 UK Biobank participants of European descent with RP and 439,294 unaffected participants from the same population, the team narrowed in on three loci with genome-wide significant ties to RP. Digging into these risk loci — found in or around the ADRA2A, IRX1, and MICB genes on chromosomes 10, 5, and 6, respectively — offered a look at potential mechanisms behind RP.

The team went on to analyze the risk variants in relation to Genotype-Tissue Expression data spanning more than four dozen tissue types, for example, searching for how the RP-related variants affect gene expression. That approach highlighted the possible roles of  the alpha-2A adrenergic receptor for adrenaline gene ADRA2A, which contributes to stress response-related small blood vessel contraction, and the IRX1 gene, which codes for a transcription factor suspected of regulating blood vessel dilation, in RP.

"Our study provides the very first robust evidence not only for concrete 'risk genes' for primary Raynaud's phenomenon (which haven't been known at all), but [also] sheds light on new mechanisms [for] a disease of, so far, idiopathic origin," Pietzner said in an email, noting that the genes identified "nicely tie on with what has been suspected about the involvement in vasospasms but point to very different receptors, compared to what has been previously thought and used to develop or repurpose drugs."

In particular, the results prompted a search for existing drug treatments that counteract expression alterations involving the candidate genes, the researchers explained, along with analyses centered on compounds that impact broader vasoconstriction or vasodilation processes indirectly implicated by the candidate genes identified.

"[O]ur results provide the first mechanisms driven investigation into treatment options," Pietzner noted.

Although "a number of medications can already inhibit alpha-2A adrenergic receptors," he explained, "none does so specifically" — an important consideration since such receptors are also expressed beyond arterial tissue.

When the researchers considered more subtle RP associations involving variants previously linked to other traits or conditions, meanwhile, they saw hints that variants that dial down type 2 diabetes risk and fasting blood glucose levels may also boost individuals' propensity for RP. On the other hand, variants that increased high-density lipoprotein cholesterol levels seemed to coincide with enhanced RP risk.

"A somewhat unexpected finding with possible relevance for patients might be the observation that participants with susceptibility to low blood glucose levels are at a higher risk for RP," Pietzner said, "which, if also relevant to the frequency of attacks, might imply that avoiding episodes of low blood glucose might be an interesting strategy or a so far underrated trigger for RP."