Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.
OBJECTIVE
Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC.


METHODS
A total of 916 subjects with CHC was enrolled from 2 centers. A gene-centric disease association study of 24,832 putative functional, single nucleotide polymorphisms (SNPs) was performed. Of the 1609 SNPs that were significantly associated (P </= .05) with advanced fibrosis in the discovery cohort (University of California San Francisco [UCSF], N = 433), the first batch of 100 SNPs were selected for validation in the replication cohort (Virginia Commonwealth University [VCU], N = 483).


RESULTS
A missense SNP in the DEAD box polypeptide 5 (DDX5) gene was significantly associated with an increased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 1.8 and 2.2, respectively). Two diplotype groups, carrying the haplotypes composed of the DDX5 SNP and 2 neighboring POLG2 SNPs were also significantly associated with an increased risk of advanced fibrosis and had comparable or better risk estimates. In addition, a missense SNP in the carnitine palmitoyltransferase 1A (CPT1A) gene was associated with a decreased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 0.3 and 0.6, respectively).


CONCLUSIONS
Subjects with CHC carrying DDX5 minor allele or DDX5-POLG2 haplotypes are at an increased risk of developing advanced fibrosis, whereas those carrying the CPT1A minor allele are at a decreased risk.
Huang
Hongjin
H
Celera Diagnostics, Alameda, California, USA. hongjin.huang@celera.diagnostics.com
Shiffman
Mitchell L
ML
Cheung
Ramsey C
RC
Layden
Thomas J
TJ
Friedman
Scott
S
Abar
Olivia T
OT
Yee
Linda
L
Chokkalingam
Anand P
AP
Schrodi
Steven J
SJ
Chan
Jason
J
Catanese
Joseph J
JJ
Leong
Diane U
DU
Ross
David
D
Hu
Xiaolan
X
Monto
Alexander
A
McAllister
Linda B
LB
Broder
Samuel
S
White
Thomas
T
Sninsky
John J
JJ
Wright
Teresa L
TL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D053487:DEAD-box RNA Helicases; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D011494:Protein Kinases / Q000235:genetics*; D020365:RNA Helicases / Q000235:genetics*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D011494:Protein Kinases; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases