Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study - Archive ouverte HAL Access content directly
Journal Articles Lancet Oncology Year : 2022

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study

(1, 2) , (2) , (2, 3) , (2) , (2) , (2) , (2) , (2, 4) , (1) , (5, 6) , (7) , (8, 9) , (10, 11, 12) , (13, 14) , (15, 16) , (17) , (18, 19) , (20, 21) , (2, 4) , (6, 5) , (1) , (22, 23) , (15, 16) , (10, 12, 11) , (6, 5) , (24, 1) , (25, 4) , (2, 26) , (2, 4) , (2, 27)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
C. Feray
  • Function : Author

Abstract

Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (pandlt;1 × 10−6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts. Findings: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10−8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10−10), PNPLA3 (rs738409; p=9·29 × 10−7), and HSD17B13 (rs72613567; p=2·49 × 10−4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10−3), TM6SF2 (rs58542926; p=4·06 × 10−5), and PNPLA3 (rs738409; p=1·17 × 10−4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10−10), TM6SF2 (1·77, 1·52–2·07; p=3·84×10−13), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10−10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. Interpretation: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.
Fichier principal
Vignette du fichier
Trépo et al-2022-Common genetic variation in alcohol-related hepatocellular carcinoma.pdf (2.98 Mo) Télécharger le fichier
Vignette du fichier
Trepo_1-s2.0-S1470204521006033-mmc1.pdf (1.43 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-03718253 , version 1 (16-09-2022)

Identifiers

Cite

E. Trepo, S Caruso, J. Yang, S Imbeaud, G Couchy, et al.. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncology, 2022, 23 (1), pp.161-171. ⟨10.1016/S1470-2045(21)00603-3⟩. ⟨hal-03718253⟩
72 View
12 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More