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Diabetes. 2017 Apr;66(4):935-947. doi: 10.2337/db16-0877. Epub 2017 Jan 27.

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity.

Author information

1
Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
2
Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
3
Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
4
Department of Pediatrics, Peking University First Hospital, Beijing, China.
5
Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
6
Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, and Department of Medicine (Endocrinology), The Warren Alpert Medical School, Brown University, Providence, RI.
7
Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.
8
State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
9
Department of Nutrition, Harvard School of Public Health, Boston, MA.
10
Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD.
11
The Institute of Neuroscience, Zhejiang University, Hangzhou, China.
12
College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China.
13
Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, and Department of Medicine (Endocrinology), The Warren Alpert Medical School, Brown University, Providence, RI wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.
14
Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.

Abstract

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (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 BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/- mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (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, P = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare NPC1 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 NPC1 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 NPC1 in the familial NP-C disease.

PMID:
28130309
DOI:
10.2337/db16-0877
[Indexed for MEDLINE]
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