Rare loss-of-function variants in npc1 predispose to human obesity

Ruixin Liu, Yaoyu Zou, Jie Hong, Min Cao, Bin Cui, Huiwen Zhang, Maopei Chen, Juan Shi, Tinglu Ning, Shaoqian Zhao, Wen Liu, Hui Xiong, Cuijie Wei, Zhengqing Qiu, Weiqiong Gu, Yifei Zhang, Wanyu Li, Lin Miao, Yingkai Sun, Minglan YangRui Wang, Qinyun Ma, Min Xu, Yu Xu, Tiange Wang, Kei Hang Katie Chan, Xianbo Zuo, Haoyan Chen, Lu Qi, Shenghan Lai, Shumin Duan, Baoliang Song, Yufang Bi, Simin Liu, Weiqing Wang, Guang Ning, Jiqiu Wang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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+/2carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/2 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.

Original languageEnglish (US)
Pages (from-to)935-947
Number of pages13
Issue number4
StatePublished - Apr 1 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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