| Title | Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity |
| 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 |
| Affiliation | SJTUSM, Shanghai Clin Ctr Endocrine & Metab Dis,Ruijin Ho, Dept Endocrinol & Metab,Natl Key Lab Med Genom, Shanghai Inst Endocrine & Metab Dis,China Natl Re, Shanghai, Peoples R China. Chinese Acad Sci, SIBS, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai, Peoples R China. SJTUSM, Shanghai, Peoples R China. SJTUSM, Shanghai Inst Pediat Res, Xinhua Hosp, Dep Pediat Endocrinol & Genet Metab, Shanghai, Peoples R China. Peking Univ, Dept Pediat, Hosp 1, Beijing, Peoples R China. Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Pediat, Beijing, Peoples R China. Peking Union Med Coll, Beijing, Peoples R China. Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. Brown Univ, Sch Publ Hlth, Ctr Global Cardiometab Hlth, Providence, RI 02912 USA. Brown Univ, Warren Alpert Med Sch, Dept Med Endocrinol, Providence, RI 02912 USA. Anhui Med Univ, Hosp 1, Inst Dermatol & Dept Dermatol, Hefei, Peoples R China. SJTUSM, State Key Lab Oncogenes & Related Genes, Div Gastroenterol & Hepatol, Renji Hosp, Shanghai, Peoples R China. Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. Johns Hopkins Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. Zhejiang Univ, Inst Neurosci, Hangzhou, Zhejiang, Peoples R China. Wuhan Univ, Inst Adv Studies, Coll Life Sci, Wuhan, Peoples R China. SJTUSM, Shanghai Clin Ctr Endocrine & Metab Dis,Ruijin Ho, Dept Endocrinol & Metab,Natl Key Lab Med Genom, Shanghai Inst Endocrine & Metab Dis,China Natl Re, Shanghai, Peoples R China. Ning, G (reprint author), Chinese Acad Sci, SIBS, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai, Peoples R China. Ning, G (reprint author), SJTUSM, Shanghai, Peoples R China. Liu, SM (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. Liu, SM (reprint author), Brown Univ, Sch Publ Hlth, Ctr Global Cardiometab Hlth, Providence, RI 02912 USA. Liu, SM (reprint author), Brown Univ, Warren Alpert Med Sch, Dept Med Endocrinol, Providence, RI 02912 USA. |
| Keywords | BODY-MASS INDEX STEROL-SENSING DOMAIN GENOME-WIDE ASSOCIATION PICK C1 PROTEIN MISSING HERITABILITY FUNCTION MUTATIONS COMPLEX DISEASES SEX-DIFFERENCES ADULT OBESITY REARED APART |
| Issue Date | 2017 |
| Publisher | DIABETES |
| Citation | DIABETES.2017,66(4),935-947. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/474420 |
| ISSN | 0012-1797 |
| DOI | 10.2337/db16-0877 |
| Indexed | SCI(E) |
| Appears in Collections: | 第一医院 |
