ABSTRACT
Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized between 2002-2019 in the Million Veteran Program and data from Vanderbilt University Medical Center's BioVU. AKI was defined as meeting a modified KDIGO Stage1 or more for two or more consecutive days or kidney replacement therapy. Control individuals were required to have one or more qualifying hospitalizations without AKI and no evidence of AKI during any other observed hospitalizations. Genome-wide association studies (GWAS), stratified by race, adjusting for sex, age, baseline estimated glomerular filtration rate (eGFR), and the top ten principal components of ancestry were conducted. Results were meta-analyzed using fixed effects models. In total, there were 54,488 patients with AKI and 138,051 non-AKI individuals included in the study. Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the FTO locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) and rs4859682 near the SHROOM3 locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). These loci colocalized with previous studies of kidney function, and genetic correlation indicated significant shared genetic architecture between AKI and eGFR. Notably, the association at the FTO locus was attenuated after adjustment for BMI and diabetes, suggesting that this association may be partially driven by obesity. Both FTO and the SHROOM3 loci showed nominal evidence of replication from diagnostic-code-based summary statistics from UK Biobank, FinnGen, and Biobank Japan. Thus, our large GWA meta-analysis found two loci significantly associated with AKI suggesting genetics may explain some risk for AKI.
ABSTRACT
Allergens, in combination with genetic predisposition, drive undifferentiated T cells towards the type 2 T cells. Some childhood infections may activate the production of a type 1 T cell profile. It is reasonable to speculate that a decrease in childhood infections may increase the incidence of allergy by allowing the immune balance to shift towards the type 2 T cells. We hypothesized that pre-exposure of mycobacterial antigens in sensitized mice would prevent the development of asthma-like conditions. Specifically, we examined the effect of mycobacterial antigens, Bacillus Calmette-Guerin (BCG) vaccine and Mycobacterium vaccae, on antigen-induced bronchoconstriction, airway hyperresponsiveness to methacholine, bronchoalveolar lavage eosinophilia, and plasma IL-4 and IL-12 levels in ovalbumin (OVA)-sensitized and challenged Balb/c mice. Challenge with OVA produced a 2-3-fold increase in bronchoconstriction within 3-5 min, followed by a delayed response after 60 min, the latter of which was significantly attenuated by both BCG and M. vaccae. Airway hyperresponsiveness to methacholine 24 h after OVA challenge was prevented by BCG and M. vaccae. Airway eosinophilia was also prevented by BCG and M. vaccae. The plasma IL-12 levels were significantly increased and plasma IL-4 levels were significantly decreased following BCG or M. vaccae administration in OVA-sensitized and challenged mice. Interestingly, a significant increase in plasma IL-12 was observed with BCG as compared to M. vaccae administration, suggesting a stronger type 1 response to BCG. These data support our hypothesis and suggest that BCG and M. vaccae may prevent the underlying pathophysiological changes in asthma.
