Rare ALB gene variants reveal an underrecognized genetic cause of high cholesterol, Geisinger study finds

DANVILLE, Pa. - A Geisinger study has identified rare loss-of-function variants in the ALB gene as a monogenic cause of severe hypercholesterolemia, revealing a previously overlooked biological pathway influencing LDL cholesterol (LDL-C) levels. The findings, published today in the Journal of the American College of Cardiology, show that genetically reduced serum albumin - driven specifically by ALB variation - can substantially increase LDL-C, with effects comparable to established familial hypercholesterolemia (FH) genes.

Albumin is the most abundant protein in human blood and plays central roles in maintaining oncotic pressure and transporting biomolecules. Genetic variation in the ALB gene largely determines differences in circulating albumin levels. Although low serum albumin commonly accompanies conditions such as liver disease, kidney disease, and nephrotic syndrome, these pathophysiological states have not fully explained how albumin relates to lipid metabolism. Prior case reports and gene discovery efforts hinted that ALB loss-of-function variants might elevate LDL-C, but whether ALB variation represents a systematic genetic cause of severe hypercholesterolemia had not been established at the population scale.

To address this question, the research team examined genetic and clinical data from more than 560,000 participants enrolled in Geisinger's MyCode Community Health Initiative and the National Institutes of Health's All of Us Research Program. Among these participants, 77 carried an ALB loss-of-function variant. Compared to non-carriers, these people had markedly lower serum albumin and substantially higher LDL-C, with effect sizes approaching those observed in carriers of established FH gene variants.

"Familial hypercholesterolemia has historically been explained by variants in LDLR, APOB, and PCSK9", said Matthew Oetjens, Ph.D., assistant professor in Geisinger's Department of Developmental Medicine and one of the study leads. "Our study shows that rare ALB variants also drive markedly elevated LDL cholesterol, establishing ALB as a new monogenic contributor to severe hypercholesterolemia and broadening the scope of genes clinicians should consider during evaluation."

Strikingly, the study also revealed a discordance between ALB-mediated reductions in albumin and other common causes of low albumin. In the general population, and among individuals with polygenic determinants of albumin, lower albumin typically coincides with lower LDL-C. In contrast, carriers of ALB variants showed the opposite pattern: substantially higher LDL-C despite genetically lower albumin. This distinctive relationship points to a mechanism operating outside the classic LDL receptor pathway.

"We don't yet know why this reverse association emerges in individuals with an ALB variant," said Alexander Berry, Ph.D., bioinformatics scientist and study co-lead. "But uncovering the mechanism could have significant implications for our understanding of high cholesterol, a major cause of atherosclerotic heart disease, and help refine how we identify and manage at-risk patients."

Taken together, these findings broaden the biological and clinical landscape of hypercholesterolemia. They highlight albumin biology - long studied for its roles in liver and kidney disease - as an important but underappreciated contributor to lipoprotein metabolism and cardiovascular risk. By expanding the set of genes known to drive severe LDL-C elevations, this work may ultimately improve detection of at-risk individuals and guide precision approaches to cardiovascular prevention.

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