Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia.
Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia.
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DOI：
10.1016/j.jlr.2022.100209
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发表时间：
2022-06
影响因子：
6.5
通讯作者：
Pullinger CR
中科院分区：
文献类型：
--
作者：
Dong W;Wong KHY;Liu Y;Levy-Sakin M;Hung WC;Li M;Li B;Jin SC;Choi J;Lopez-Giraldez F;Vaka D;Poon A;Chu C;Lao R;Balamir M;Movsesyan I;Malloy MJ;Zhao H;Kwok PY;Kane JP;Lifton RP;Pullinger CR
低水平的高密度脂蛋白胆固醇（HDL-C）与动脉粥样硬化性冠心病的风险增加有关。HDL-C水平的遗传性很高。在这项研究发现研究中，我们使用全外显子组测序来鉴定可能在决定HDL-C水平方面发挥重要作用的破坏性基因变异。我们研究了204名平均HDL-C水平为27.8 ± 6.4 mg/dl（范围：4-36 mg/dl）的个体。通过统计基因负荷测试和通过对候选基因列表进行过滤来分析数据。在104个公认的HDL候选基因中的45个中，我们发现了120个可能具有破坏性的变异体（116个杂合子; 4个纯合子）。具有最高损害性变体患病率的那些是ABCA 1（n = 20）、STAB 1（n = 9）、OSBPL 1A（n = 8）、CPS 1（n = 8）、CD 36（n = 7）、LRP 1（n = 6）、ABCA 8（n = 6）、GOT 2（n = 5）、AMPD 3（n = 5）、WWOX（n = 4）和IRS 1（n = 4）。对损伤性错义或功能丧失变异的二项式分析确定了ABCA 1和LDLR基因在全基因组意义上。总之，对低HDL-C个体的全外显子组测序表明，ABCA 1和LDLR基因中罕见变异的损害负担特别高，并揭示了HDL候选基因中的大量出现，包括全基因组关联研究中发现的许多基因报告。这些基因中的许多基因参与癌症生物学，这符合HDL缺乏与癌症风险增加相关的流行病学发现，从而提出了HDL基因组学的新领域。
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4–36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.8
作者：
Blaho VA;Galvani S;Engelbrecht E;Liu C;Swendeman SL;Kono M;Proia RL;Steinman L;Han MH;Hla T
通讯作者：
Hla T
影响因子：
4.4
作者：
Gregg, Richard E.;Wetterau, John R.
通讯作者：
Wetterau, John R.
影响因子：
4.6
作者：
Christensen PM;Bosteen MH;Hajny S;Nielsen LB;Christoffersen C
通讯作者：
Christoffersen C
影响因子：
5.8
作者：
Haase, Christiane L.;Tybjaerg-Hansen, Anne;Frikke-Schmidt, Ruth
通讯作者：
Frikke-Schmidt, Ruth