Copy Number Variation in the GSTM1 and GSTT1 Genes and the Risk of Liver Cirrhosis in Eastern Ethiopia

Abstract

Abraham Nigussie Mekuria,1 Tamrayehu Seyoum,2 Dawit Hailu Alemayehu,2 Markos Abebe,2 Teshome Nedi,1 Tefera Abula,1 Yun Yun Gong,3 Ephrem Engidawork1 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Biotechnology and Bioinformatics, Armauer Hansen Research Institute, Addis Ababa, Ethiopia; 3School of Food Science and Nutrition, University of Leeds, Leeds, UKCorrespondence: Ephrem Engidawork, Email [email protected]: Polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) can cause an entire gene deletion. The current methodology can accurately identify GSTM1 and GSTT1 copy number variants (CNVs), which may shed light on the true contribution of each gene copy to the cellular detoxification process and disease risk. Because liver cirrhosis is becoming a critical worldwide health issue, this study determined the CNVs of GSTM1 and GSTT1 and their relationship to the risk of liver cirrhosis.Methods: In this study, we compared 106 patients with liver cirrhosis to 104 healthy controls. Real-time PCR was used to identify the CNVs of GSTM1 and GSTT1. Logistic and linear regression models were used to estimate the relationship between liver cirrhosis and clinical chemistry variables with the CNVs, respectively.Results: In 3.3% of the study participants, > 2 copies of the GSTM1 or GSTT1 genes were detected. GSTT1 carriers had a significantly lower risk of liver cirrhosis (p< 0.05) compared with individuals who had homozygous deletion (adjusted odds ratio (AOR) = 0.47; 95% CI: 0.25, 0.86). This risk reduction was significant (p< 0.05) in patients with a single copy of the GSTT1 gene (AOR = 0.48; 95% CI: 0.25, 0.91). Those with ≥ 2 copies of combined GSTM1 and GSTT1 also had a significantly (p< 0.05) lower risk of developing liver cirrhosis compared with double null genotypes (AOR = 0.38; 95% CI: 0.16, 0.91, p trend < 0.001). Moreover, ≥ 2 copies of combined GSTM1 and GSTT1 genes were associated with a substantial decrease in alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels, respectively.Conclusion: A single copy number of GSTT1, and ≥ 2 copies of combined GSTM1 and GSTT1 genes were associated with a reduced risk of liver cirrhosis in Ethiopians. These findings underscore the importance of gene–environment interactions in the multifactorial development of liver cirrhosis.Keywords: liver cirrhosis, copy number variation, glutathione S-transferase genes, Ethiopia

Keywords

• liver cirrhosis
• copy number variation
• glutathione s-transferase genes
• ethiopia