Table 3.

Replication of TERT variants in patients with alcohol-related and chronic HCV-related cirrhosis and in population-based cohorts

Cohort	Controls	Cases phenotype (ICD-10)	N cases | controls	TERT Variant	EA	P value	OR (95% CI)
Current study*	ALD cirrhosis*	C22.0 Liver cell carcinoma (HCC) in alcohol-related cirrhosis	1214 | 1866	rs2242652	A	6.40×10−9	0.61 (0.52 to 0.72)
Replication cohorts
Trépo et al†	ALD F0-F4 fibrosis	C22.0 HCC in alcohol-related liver disease (F0-F4 fibrosis)	775 | 1332	rs2242652	A	0.179	0.89 (0.75 to 1.06
Stop-HCV‡	HCV cirrhosis	C22.0 Liver cell carcinoma (HCC) in HCV-related cirrhosis	169 | 890	rs2242652	A	0.047 §	0.72 (0.53 to 0.99)
Zhang et al¶	Healthy volunteers	C22.0 Liver cell carcinoma (HCC)	473 | 564	rs2242652	A	0.004	0.70 (0.55 to 0.90)
Dong et al**	Healthy volunteers	C22.0 Liver cell carcinoma (HCC) (hepatitis-induced)	162 | 106	rs10069690	T	0.00014§	0.36 (0.21 to 0.63)
FinnGen††	General population	C22 malignant neoplasm of liver and intrahepatic bile duct	442 | 204 070	rs2242652	A	0.007	0.80 (0.68 to 0.94)
UKBB‡‡	General population	C22 malignant neoplasm of liver and intrahepatic bile duct	874 | 348 465	rs2242652	A	0.027	0.87 (0.78 to 0.97)
UKBB‡‡	General population	C22.0 Liver cell carcinoma (HCC)	383 | 348 956	rs2242652	A	0.028	0.80 (0.66 to 0.98)
BBJ Japan§§	BBJ population¶¶	C22.0 Liver cell carcinoma (HCC)	1866 | 195 745	rs72709458	T	0.00031	0.84 (0.76 to 0.92)

*Combined effect estimates of stage 1 and 2 samples of current study as shown in table 1 (for comparison).

†Cases: patients with ALD (80% with F3-4 fibrosis; 20% F0-2 fibrosis) and HCC, controls: patients with ALD (90% with F3-4 fibrosis, 10% F0-2 fibrosis) from Trépo et al.¹⁴

‡Cases: patients with HCV related cirrhosis and HCC, controls: patients with HCV related cirrhosis without HCC (online supplemental methods F).

§Allelic ORs were calculated from 2×2 tables on allele counts. Significance was calculated as 1 df χ² test.

¶Zhang et al,⁵² Huang et al ⁵¹ Han Chinese patients with HCC (individuals were excluded from the study if they had HCV).

**Dong et al ^{61 62} male Han Chinese patients with viral hepatitis-induced primary hepatocellular carcinoma (r2=0.85 between rs10069690:T and rs2242652:A, both variants are in high linkage disequilibrium).

††General population controls (excluding all cancers).

‡‡As UKB data were incorporated into our discovery analysis, further interrogation of liver cancer phenotypes from UKB does not constitute independent validation.

§§Variants rs2242652 and rs10069690 were not available in the summary GWAS data from Ishigaki et al ⁶³ (PMID: 32514122, publicly available from http://jenger.riken.jp/en/result) (rs72709458 is the closest proxy to rs2242652 (r2=0.973)).

¶¶Removed diseases from control samples (biliary tract cancer, oesophageal cancer, gastric cancer, colorectal cancer and pancreatic cancer).

ALD, alcohol liver disease; BBJ, BioBank Japan; EA, effect allele; FinnGen, FinnGen Biobank; GWAS, Genome-Wide Association Studies; HCV, hepatitis C virus; ICD, International Classification of Diseases;; UKB, UK Biobank.