Evaluation of integrin beta 5 (ITBG5) haplotypes as genetic risk factors for advanced liver fibrosis in a large Fibroscan-staged cohort

Introduction: A recent genome wide association scan (GWAS) identified specific ITGB5 variants as potential risk factors for advanced fibrosis in a small cohort of patients with chronic hepatitis C virus (HCV) infection (Lempicki et al. AASLD 2009;1385A). Our aim now was to validate this finding in larger cohort of HCV patients and to test whether the association is also present in patients with other chronic liver diseases.

Patients and methods: Overall, 882 patients of Caucasian descent were included in the study. The majority of patients tested positive for HCV (N=520). Liver stiffness was determined in all patients by transient elastography. Patients were stratified according to liver stiffness values into a non-significant fibrosis group (<7.5 kPa) and a significant fibrosis group (≥7.5 kPa). In addition, histological fibrosis stages were determined by liver biopsy in 265 patients. All patients were genotyped for a critical intronic variant in the ITGB5 gene (rs126565; A>G), which showed the strongest association with advanced fibrosis in the previous study. Genotyping was performed using 5′ fluorescent dye labelled exonuclease assays.

Results: Live stiffness was not associated with ITGB5 genotypes in the overall cohort. Subgroup analysis in patients with HCV infection was negative either. We specifically analyzed therapy naive HCV patients (N=246). However, allele and genotype distributions did not differ between the two fibrosis groups. We also tested for associations with histological liver fibrosis stages, but no differences in allele or genotype distributions were detected.

Conclusions: We speculate that the recently reported association of variants in the ITGB5 gene with liver fibrosis represents a false positive GWAS result. The role of integrin beta 5 in liver fibrogenesis remains tentative.