Genetic association studies in critically ill patients: a systematic review

Critical illness is complex, and genetic research holds the potential to uncover underlying disease mechanisms. However, existing research results have not been systematically summarized. This study aims to compile all genetic association studies in critically ill patients and assess their risks of bias.

We systematically reviewed PubMed, EMBASE, and the Cochrane Library (PROSPERO protocol: CRD42021209744) and conducted a bias risk assessment of identified studies using a newly developed risk-of-bias assessment tool for genetic association studies. We compiled all significant single nucleotide polymorphisms (SNPs) from the studies identified in our systematic review and conducted a lookup in the results of two genome-wide association studies (GWASs) in critically ill patients.

We identified a total of 61 studies that evaluated genetic variants with various traits in adult intensive care patients, encompassing a total of 126 genetic loci and focussing on six clustered critical care-related traits. Assessment of the risk of bias across these studies revealed that 97% of the studies demonstrated some concerns or high risk of bias and only two studies (3%, both GWAS), had an overall low risk of bias. Only two significantly associated SNPs emerged from the two studies assessed to have a low risk of bias. One SNP (rs4957796) in FER was associated with 28-day survival (p = 3.4 × 10^-9) and mortality (p = 5.6 × 10^-8), and rs9508032 in FLT1 was associated with respiratory failure (p = 5.2 × 10^-8). Fifty-four significant associations were replicated in the candidate gene studies, but most had an overall high risk of bias. Only one association, of rs2569190 in CD14 with mortality, remained significant after multiple testing correction.

Our systematic review underscored a deficiency in high-quality genetic research in critical care medicine. The detected gaps emphasize an urgent need for additional rigorous genetic association studies that are preferably genome-wide, to enhance our understanding of the underlying mechanisms of critical illness.

Wenbo Zhang was financially supported by a grant from the China Scholarship Council (File no. 202006210041). Carlos Flores was funded by Instituto de Salud Carlos III (PI23/00980 and CB06/06/1088) and co-financed by the European Regional Development Fund, "A way of making Europe" from the European Union; and the agreement OA23/043 with Instituto Tecnológico y de Energías Renovables (ITER) to strengthen scientific and technological education, training, research, development and scientific innovation in genomics, epidemiological surveillance based on massive sequencing, personalized medicine, and biotechnology. Eva Suarez-Pajes was financially supported by Agencia Canaria de Investigación, Innovación y Sociedad de la Información de la Consejería de Economía, Conocimiento y Empleo y por el Fondo Social Europeo (FSE) Programa Operativo Integrado de Canarias 2014-2020, Eje 3 Tema Prioritario 74 (85%) (TESIS2022010042).