Evaluation of angiotensinogen c.1-44G>A and p.M268T variants as risk factors for fibrosis progression in chronic hepatitis C and liver diseases of various etiologies.
BACKGROUND
Hepatic stellate cells express all components of the renin-angiotensinogen (AGT) system and secrete active angiotensin II. Animal studies provided evidence that angiotensin II stimulates the accumulation of extracellular matrix by enhancing transforming growth factor beta1 production. A functional genetic alteration in the human AGT promoter (c.1-44G>A) has been linked to accelerated progression of fibrosis in hepatitis C virus infection.


METHODS
We enrolled 2154 patients with chronic liver disease of various etiologies, including 1286 individuals with chronic hepatitis C virus infection as well as 207 healthy volunteers. We performed genotyping for two AGT variants, c.1-44G>A and c.803T>C (p.M268T), by melting curve analysis using fluorescence resonance energy transfer probes.


RESULTS
Allele frequencies and genotype distributions of both variants did not differ between patients and controls. Genotype frequencies of the c.1-44G>A variant were GG 31.0%, GA 45.6%, and AA 23.4% in patients and GG 30.0%, GA 47.8%, and AA 22.2% in controls. The genotype frequencies of p.M268T, which is in strong linkage disequilibrium with c.1-44G>A, were MM 30.8%, MT 45.5%, and TT 23.4% in patients and MM 29.0%, MT 48.8%, and TT 22.2% in controls. Both variants were associated with neither higher stages of fibrosis nor requirement for liver transplantation in any of the diagnosis subgroups. Particularly, these genetic alterations were not associated with progressive fibrosis in chronic HCV infection.


CONCLUSIONS
In contrast to previous reports, both AGT variants do not predispose to the progression of fibrosis in chronic liver disease.
Halangk
Juliane
J
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Berg
Thomas
T
Neumann
Konrad
K
Sarrazin
Christoph
C
Hinrichsen
Holger
H
Fitz
Carolin
C
Puhl
Gero
G
Mueller
Tobias
T
Neuhaus
Peter
P
Wiedenmann
Bertram
B
Witt
Heiko
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000808:Angiotensinogen / Q000235:genetics*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D055166:Hepatic Stellate Cells / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015810:Linkage Disequilibrium; D008107:Liver Diseases / Q000235:genetics*; D008108:Liver Diseases, Alcoholic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D055815:Young Adult
D000808:Angiotensinogen