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

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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 iPLEX ^TM 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.

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Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Jingshan Chen, Barbara K. Lipska, Nader Halim … (2004)

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

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Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Kirk Lohmueller, Celeste Pearce, Malcolm C. Pike … (2003)

Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.

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Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

Sara Nisula, Kirsi-Maija Kaukonen, Suvi Vaara … (2013)

We aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs. This prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days. We included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality. The incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.

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Journal

Journal ID (nlm-ta): J Clin Med

Journal ID (iso-abbrev): J Clin Med

Journal ID (publisher-id): jcm

Title: Journal of Clinical Medicine

Publisher: MDPI

ISSN (Electronic): 2077-0383

Publication date (Electronic): 11 March 2019

Publication date Collection: March 2019

Volume: 8

Issue: 3

Electronic Location Identifier: 342

Affiliations

[1 ]Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland; suvi.vaara@ 123456hus.fi (S.T.V.); ville.pettila@ 123456hus.fi (V.P.)

[2 ]Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 000014 Helsinki, Finland; mari.kaunisto@ 123456helsinki.fi

Author notes

[* ]Correspondence: laura.vilander@ 123456helsinki.fi ; Tel.: +358-505-702-266

[†]

Membership of the The FINNAKI Study Group is provided in the Acknowledgments.

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Laura M. Vilander https://orcid.org/0000-0003-4332-8359

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Publisher ID: jcm-08-00342

DOI: 10.3390/jcm8030342

PMC ID: 6463106

PubMed ID: 30862128

SO-VID: ae55fe99-5710-4bd9-a88f-3fde21a12970

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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

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Most cited references 52

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

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