Three variants in the nicotinamide adenine dinucleotide phosphate oxidase complex are associated with HCV-related liver damage

Abstract

Approximately 71 million people are chronically infected with the hepatitis C virus (HCV), a potentially lethal pathogen. HCV generates oxidative stress correlating with disease severity. HCV proteins increase reactive oxygen species production by stimulating nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity. Reactive oxygen species are necessary for host defense and cell signaling; however, elevated NOX activity contributes to cancer, and NOX overexpression is associated with hepatic fibrosis. Our aim was to investigate whether single nucleotide polymorphisms (SNPs) in NOX family members are associated with HCV-related liver damage. Three hundred and thirty-one individuals of European ancestry and 90 individuals of African ancestry, all diagnosed with HCV, were genotyped for 243 tagSNPs in NOX enzymes and their regulatory factors. Pathology scores were available for 288 Caucasians and 71 Africans, and mortality status was determined for all subjects. SNPs were tested for association with pathology scores and as predictors of mortality. In Africans, homozygosity for the A allele of rs12753665 (neutrophil cytosolic factor 2) and homozygosity for the T allele of rs760519 (neutrophil cytosolic factor 4) were associated with and predictive of higher rates of advanced fibrosis and cirrhosis compared to other genotypes after controlling for age and sex. In Caucasians, homozygosity for the T allele of rs2292464 (dual oxidase 1) was associated with and predictive of decreased periportal inflammation after controlling for age and sex. No SNPs were significant predictors of mortality. Conclusion: In this exploratory study, three NOX-related polymorphisms in two ethnic groups were significantly associated with hepatic inflammation and fibrosis. Future studies investigating these SNPs in larger cohorts of patients with HCV are warranted. (Hepatology Communications 2017;1:973-982).

Figure 1

Number of patients with HCV in the African cohort, by rs12753665 genotype, who reached advanced fibrosis/cirrhosis versus none, mild, or moderate fibrosis over the course of treatment. Gray represents none, mild, or moderate fibrosis (Ishak fibrosis score 0‐4); black represents advanced fibrosis or cirrhosis (Ishak fibrosis score 5‐6).

Figure 2

Number of patients with HCV in the African cohort, by rs760519 genotype, who had none to mild, moderate, or advanced fibrosis/cirrhosis at the onset of treatment. Light gray represents none to mild fibrosis (Ishak fibrosis score 0‐2); dark gray represents moderate fibrosis (Ishak fibrosis score 3‐4); black represents advanced fibrosis or cirrhosis (Ishak fibrosis score 5‐6).

Figure 3

Number of patients with HCV in the Caucasian cohort, by rs2292464 genotype, who had none to moderate versus advanced periportal inflammation. Gray represents none to moderate periportal inflammation (score 0‐3); black represents advanced periportal inflammation (score 4‐6).