Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach.
Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach.
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DOI：
10.1371/journal.pgen.1003063
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Tybjærg-Hansen A
中科院分区：
文献类型：
--
作者：
Haase CL;Frikke-Schmidt R;Nordestgaard BG;Tybjærg-Hansen A
罕见的遗传变异，通过基因座的详细重测序确定，可能有助于复杂的性状。我们使用载脂蛋白A-I基因（APOA 1），一种主要的高密度脂蛋白（HDL）基因，和基于人群的重测序来确定遗传变异的谱，这些变异的表型特征，以及这些结果如何与基于重测序的结果相比，只有载脂蛋白A-I（apoA-I）分布的极端。首先，我们在哥本哈根城市心脏研究中对10，330名基于人群的参与者进行了APOA 1重新测序。遗传变异的谱和分布被确定为重新测序的个体数量的函数。其次，测定了非同义（NS）和同义（S）变体的apoA-I和HDL胆固醇表型，并在哥本哈根一般人群研究（n = 45，239）中进行了验证。 第三，观察到的表型进行了比较，预测使用极端表型方法的基础上apoA-I分布。我们的结果如下：首先，基于人群的APOA 1重测序鉴定出40种变体，其中只有7种（18%）的次要等位基因频率> 1%，大多数非常罕见。其次，一般人群中0.27%的个体为NS变异杂合子，其与apoA-I（高达39 mg/dL）和/或HDL胆固醇（高达0.9 mmol/L）的显著降低相关，令人惊讶的是，0.41%的个体为易患淀粉样变性的变异杂合子。NS变异与心肌梗死（MI）的风险比为1.72（1.09-2.70）相关，主要由A164 S驱动，A164 S是一种与apoA-I或HDL胆固醇水平无关的变异。第三，使用极端apoA-I表型方法，NS变体正确预测了基于群体的重测序中观察到的apoA-I表型。然而，使用极端方法，79%（筛选第0- 1百分位数）和21%（筛选第0- 20百分位数）的所有变体未被识别;其中包括先前与淀粉样变性相关的变体。基于人群的APOA 1重新测序发现了大多数与apoA-1和HDL胆固醇水平降低和/或易患淀粉样变性相关的罕见NS变体。此外，NS变异与MI风险增加相关。罕见的遗传变异，通过基因座的详细重测序确定，可能有助于复杂的性状。我们使用载脂蛋白A-I基因（APOA 1），一种主要的高密度脂蛋白（HDL）基因，和基于人群的重测序来确定遗传变异的谱，这些变异的表型特征，以及这些结果如何与基于重测序的结果相比，只有载脂蛋白A-I（apoA-I）分布的极端。通过对> 10，000名丹麦人的APOA 1进行重新测序并对另外> 45，000人进行基因分型，我们表明基于人群的APOA 1重新测序鉴定了大多数罕见的遗传变异，这些变异相对频繁：0.27%的人群为APOA 1非同义（NS）变异杂合子，与apoA-I和HDL胆固醇显著降低相关，和0.41%是易患淀粉样变性的变异体的杂合子。NS变异与心肌梗死（MI）的风险比为1.72（1.09-2.70）相关，主要由A164 S驱动，A164 S是一种与apoA-I或HDL胆固醇水平无关的变异。仅对apoA-I分布的极端进行重测序，所有变体中的79%至21%未被鉴定;其中包括先前与淀粉样变性相关的变体。这些结果提供了直接的证据表明，APOA 1中罕见的NS变异导致apoA-I和HDL胆固醇水平降低，对淀粉样变性易感，并增加了一般人群中MI的风险。
Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09–2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0–1st percentile) and 21% (screening 0–20th percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI. Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. By resequencing APOA1 in >10,000 Danes and genotyping an additional >45,000, we show that population-based resequencing of APOA1 identifies a majority of rare genetic variants that together are relatively frequent: 0.27% of the population are heterozygous for nonsynonymous (NS) variants in APOA1 that associate with substantial reductions in apoA-I and HDL cholesterol, and 0.41% are heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09–2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Resequencing only the extremes of the apoA-I distribution, between 79% and 21% of all variants are not identified; among these are variants previously associated with amyloidosis. These results provide direct evidence that rare NS variants in APOA1 contribute to low apoA-I and HDL cholesterol levels, to susceptibility to amyloidosis, and to risk of MI in the general population.
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DOI：
10.1073/pnas.88.7.2793
发表时间：
1991-04-01
影响因子：
11.1
作者：
MATSUNAGA, T;HIASA, Y;HAMAGUCHI, H
通讯作者：
HAMAGUCHI, H
影响因子：
5.5
作者：
Benson, MD
通讯作者：
Benson, MD
影响因子：
19.6
作者：
Persey, MR;Booth, DR;Pepys, MB
通讯作者：
Pepys, MB
影响因子：
5.3
作者：
Recalde, D;Velez-Carrasco, W;Pocovi, M
通讯作者：
Pocovi, M
影响因子：
5.3
作者：
Fullerton, SM;Buchanan, AV;Weiss, KM
通讯作者：
Weiss, KM