Abstract P3002: Hypoalbuminemia genetic variants are associated with higher cholesterol levels but not atherosclerotic heart disease

Introduction: Secondary hypoalbuminemia is associated with many clinical conditions including hypercholesterolemia, liver disease, kidney disease, and diabetes. These clinical conditions are often associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown if primary hypoalbuminemia from genetic causes (rare monogenic variants or polygenic score [PGS]) is associated with hypercholesterolemia and ASCVD risk similar to secondary hypoalbuminemia. Here, we tested the hypothesis that primary hypoalbuminemia has the same association with cholesterol and incident ASCVD as secondary hypoalbuminemia. Methods: Geisinger’s MyCode cohort is a US-based healthcare cohort with linked genomic and electronic health record data for all participants. Among 146,030 MyCode participants with serum albumin measurements, a rare loss-of-function ALB variant was identified in 30 subjects. An albumin level PGS was calculated for each participant. Regression coefficients were calculated using linear models and hazard ratios (HR) were calculated using Cox proportional hazard models controlling for age at first serum albumin measurement, sex, diabetes, and principal components of ancestry. Results: With regard to LDL-C level, across the entire cohort, each standard deviation (SD) reduction in serum albumin was associated with a 3.4mg/dL (95% confidence interval [CI], 3.2-3.6) decrease in LDL-C. The relationship between the albumin PGS and LDL-C followed the same pattern. Each SD reduction in albumin PGS was associated with a 0.7mg/dL decrease in LDL-C (95% CI, 0.5-0.9). In contrast, ALB variant carriers had 0.69g/dL (95% CI, 0.57-0.81) lower albumin, but 37.7mg/dL (95% CI, 23.3-52.1) higher LDL relative to non-carriers. Contradictory results were observed with regard to ASCVD. Across the entire cohort, a reduction in serum albumin was associated with increased incident ASCVD (HR, 1.13 per SD reduction in albumin; 95% CI, 1.12-1.14; p=3.1x10 -90 ). However, neither the albumin PGS (HR, 0.99 per SD reduction in albumin PGS; 95% CI, 0.98-1.00; p=0.19) nor ALB variants (HR, 0.6; 95% CI, 0.19-1.85; p=0.37) were associated with incident ASCVD. Conclusions: The association of hypoalbuminemia with ASCVD is likely related to secondary causes as no association of albumin with incident ASCVD was seen with genetic causes. ALB variants are novel in that they are associated with higher LDL-C but are unrelated to incident ASCVD. Further investigation of the ALB gene is warranted.