PLIN1 haploinsufficiency causes a favorable metabolic profile

Abstract

CONTEXT: PLIN1 encodes Perilipin-1 which coats lipid droplets in adipocytes and is involved in droplet formation, triglyceride storage and lipolysis. Rare PLIN1 frameshift variants that extend the translated protein have been described to cause lipodystrophy. OBJECTIVE: To test whether PLIN1 protein-truncating variants cause lipodystrophy in a large population-based cohort. DESIGN: We identified individuals with PLIN1 PTVs in individuals with exome data in UK Biobank. We performed gene-burden testing for individuals with PLIN1 PTVs. We replicated the associations using data from the T2D Knowledge portal. We performed a phenome-wide association study using publicly available association statistics. SETTING: A population-based cohort and a T2D case/control study. PARTICIPANTS: 362,791 individuals in UK Biobank and 43,125 individuals in the T2D Knowledge portal.Main Outcome Measures: Twenty-two diseases and traits relevant to lipodystrophy. RESULTS: The 735 individuals with PLIN1 protein-truncating variants had a favourable metabolic profile. These individuals had increased HDL cholesterol (0.12mmol/L, 95% CI: 0.09, 0.14, P=2x10 -18), reduced triglycerides (-0.22 mmol/L 95% CI: -0.29, -0.14, P=3x10 -11), reduced waist hip ratio (-0.02, 95% CI: -0.02, -0.01, P=9x10 -12) and reduced systolic blood pressure (-1.67 mmHg, -3.25, -0.09, P=0.05). These associations were consistent in the smaller T2D knowledge portal cohort. In UK Biobank, PLIN1 PTVs were associated with reduced risk of myocardial infarction (OR=0.59, 95% CI: 0.35, 0.93, P=0.02) and hypertension (OR=0.85, 95% CI: 0.73, 0.98, P=0.03), but not Type 2 diabetes (OR=0.99 95% CI: 0.63,1.51, P=0.99). CONCLUSION: Our study suggests that PLIN1 haploinsufficiency causes a favourable metabolic profile and may protect against cardiovascular disease.