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Researchers find genetic variant linked to reduced risk for CAD
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Researchers reported in The New England Journal of Medicine that they have found a variant of the ASGR1 gene associated with reduced risk for CAD.
Another loss-of-function ASGR1 variant was associated with decreased levels of non-HDL.
The researchers sequenced the genomes of 2,636 individuals from Iceland to identify variants affecting levels on non-HDL.
Once variants were identified, they were imputed into the genomes of 398,000 living or dead individuals from Iceland. Of those samples, 119,146 provided information on non-HDL levels.
Paul Nioi, PhD, from deCODE Genetics–Amgen in Reykjavik, Iceland, and colleagues identified a noncoding 12-base-pair deletion in intron 4 of ASGR1 “that renders a truncated protein prone to degradation.”
The researchers then assessed the effects of the variant, called del12, on risk for CAD in five patient populations of European descent: 42,524 patients with CAD and 249,414 controls without CAD.
Compared with noncarriers, heterozygous carriers of the variant, approximately one in 120 people in the cohort, had lower levels of non-HDL (difference, 15.3 mg/dL; P = 1 x 10–16) and lower risk for CAD (difference, 34%; 95% CI, 21-45; P = 4 x 10–6; OR for Icelandic population = 0.64; 95% CI, 0.51-0.8; OR for non-Icelandic population = 0.69; 95% CI, 0.51-0.95; OR for combined populations = 0.66; 95% CI, 0.55-0.79), according to the researchers.
When Nioi and colleagues screened an extended data set including genomes from 5,817 individuals from Iceland, they found another loss-of-function variant on ASGR1, called p.W158X and existing in approximately one in 1,850 people. Carriers of the variant had lower levels of non-HDL than noncarriers (difference, –24.9 mg/dL; 95% CI, –40.6 to –9.3; P = 1.8 x 10–3), but there was no significant difference in CAD risk between carriers and noncarriers (OR = 0.65; 95% CI, 0.26-1.4).
“These variants disrupt ASGR1 function and represent a link between the sialylation pathway and atherosclerotic diseases,” the researchers wrote. – by Erik Swain
Disclosure : The study was funded in part by an unrestricted grant from the Novo Nordisk Foundation. Nioi reports receiving personal fees from Amgen and holding a pending patent. Please see the full study of a list of the other researchers’ relevant financial disclosures.
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