Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality.
Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality.
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DOI：
10.1016/j.ebiom.2016.08.043
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发表时间：
2016-10
期刊：
影响因子：
11.1
通讯作者：
Brunkhorst, Frank M.
中科院分区：
文献类型：
--
作者：
Scherag, Andre;Schoeneweck, Franziska;Kesselmeier, Miriam;Taudien, Stefan;Platzer, Matthias;Felder, Marius;Sponholz, Christoph;Rautanen, Anna;Hill, Adrian V. S.;Hinds, Charles J.;Hossain, Hamid;Suttorp, Norbert;Kurzai, Oliver;Slevogt, Hortense;Giamarellos-Bourboulis, Evangelos J.;Armaganidis, Apostolos;Trips, Evelyn;Scholz, Markus;Brunkhorst, Frank M.
败血症是宿主对感染的反应失调，导致危及生命的器官功能障碍，具体情况因宿主基因组因素而异。我们对 740 名成年脓毒症患者进行了一项全基因组关联研究 (GWAS)，重点关注 28 天死亡率作为结果。具有相关关联证据的变异 (p≤10−5) 在另外两项 GWA 研究 (n = 3470) 中得到验证，并且在独立的外显子组测序研究 (n = 74) 中评估了与变异相关的基因编码区。在发现 GWAS 中，我们鉴定了 243 个常染色体变异，它们聚集在 14 个位点 (p≤10−5)。对于位于 VPS13A 基因中染色体 9q21.2 的错义变体，观察到了最佳关联信号（rs117983287；p = 8.16 × 10−8）。 VPS13A 得到了额外 GWAS (p = 0.03) 和测序数据 (p = 0.04) 的进一步支持。此外，CRISPLD2 (p = 5.99 × 10− 6) 和染色体 13q21.33 上的区域 (p = 3.34 × 10− 7) 得到了我们的数据和外部生物学证据的支持。我们发现了 14 个位点，这些位点具有与 28 天死亡率相关的提示性证据，并在独立数据集中找到了其中三个位点的支持性、趋同性证据。阐明VPS13A、CRISPLD2和13号染色体位点的潜在生物学机制应该是未来研究活动的重点。染色体 9q21.2 上 VPS13A 的低频错义变异与脓毒症后 28 天死亡率相关。CRISPLD2 中常见的内含子变异也得到支持，据报道与降钙素原水平相关。同样支持的是染色体 13q21.33 上的基因间频繁变异——与慢性肾病相关的区域。脓毒症是宿主对感染的反应失调，导致危及生命的器官功能障碍，已知这种反应因宿主基因组因素而异。然而，迄今为止，检测与脓毒症结局相关的遗传变异一直具有挑战性。我们对 740 名成年脓毒症患者进行了一项发现性全基因组关联研究 (GWAS)，寻找随 28 天死亡率变化的变异。我们通过 3544 名成年患者的额外 GWAS 和外显子组测序数据来跟踪我们的最佳发现，并报告了包括基因 VPS13A 和 CRISPLD2 在内的三个区域，这些区域得到了我们的数据和外部生物学证据的支持。
Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28 day mortality as outcome. Variants with suggestive evidence for an association (p ≤ 10− 5) were validated in two additional GWA studies (n = 3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n = 74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p ≤ 10− 5). The best association signal (rs117983287; p = 8.16 × 10− 8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p = 0.03) and sequencing data (p = 0.04). Furthermore, CRISPLD2 (p = 5.99 × 10− 6) and a region on chromosome 13q21.33 (p = 3.34 × 10− 7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28 day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities. A low frequency missense variant in VPS13A on chromosome 9q21.2 was associated with 28 day mortality after sepsis A frequent intronic variant in CRISPLD2 was also supported and was reported to be associated with procalcitonin levels Similarly supported was an intergenic frequent variant on chromosome13q21.33 – a region related to chronic kidney disease Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that is known to vary by host genomic factors. However, the detection of genetic variants related to sepsis outcomes has been challenging so far. We conducted a discovery genome-wide association study (GWAS) in 740 adult patients with sepsis looking for variants that vary with 28 day mortality. We followed-up our best findings by additional GWAS and exome sequencing data in 3544 adult patients and report three regions including the genes VPS13A and CRISPLD2 that were supported by our data and external biological evidence.
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影响因子：
120.7
作者：
Brunkhorst, Frank M.;Oppert, Michael;Welte, Tobias
通讯作者：
Welte, Tobias
影响因子：
3.7
作者：
Petersen, Liselotte;Andersen, Per Kragh;Sorensen, Thorkild I. A.
通讯作者：
Sorensen, Thorkild I. A.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1136/bmj.h5651
发表时间：
2015-11-04
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Burke JF;Sussman JB;Kent DM;Hayward RA
通讯作者：
Hayward RA