Inactivating mutations in NPC1L1 and protection from coronary heart disease.
Inactivating mutations in NPC1L1 and protection from coronary heart disease.
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DOI：
10.1056/nejmoa1405386
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发表时间：
2014-11-27
期刊：
影响因子：
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通讯作者：
Kathiresan S
中科院分区：
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作者：
Myocardial Infarction Genetics Consortium Investigators;Stitziel NO;Won HH;Morrison AC;Peloso GM;Do R;Lange LA;Fontanillas P;Gupta N;Duga S;Goel A;Farrall M;Saleheen D;Ferrario P;König I;Asselta R;Merlini PA;Marziliano N;Notarangelo MF;Schick U;Auer P;Assimes TL;Reilly M;Wilensky R;Rader DJ;Hovingh GK;Meitinger T;Kessler T;Kastrati A;Laugwitz KL;Siscovick D;Rotter JI;Hazen SL;Tracy R;Cresci S;Spertus J;Jackson R;Schwartz SM;Natarajan P;Crosby J;Muzny D;Ballantyne C;Rich SS;O'Donnell CJ;Abecasis G;Sunaev S;Nickerson DA;Buring JE;Ridker PM;Chasman DI;Austin E;Kullo IJ;Weeke PE;Shaffer CM;Bastarache LA;Denny JC;Roden DM;Palmer C;Deloukas P;Lin DY;Tang ZZ;Erdmann J;Schunkert H;Danesh J;Marrugat J;Elosua R;Ardissino D;McPherson R;Watkins H;Reiner AP;Wilson JG;Altshuler D;Gibbs RA;Lander ES;Boerwinkle E;Gabriel S;Kathiresan S
依折麦布通过抑制尼曼-匹克C1样1（NPC 1 L1）蛋白的活性降低低密度脂蛋白（LDL）胆固醇的血浆水平。然而，这种抑制是否会降低冠心病的风险尚不清楚。人类基因突变可以模拟一种抑制性药物的作用，因此可以用来推断该药物的潜在作用。我们对7364名冠心病患者和14,728名无冠心病的对照者（欧洲、非洲或南亚血统）的NPC 1 L1外显子进行了测序。我们鉴定了失活突变（无义突变、剪接位点突变或移码突变）的携带者。此外，我们对22,590例冠心病患者和68,412例对照者的一种特异性失活突变（p.Arg406X）进行了基因分型。我们检测了失活突变的存在与血脂水平和冠心病风险之间的关系。通过测序，我们确定了15种不同的NPC 1 L1失活突变;每650人中约有1人是其中1种突变的杂合子携带者。NPC 1 L1失活突变的杂合子携带者的平均LDL胆固醇水平比非携带者低12 mg/dl（0.31 mmol/L）（P = 0.04）。携带者与冠心病风险相对降低53%相关（携带者的比值比为0.47; 95%可信区间为0.25 ~ 0.87; P = 0.008）。总的来说，29，954名冠心病患者中只有11人有失活突变（携带频率，0.04%），而83，140名对照中有71人（携带频率，0.09%）。研究发现，破坏NPC 1 L1功能的天然突变与血浆LDL胆固醇水平降低和冠心病风险降低有关。（由美国国立卫生研究院和其他机构资助。
Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)