BCL2 genetic variants are associated with acute kidney injury in septic shock*

Abstract

Objective: Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential susceptibility. To identify genetic variants linked to acute kidney injury susceptibility, we conducted a high-density genotyping association study in a large population of patients with septic shock.

Design: Retrospective study.

Setting: Tertiary academic medical center.

Patients: One thousand two hundred and sixty-four patients with septic shock were analyzed to elucidate clinical risk factors associated with the development of acute kidney injury. Among them, 887 Caucasian patients were randomly split into discovery and validation cohorts and genotyped using the Illumina Human-CVD BeadChip (Illumina, San Diego, CA).

Interventions: None.

Measurements and main results: Six hundred and twenty-seven of the 1,264 patients with septic shock and 441 of the 887 patients with genotyping data developed acute kidney injury within the first 72 hrs of intensive care unit admission. Five single nucleotide polymorphisms were associated with acute kidney injury in both the discovery and validation cohorts. Two of these were in the BCL2 gene and both were associated with a decreased risk of acute kidney injury (rs8094315: odds ratio 0.61, p = .0002; rs12457893: odds ratio 0.67, p = .0002, both for combined data). Bcl-2 is involved in the apoptosis pathway, which has previously been implicated in acute kidney injury. Another single nucleotide polymorphism was in the SERPINA4 gene, whose protein product, kallistatin, has been linked to apoptosis in the kidney.

Conclusions: Large-scale genotyping reveals two single nucleotide polymorphisms in the BCL2 gene and a single nucleotide polymorphism in the SERPINA4 gene associated with a decreased risk of developing acute kidney injury, supporting the putative role of apoptosis in the pathogenesis of acute kidney injury.

Figure 1

Schematic of study design. AKI: acute kidney injury.

Figure 2

Association results and linkage disequilibrium (LD) plots of BCL2 (A) and SERPINA4-SERPINA5 regions (B). The upper panels show P-values for association testing (combined data) by logistic regression analysis, adjusted for age, gender, and Acute Physiology and Chronic Health Evaluation (APACHE) III score. The lower panels present LD plot (using D′) based on single nucleotide polymorphisms with minor allele frequency > 0.05 using HapMap phase 2 individuals of European background. The regional association plots were generated using the web-based tool SNAP version 2.2; the LD plots were generated by Haploview 4.2 software. BCL2: B-cell CLL/lymphoma 2. SERPINA4: serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 4. SERPINA5: serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), membre 5.