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

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 4; pp. 935 - 947
• Main Authors: Liu, Ruixin, Zou, Yaoyu, Hong, Jie, Cao, Min, Cui, Bin, Zhang, Huiwen, Chen, Maopei, Shi, Juan, Ning, Tinglu, Zhao, Shaoqian, Liu, Wen, Xiong, Hui, Wei, Cuijie, Qiu, Zhengqing, Gu, Weiqiong, Zhang, Yifei, Li, Wanyu, Miao, Lin, Sun, Yingkai, Yang, Minglan, Wang, Rui, Ma, Qinyun, Xu, Min, Xu, Yu, Wang, Tiange, Chan, Kei-Hang Katie, Zuo, Xianbo, Chen, Haoyan, Qi, Lu, Lai, Shenghan, Duan, Shumin, Song, Baoliang, Bi, Yufang, Liu, Simin, Wang, Weiqing, Ning, Guang, Wang, Jiqiu
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2017
• Subjects: Adult; Animals; Asian Continental Ancestry Group - genetics; Carrier Proteins - genetics; Case-Control Studies; China; Cholesterol; Diabetes; Diet; Diet, High-Fat; Female; Frameshift Mutation; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Heterozygote; Humans; Male; Membrane Glycoproteins - genetics; Mice; Middle Aged; Mutation; Obesity; Obesity - genetics; Obesity, Morbid - genetics; Phenotype; Proteins - genetics; Young Adult
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db16-0877

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