Some evidence has indicated a role of NPC1 for obesity traits. However, whether the loss-of-function mutations in NPC1 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 NPC1 mutations on adiposity. We found that male NPC1+/- carriers had a significantly higher body mass index (BMI) than matched controls or the whole population-based controls. Consistently, male Npc1+/- mice had increased fat storage under high-fat diet. We further conducted an in-depth assessment of rare variants in NPC1 gene in young, severely obese subjects and lean controls, and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency (MAF) < 1%) that were significantly associated with increased risk of obesity (3.40% vs. 0.73% in cases and controls, respectively; P = 0.0008; OR = 4.8; 95% CI, 1.7-13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damaged rare variants. In summary, rare loss-of-function NPC1 mutations were identified to associate with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to NPC1’s role for the familial NP-C disease.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0877/-/DC1.
- Received July 18, 2016.
- Accepted January 16, 2017.
- © 2017 by the American Diabetes Association.