Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males.
BACKGROUND
Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear.


OBJECTIVE
To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males.


METHODS
We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction.


RESULTS
Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation.


CONCLUSIONS
The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Texas Medical Center Digestive Disease Center Houston, TX, USA ; Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA.
Donna L
DL
White
Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Department of Pediatrics, Baylor College of Medicine Houston, TX, USA.
Yanhong
Y
Liu
Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA ; Section of Endocrinology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA.
Jose
J
Garcia
Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Texas Medical Center Digestive Disease Center Houston, TX, USA ; Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA.
Hashem B
HB
El-Serag
Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Texas Medical Center Digestive Disease Center Houston, TX, USA ; Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA.
Li
L
Jiao
Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA ; Department of Pediatrics, Baylor College of Medicine Houston, TX, USA.
Spiridon
S
Tsavachidis
Department of Molecular and Human Genetics, Baylor College of Medicine Houston, TX, USA.
Luis M
LM
Franco
Department of Systems Biology, MD Anderson Cancer Center Houston, TX, USA.
Ju-Seog
JS
Lee
Section of Infectious Diseases, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine Houston, TX, USA.
Shahriar
S
Tavakoli-Tabasi
Department Molecular and Cell Biology and Department of Medicine, Baylor College of Medicine Houston, TX, USA.
David
D
Moore
Department of Oncology, Georgetown University Medical Center Washington, DC, USA.
Radoslav
R
Goldman
Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA.
Jill
J
Kuzniarek
Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA.
David J
DJ
Ramsey
Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA ; Texas Medical Center Digestive Disease Center Houston, TX, USA ; Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, TX, USA.
Fasiha
F
Kanwal
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center Houston, TX, USA ; Section of Endocrinology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, TX, USA.
Marco
M
Marcelli
Epidemiology; carcinogenesis; digestive system; endocrinology; genetics; hepatology; infectious diseases