CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications.
This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.
N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, 3 Gubkin Street, Moscow, 117971, Russia, salnikovalyubov@gmail.com.
Lyubov E
LE
Salnikova
Tamara V
TV
Smelaya
Arkadiy M
AM
Golubev
Alexander V
AV
Rubanovich
Viktor V
VV
Moroz
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000808:Angiotensinogen / Q000235:genetics*; D016022:Case-Control Studies; D017714:Community-Acquired Infections / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D011014:Pneumonia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D055815:Young Adult
C534931:AGT protein, human; C544065:AGTR1 protein, human; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D019363:Cytochrome P-450 CYP1A1; D005721:Glutamate-Cysteine Ligase