Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lancet Respir Med. 2015 Jan;3(1):53-60. doi: 10.1016/S2213-2600(14)70290-5. Epub 2014 Dec 18.
Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival.
We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died.
In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined.
We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification.
European Commission and the Wellcome Trust.
脓毒症仍然是全球范围内导致死亡、残疾和医疗支出的主要原因。尽管有证据表明宿主遗传学可以影响脓毒症的结局，但尚未令人信服地复制出特定的基因座。本研究旨在确定影响脓毒症存活的遗传变异。
我们在三个独立的白人成年患者队列中进行了全基因组关联研究，这些患者因肺炎或腹腔内感染（根据国际共识标准定义）入住重症监护病房，患有脓毒症、严重脓毒症或感染性休克（队列 1-3，n=2534 例患者）。主要结局为 28 天存活率。来自所有三个队列的 1553 例脓毒症患者的肺炎队列的结果进行了荟萃分析，其中 359 例患者在入住重症监护病房后 28 天内死亡。对进一步在因肺炎导致脓毒症的 538 例白人患者（队列 4）中进行了最显著相关的单核苷酸多态性（SNP）基因分型，其中 106 例患者死亡。
在三个独立肺炎队列的全基因组荟萃分析中（队列 1-3），FER 基因中的常见变体与存活率强烈相关（p=9.7×10(-8)）。在另外一个队列（队列 4）中进一步对顶级关联 SNP（rs4957796）进行基因分型，得到了合并 p 值为 5.6×10(-8)（比值比 0.56，95%CI 0.45-0.69）。在时间事件分析中，每个等位基因使 28 天内的死亡率降低了 44%（死亡风险比 0.56，95%CI 0.45-0.69；在调整年龄和按队列分层后，似然比检验 p=3.4×10(-9)）。携带 CC 基因型的患者死亡率为 9.5%，携带 TC 基因型的患者死亡率为 15.2%，携带 TT 基因型的患者死亡率为 25.3%。当肺炎和腹腔内感染导致的脓毒症患者合并时，未发现显著的遗传关联。
我们已经确定了 FER 基因中的常见变体，这些变体与肺炎导致的脓毒症死亡风险降低相关。FER 基因和相关的分子途径可能是治疗或预防的潜在新靶点，也是风险分层的生物标志物开发的候选者。
欧盟委员会和惠康信托基金会。
