Rare Loss-of-Function Variants in <i>NPC1</i> Predispose to Human Obesity

Abstract

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (<i>NPC1</i>) for obesity traits. However, whether the loss-of-function mutations in <i>NPC1</i> cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous <i>NPC1</i> mutations on adiposity. We found that male <i>NPC1^+/-</i> carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male <i>NPC1^+/-</i> mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the <i>NPC1</i> gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in <i>NPC1</i> (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, <i>P</i> = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare <i>NPC1</i> variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function <i>NPC1</i> mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of <i>NPC1</i> in the familial NP-C disease.