Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Abstract

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEXTM Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89–1.28, p = 0.51) and 0.92 (95% CI 0.80–1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.

Ethnicity-Stratified Analysis of the Association between TNF-α Genetic Polymorphisms and Acute Kidney Injury: A Systematic Review and Meta-Analysis

“…Another possible explanation is that the distribution of TNF- α rs1800629 alleles is population dependent. In the present meta-analysis, the frequencies of the rs1800629 A allele in the control group were 6.26% for Asians [ 16 , 17 ] and 14.90% for Caucasians [ 14 , 15 , 19 – 21 ]. This result was similar to that of the 1000 Genomes Project (as shown in Table 3 ) and that reported by Zhang et al (8.20% for Asians and 15.70% for Caucasians) [ 27 ].…”

“…The remaining 17 studies were then reviewed in full text, and 9 studies were excluded, among which 2 lacked control groups and the others lacked detailed genotype data. Finally, 8 eligible studies [ 14 , 15 – 21 ] including 6694 patients (2559 cases and 4135 controls) were chosen to be analyzed ( Table 1 ). Within all of the included studies, there were 7 studies related to TNF- α rs1800629 polymorphism and 3 studies related to TNF- α rs1799964 polymorphism.…”

“…Within all of the included studies, there were 7 studies related to TNF- α rs1800629 polymorphism and 3 studies related to TNF- α rs1799964 polymorphism. Regarding the TNF- α rs1800629 studies, the subjects in 5 studies [ 14 , 15 , 19 – 21 ] were Caucasians and the subjects in the other 2 were Asians [ 16 , 17 ]. Regarding the TNF- α rs1799964 studies, all the 3 included studies were conducted in the Asian population [ 16 – 18 ].…”

“…Several possible explanations may account for these findings. One of the reasons is that the studies conducted in Caucasians mainly included critically ill patients from the intensive care unit with severe infection [ 14 , 19 – 21 ] or underwent cardiac surgery [ 15 ]. The patients included in Asian studies underwent coronary artery intervention [ 17 ] or were pediatric patients [ 16 ], with a lower incidence of comorbidity or better baseline renal function.…”

“…Even though several studies made an attempt to explore the genetic association between TNF- α and AKI risk [ 14 – 21 ], these studies had inconsistent results or small sample size. Therefore, we aimed to conduct this study to assess the genetic association as well as the ethnic difference of two TNF- α SNPs (rs1800629 and rs1799964) with AKI risk.…”