Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

先前的遗传关联研究未能确定与脓毒症密切相关的基因座，尽管有证据表明可能涉及遗传因素，但尚未发表对脓毒症休克患者的遗传关联研究或多基因风险评分分析。我们在脓毒性休克患者的随机对照试验中系统地收集了基因型和临床结果数据，以丰富疾病相关遗传变异的存在。我们使用 493 名感染性休克患者和 2442 名人群对照对感染性休克的易感性和死亡率进行了全基因组关联研究，并进行了多基因风险评分分析，以评估感染性休克风险/死亡率与临床相关特征之间的遗传重叠。一种变体，rs9489328，位于AL589740. 1非编码 RNA，与感染性休克显着相关 ( p = 1.05 × 10 –10 )；但是，这很可能是误报。我们无法复制先前报告的与败血症易感性和死亡率相关的变异（先前扫描中p < 1.00 × 10 –6）。血细胞比容和粒细胞计数的多基因风险评分与 28 天死亡率呈负相关（p = 3.04 × 10 –3；p = 2.29 × 10 –3），C 反应蛋白水平评分与感染性休克的易感性呈正相关( p = 1.44 × 10 –3）。结果表明，大效应的常见变异不会影响感染性休克的易感性、死亡率和分辨率；然而，临床相关性状的遗传倾向与脓毒症个体的易感性和死亡率增加显着相关。