Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock

Abstract

BackgroundAcute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/septic shock, in Finland.MethodsThis is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEXTM Assay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software.ResultsWe found no significant associations between the SNPs and severe AKI in patients with sepsis/septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p = 0.04276) associated with stage 2–3 AKI after adjusting for clinical and demographic variables.ConclusionsThe SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2–3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1631-3) contains supplementary material, which is available to authorized users.

Genetic association in female stress urinary incontinence based on proteomic findings: a case-control study

“…Following up on cumulative findings in urine and serum samples in the identical study population, we selected the genes SERPINA5 and UMOD for genetic analysis. Several SNPs were identified in the past for both genes [25][26][27][28][29][30]. In addition, we aimed to replicate previous studies associating SNPs of COL1A1 and MMP1 genes to SUI [9,31].…”

The SERPINA4 rs2070777 AA Genotype is Associated with an Increased Risk of Recurrent Miscarriage in a Southern Chinese Population

“…Vilander LM et al found that the SERPINA4 SNP rs2093266 contributes to the development of severe acute kidney injury. 26 PAI-1 belongs to the SERPIN family, which contributes to an increased risk of recurrent miscarriage. 21 Tamar Madar et al found that low levels of circulating alpha-1 antitrypsin, which belongs to the SERPIN family, are associated with spontaneous abortion.…”

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

“…Variations in or nearby genes related to inflammation, circulation, and cell survival have been suggested in candidate polymorphism studies regarding AKI [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. Additionally, the first hypothesis-free studies in AKI genetic predisposition have been published [28,29,30], with some replicated associations [31]. We chose to test polymorphisms in TNFA (rs1800629 [8,19,21,22,23,24,25,26,27]), IL6 (rs1800796 [24,26] and rs1800795 [19,24,26], rs10499563, rs1474347, rs13306435, rs2069842 and rs2069830), CXCL8 (rs4073 [27]), IL10 (rs1800896 [19,21,23,25,26]), NOS3 (rs2070744 [13,24]), NFKB1A (rs1050851 [32]), AGT (rs699 and rs2493133 [24]), VEGFA (rs2010963 and rs3025039 [27]), EPO (rs1617640 [14]), SUFU (rs10748825 [9]), HIF1A (rs11549465 [15]), PNMT (rs876493 [17]), MPO (rs7208693 [16]), COMT (rs4680 [10,11,12]), HSPB1 (rs2868371 [33]), SFTPD (rs2243639 and rs721917 [34]), HAMP (rs10421768 [35]) and BBS9 (rs10262995 [30]) genes (see d...…”

“…In the tertiary analysis we included patients with chronic kidney disease and compared patients with KDIGO stage 2 or 3 AKI to patients without AKI in an adjusted analysis. We used similar covariates to our previously published article [31] (liver failure, body mass index (BMI), use of nonsteroidal anti-inflammatory drugs (NSAID) or warfarin as permanent medication, use of contrast dye prior to ICU admission, use of colloids prior to ICU admission, use of albumin prior to ICU admission, minimum platelet count, and simplified acute physiology score (SAPS) II without renal and age points), omitting the infection focus for irrelevant information, and maximum leucocyte count and operative admission to avoid multicollinearity, while including cardiac surgery status as well as sepsis status. The missing data within covariates (altogether 2.4%) were addressed by imputing (see ESM for details).…”