Monogenic ALB Variants as Determinants of Severe Hypercholesterolemia: A Population-Based Cohort Study.
BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants in the ALB gene, which encodes albumin, is a known cause of congenital hypoalbuminemia. Studies have also shown that heterozygous ALB LoF variants are associated with increases in low-density lipoprotein cholesterol (LDL-C), comparable to those seen in familial hypercholesterolemia. OBJECTIVES: This study examined the effect of ALB LoF variants and other causes of low albumin on LDL-C levels in 2 population biobanks. METHODS: This study used data from 2 large cohorts with linked electronic health record and genetic information: Geisinger's MyCode Community Health Initiative, a health care population based in Pennsylvania, USA; and the National Institutes of Health All of Us Research Program, a nationwide epidemiologic cohort. LDL-C values were adjusted for lipid-lowering medication use. Myocardial infarction diagnoses were extracted from electronic health records using International Classification of Diseases codes. A polygenic score for serum albumin was calculated for participants of European ancestry. Linear regression models were used to estimate associations, and results were meta-analyzed across cohorts using fixed-effects models. RESULTS: Among 155,530 MyCode and 405,701 All of Us adult participants, 77 individuals (1 of 7,289) carried an ALB LoF variant. Among noncarriers, a 1 g/dL decrease in serum albumin was associated with a 10.9 mg/dL (95% CI:, 10.4-11.4) decrease in LDL-C. In contrast, ALB LoF variants were associated with a 0.69 g/dL (95% CI: 0.60-0.78) reduction in serum albumin and a 38.3 mg/dL (95% CI: 28.2-48.5) increase in LDL-C. Paradoxically, whereas monogenic determinants of hypoalbuminemia were associated with increased LDL-C, polygenic determinants of lower albumin were associated with a 0.22 mg/dL (95% CI: 0.17-0.26) decrease in LDL-C per decile. CONCLUSIONS: ALB LoF variants represent a previously underrecognized monogenic cause of elevated LDL-C, with effect sizes slightly less than canonical familial hypercholesterolemia variants. The divergent effects of ALB-mediated vs polygenic or physiological reductions in albumin on LDL-C suggest distinct underlying mechanisms.