Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels
Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels
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DOI：
10.1073/pnas.0508483103
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发表时间：
2006-02-07
影响因子：
11.1
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
--
作者：
Cohen, JC;Pertsemlidis, A;Hobbs, HH
最近提出了一种理解数量性状的方法，该方法基于以下发现：某些基因中的非同义（NS）序列变体优先富集在群体分布的一端。NS变异体虽然个别罕见，但累积频繁并影响定量性状，如血浆脂蛋白水平。在这里，我们使用NS变体技术来证明NPC 1 L1的遗传变异有助于胆固醇吸收和低密度脂蛋白（LDL）血浆水平的变化。在一项基于人群的研究中，血浆菜油甾醇（一种植物甾醇）与胆固醇前体（一种胆固醇前体）的比值被用于估计相对胆固醇吸收。NPC 1 L1的非同义序列变异在低吸收者（n = 26/256）中比在高吸收者（n = 5/256）中多5倍（P < 0.001）。在1，832名非洲裔美国人中发现了6%的低吸收者中发现的罕见变异体，并与低密度脂蛋白胆固醇（LDL-C）的血浆水平较低相关（96 +/- 36 mg/dl vs. 105 +/- 36 mg/dl; P = 0.005）。这些数据与先前的发现一起揭示了LDL-C水平的遗传结构，该遗传结构不符合当前的数量性状模型，并表明LDL-C的遗传方差的显著部分是由于具有适度影响的多个等位基因，这些等位基因在人群中以低频率存在。
An approach to understand quantitative traits was recently proposed based on the finding that nonsynonymous (NS) sequence variants in certain genes are preferentially enriched at one extreme of the population distribution. The NS variants, although individually rare, are cumulatively frequent and influence quantitative traits, such as plasma lipoprotein levels. Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs). The ratio of plasma campesterol (a plant sterol) to lathosterol (a cholesterol precursor) was used to estimate relative cholesterol absorption in a population-based study. Nonsynonymous sequence variations in NPC1L1 were five times more common in low absorbers (n = 26 of 256)than in high absorbers (n = 5 of 256) (P < 0.001). The rare variants identified in low absorbers were found in 6% of 1,832 African-Americans and were associated with lower plasma levels of LDL cholesterol (LDL-C) (96 +/- 36 mg/dl vs. 105 +/- 36 mg/dl; P = 0.005). These data, together with prior findings, reveal a genetic architecture for LDL-C levels that does not conform to current models for quantitative traits and indicate that a significant fraction of genetic variance in LDL-C is due to multiple alleles with modest effects that are present at low frequencies in the population.