Hernandez-Beeftink Tamara, Marcelino-Rodríguez Itahisa, Guillen-Guio Beatriz, Rodríguez-Pérez Héctor, Lorenzo-Salazar Jose M, Corrales Almudena, Díaz-de Usera Ana, González-Montelongo Rafaela, Domínguez David, Espinosa Elena, Villar Jesús, Flores Carlos
Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
Research Unit, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain.
Front Med (Lausanne). 2022 Mar 8;9:754440. doi: 10.3389/fmed.2022.754440. eCollection 2022.
Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction. Although the ancestral genetic background is a relevant factor for sepsis susceptibility, there is a lack of studies using the genetic singularities of a recently admixed population to identify loci involved in sepsis susceptibility. Here we aimed to discover new sepsis loci by completing the first admixture mapping study of sepsis in Canary Islanders, leveraging their distinctive genetic makeup as a mixture of Europeans and African ancestries. We used a case-control approach and inferred local ancestry blocks from genome-wide data from 113,414 polymorphisms genotyped in 343 patients with sepsis and 410 unrelated controls, all ascertained for grandparental origin in the Canary Islands (Spain). Deviations in local ancestries between cases and controls were tested using logistic regressions, followed by fine-mapping analyses based on imputed genotypes, functional assessments, and gene expression analysis centered on the region of interest. The admixture mapping analysis detected that local European ancestry in a locus spanning 1.2 megabases of chromosome 8p23.1 was associated with sepsis (lowest = 1.37 × 10; Odds Ratio [OR] = 0.51; 95%CI = 0.40-0.66). Fine-mapping studies prioritized the variant rs13249564 within intron 1 of gene associated with sepsis ( = 9.94 × 10; OR = 0.65; 95%CI = 0.50-0.84). Functional and gene expression analyses focused on 8p23.1 allowed us to identify alternative genes with possible biological plausibility such as defensins, which are well-known effector molecules of innate immunity. By completing the first admixture mapping study of sepsis, our results revealed a new genetic locus (8p23.1) harboring a number of genes with plausible implications in sepsis susceptibility.
脓毒症是一种对感染的严重全身性炎症反应，伴有器官功能障碍。尽管祖先遗传背景是脓毒症易感性的一个相关因素，但缺乏利用近期混合人群的遗传独特性来识别参与脓毒症易感性的基因座的研究。在这里，我们旨在通过完成对加那利群岛居民脓毒症的首次混合映射研究来发现新的脓毒症基因座，利用他们独特的遗传构成，即欧洲人和非洲人祖先的混合。我们采用病例对照方法，从343例脓毒症患者和410名无关对照的全基因组数据中推断局部祖先块，所有这些个体均确定其祖父母来自西班牙加那利群岛。使用逻辑回归测试病例和对照之间局部祖先的偏差，随后基于推断基因型、功能评估和以感兴趣区域为中心的基因表达分析进行精细映射分析。混合映射分析检测到，8号染色体p23.1上一个跨度为1.2兆碱基的基因座中的局部欧洲祖先与脓毒症相关（最低 = 1.37 × 10；优势比[OR] = 0.51；95%置信区间 = 0.40 - 0.66）。精细映射研究将与脓毒症相关的基因内含子1中的变体rs13249564作为优先研究对象（ = 9.94 × 10；OR = 0.65；95%置信区间 = 0.50 - 0.84）。对8p23.1进行的功能和基因表达分析使我们能够识别具有可能生物学合理性的替代基因，如防御素，它们是众所周知的先天免疫效应分子。通过完成脓毒症的首次混合映射研究，我们的结果揭示了一个新的基因座（8p23.1），其中包含一些对脓毒症易感性有合理影响的基因。
