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LDLR Variant Linked to Increased Blood Lipid, Heart Disease Levels in Greenland Population

Greenland Harbor

NEW YORK – An LDLR gene variant previously implicated in low density lipoprotein (LDL) cholesterol levels in other Arctic populations appears to be linked to both LDL cholesterol and heart disease in Greenland, where the missense variant is found at particularly high frequency, new research suggests.

"[T]he large effect size for LDL cholesterol, combined with the high frequency of the variant, meant that the variant has a large population-level impact," co-senior and co-corresponding author Torben Hansen, a researcher affiliated with the University of Copenhagen and the University of Southern Denmark, and his colleagues wrote, calling the risk variant "a simple marker that could be used as an early indicator of further risk of elevated lipid levels and [cardiovascular disease (CVD)]."

For their study, published in Human Genetics and Genomics Advances on Thursday, researchers from Denmark, Greenland, the US, and Norway first tapped into data for almost 5,100 Greenlanders enrolled in several population studies or surveys between the late 1990s and 2010. Using registry data for these individuals, they looked at the prevalence of an LDLR gene variant called p.G137S that was previously flagged as an Arctic-specific variant with ties to blood lipids in Greenland, where individuals typically have Inuit and/or European ancestry.

"This variant is located in exon 4, which encodes the ligand binding domain of the receptor, and has been predicted to be deleterious, and to reduce LDLR ligand binding by around 60 percent," the authors wrote, noting that p.G137S "has been shown to be associated with markedly elevated levels of LDL cholesterol, total cholesterol, and apolipoprotein B, yet it is not known if the variant is associated with increased risk of CVD."

Along with available data on heart disease, lipid, and metabolic traits in the Greenland population cohorts, the team considered nuclear magnetic resonance (NMR)-based blood plasma lipoprotein concentrations for 1,629 more individuals from Greenland.

Almost 30 percent of the Greenlanders considered carried at least one copy of the LDLR p.G137S variant, the researchers reported. As expected, homozygous versions of the variant that affected both copies of the LDLR gene had the most pronounced ties to blood lipid levels: blood levels of LDL cholesterol exceeded those used to diagnose familial hypercholesterolemia in more than half of participants with two copies of the p.G137S variant.

But the team also saw high LDL cholesterol levels in more than one-quarter of heterozygous p.G137S carriers carrying just one copy of the lipid-linked allele, suggesting the variant may have large lipid and cardiovascular effects across the population.

From there, the investigators delved further into potential lipid and heart disease impacts of the LDLR variant. Their data suggested that p.G137S was associated with everything from atherosclerotic lipid profiles to heart disease or a history of coronary operations to peripheral artery disease.

"[T]he common p.G137S variant had a major effect on the circulating lipid profile of Greenlanders, where carriers were characterized by an atherogenic lipid profile including elevated levels of LDL, cholesterol, total cholesterol, and apolipoprotein B as well as an increased risk of CVD," the authors wrote.

Roughly 10 percent of individuals with two copies of the p.G137S variant had documented prescriptions for cholesterol-lowering drugs, the team explained, noting that prescriptions for the drugs were also uncovered in just a fraction of participants with high LDL cholesterol levels in general.

"[T]here are many currently untreated individuals with very high lipid levels who potentially could benefit from treatment irrespective of other CVD risk factors," the authors suggested, adding that "a screening program for the p.G137S variant could be highly useful for early identification of individuals at increased CVD risk, hence, potentially improving preventive care and public health."