Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity
Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity
复制标题
NPC1 中罕见的功能丧失变异易导致人类肥胖。
DOI：
10.2337/db16-0877
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发表时间：
2017-04-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Jiqiu
中科院分区：
文献类型：
--
作者：
Liu, Ruixin;Zou, Yaoyu;Wang, Jiqiu
上海某临床中心Niemann-Pick C1型(NPC1)基因在肥胖性状中的作用然而，NPC1功能缺失突变是否会导致人类肥胖尚不清楚。我们招募了25名罕见的常染色体隐性遗传C型尼曼-皮克病(NP-C)先证者及其父母，以评估NPC1杂合突变对肥胖的影响。我们发现，男性NPC1(+/-)携带者的BMI显著高于匹配的对照组或整个基于人群的对照组。一贯地，雄性NPC1(+/-)小鼠在食用高脂肪饮食的同时增加了脂肪储存。我们进一步对NPC1基因的罕见变异进行了深入的评估，发现NPC1基因的17个罕见非同义/移码变异(微小等位基因频率和1%)与肥胖风险增加显著相关，在肥胖组和对照组分别为3.40%和0.73%，P=0.0008，优势比=4.8，95%可信区间1.7~13.2，表明罕见的NPC1变异在中国青年病态肥胖者中丰富。重要的是，携带胆固醇运输能力严重受损的稀有变体的参与者比携带轻度/无损伤稀有变体的参与者有更多的脂肪积累。综上所述，罕见的NPC1功能缺失突变被证实与人类肥胖有关，具有高外显性，除了NPC1在家族性NP-C疾病中的作用外，还提供了潜在的肥胖症治疗干预措施。
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.