PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis.
OBJECTIVE
Several studies have reported an association between the genetic variant rs738409 (G) in the PNPLA3 gene and the risk of cirrhosis in various liver diseases. Our purpose was to assess the influence of this polymorphism on the risk of hepatocellular carcinoma (HCC) occurrence in two distinct longitudinal cohorts of patients with cirrhosis as well as its possible usefulness in HCC-risk model prediction.


METHODS
PNPLA3 rs738409 genotypes were assessed in 279 patients with alcoholic- and 253 patients with HCV-related cirrhosis. These patients were followed-up and screened for the risk of HCC, and the influence of rs738409 on the occurrence of liver cancer was assessed using the Kaplan-Meier method, then according to the multivariate Cox model.


RESULTS
In patients with HCV-related cirrhosis, rs738409 genotypes did not influence the risk of HCC development (log-rank = 0.7) or death (log-rank = 0.2). Conversely, in patients with alcoholic cirrhosis, the rs738409 (GG) genotype was an independent risk factor for HCC occurrence (HR = 1.72 [1.21-2.45], log-rank = 0.002) as well as older age, male gender, and higher BMI. Combining these features enabled HCC-risk stratification of this population into three groups with the 6-year cumulative incidence ranging from 3.4% (low risk, n = 58), 12.2% (intermediate risk, n = 163), and 51.7% (high risk, n = 58), respectively (HR = 4.3 [2.7-6.4]; log-rank <0.0001).


CONCLUSIONS
This study provides key data that affirm the influence of the rs738409 (GG) genotype on the occurrence of HCC in patients with alcoholic cirrhosis. Its combination with clinical features refines the selection of patients at higher risk of liver cancer development.
University Paris 13-UFR SMBH/INSERM U698, Bobigny, France.
Erwan
E
Guyot
Angela
A
Sutton
Pierre
P
Rufat
Christelle
C
Laguillier
Abdellah
A
Mansouri
Richard
R
Moreau
Nathalie
N
Ganne-Carrié
Michel
M
Beaugrand
Nathalie
N
Charnaux
Jean-Claude
JC
Trinchet
Pierre
P
Nahon
D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000150:complications* / Q000821:virology*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications*; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent