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

E. Trepo 1, 2 S Caruso 2 J. Yang 2, 3 S Imbeaud 2 G Couchy 2 Q. Bayard 2 E. Letouze 2 N Ganne-Carrie 2, 4 C. Moreno 1 A. Oussalah 5, 6 C. Feray 7 J.F. Blanc 8, 9 Bruno Clément 10, 11, 12 P Hillon 13, 14 J Boursier 15, 16 V. Paradis 17 J. Calderaro 18, 19 V. Gnemmi 20, 21 J.-C. Nault 2, 4 J.-L. Gueant 6, 5 J. Deviere 1 I Archambeaud 22, 23 C. Vitellius 15, 16 B. Turlin 10, 12, 11 J.-P. Bronowicki 6, 5 T. Gustot 24, 1 A. Sutton 25, 4 M Ziol 2, 26 P. Nahon 2, 4 J Zucman-Rossi 2, 27, * 
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.
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https://hal.archives-ouvertes.fr/hal-03718253
Contributor : Laurent Jonchère Connect in order to contact the contributor
Submitted on : Friday, September 16, 2022 - 9:48:19 AM
Last modification on : Tuesday, November 22, 2022 - 2:26:16 PM

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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⟩

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