Härtel Christoph, Schultz Christian, Herting Egbert, Göpel Wolfgang
Department of Pediatrics, University of Lübeck Children's Hospital, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Acta Paediatr. 2007 Feb;96(2):158-65. doi: 10.1111/j.1651-2227.2007.00128.x.
In recent years, tremendous effort has been carried out to study the genetic basis of susceptibility to development, progression and severity of complex diseases and response to therapy. The ultimate goal of these investigations is to find new tools for prevention and treatment of these complex diseases, such as sepsis in very-low-birth-weight (VLBW) infants. VLBW cohorts have a restricted clinical risk profile for the development of sepsis including immaturity of immune functions and antenatal/perinatal risk factors but also a significant event rate of sepsis within a short period of observational time. Therefore, prospective VLBW cohorts are advantageous for the investigation of candidate genetic risk factors of sepsis compared to adult cohorts. Furthermore, environmental factors are much better documented and highly controlled for VLBW infants in a standardized NICU setting compared to adult cohorts which are influenced by a variety of environmental risk factors, e.g. habits and comorbidities.
The aim of this review is to discuss the value and limitations of genetic association studies in VLBW infant cohorts exemplifying recent findings for genetic susceptibility to neonatal sepsis.
Published Medline articles reporting on studies of associations between genetic polymorphisms, neonatal sepsis and septic shock in VLBW infants.
Up-to-date, the classical approach to investigate the genetic component of susceptibility to sepsis in VLBW infants by means of twin and concordance studies has not been implemented yet. Regarding the interpretation of data from current genetic association studies, one should be aware of significant differences in cohort size, study design and definition of cases, controls and clinical end points. Furthermore, the contribution of genetic variants to susceptibility to sepsis may be specifically influenced by the immaturity of the immune response in VLBW infants, the selectivity of responsiveness to certain pathogens and the genotopyic/phenotypic variability of pathogens. We provide implications for the conduct and evaluation of future association studies with particular reference to methodological quality standards.
近年来，人们付出了巨大努力来研究复杂疾病发生、发展、严重程度以及对治疗反应的遗传易感性基础。这些研究的最终目标是找到预防和治疗这些复杂疾病的新工具，比如极低出生体重（VLBW）婴儿的败血症。VLBW队列中败血症发生的临床风险特征有限，包括免疫功能不成熟以及产前/围产期风险因素，但在短时间观察期内败血症的发生率也很高。因此，与成人队列相比，前瞻性VLBW队列有利于研究败血症的候选遗传风险因素。此外，与受多种环境风险因素（如生活习惯和合并症）影响的成人队列相比，在标准化新生儿重症监护病房（NICU）环境中，VLBW婴儿的环境因素记录得更好且得到了高度控制。
本综述旨在讨论在VLBW婴儿队列中进行基因关联研究的价值和局限性，并举例说明近期关于新生儿败血症遗传易感性的研究结果。
发表在Medline上的文章，报道了VLBW婴儿基因多态性、新生儿败血症和感染性休克之间关联的研究。
目前，尚未采用经典方法通过双胞胎和一致性研究来调查VLBW婴儿败血症易感性的遗传成分。在解释当前基因关联研究的数据时，应注意队列规模、研究设计以及病例、对照和临床终点定义方面的显著差异。此外，基因变异对败血症易感性的影响可能会受到VLBW婴儿免疫反应不成熟、对某些病原体反应的选择性以及病原体基因型/表型变异性的特殊影响。我们针对未来关联研究的开展和评估提出了建议，特别参考了方法学质量标准。
