期刊
DIABETES
卷 66, 期 4, 页码 935-947出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-0877
关键词
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资金
- National Natural Science Foundation of China [81522011, 81570757, 81570758, 81370963, 81370949]
- National International Science Cooperation Foundation [2015DFA30560]
- National Basic Research Program of China [2015CB553601]
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81621061]
- Shanghai Sailing Program [16YF1409800]
- Brown University Endowment for Brazil and China Initiatives
- American Heart Association
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases in the U.S.
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.
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