Genetic variation inTERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

Abstract

ObjectiveHepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.DesignPatients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina).ResultsAssociations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10−9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10−5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10−44).ConclusionThis study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients

“…The three genetic parameters remaining in the final risk score were TM6SF2 rs10401969, HSD17B13 rs6834314 and PNPLA3 rs738409. All three risk loci are not only established risk factors for alcohol-associated cirrhosis but also for alcohol-related HCC [ 7 , 8 , 10 , 26 ]. Rs738409 in PNPLA3, which results in an amino acid exchange at position 148 from isoleucine to methionine, proved superior to both investigated SAMM50 variants in our analysis.…”

“…Once patients have developed chronic liver disease, the risk for HCC is strongly modulated by the presence of genetic risk factors [ 1 ]. Different genetic loci were discovered and validated in large patient cohorts, with some increasing the risk for HCC, such as the presence of the PNPLA3 minor variant 148M [ 1 , 7 , 8 ], and with others reducing the risk, such as the HSD17B13 rs72613567:TA variant [ 9 , 10 ]. Attempts were made to develop genetic risk profiles that may be used to select patients at particularly high risk [ 11 ].…”

Association between telomere length and hepatocellular carcinoma risk: A Mendelian randomization study

“…Among the susceptibility variants, PNPLA3 , SAMM50 , and TM6SF2 variants are considered as risk factors for HCC, while locus rs2242652 in TERT served as a protective factor. 3 , 4 , 5 …”

High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis

“… 5 However, protective genetic variants, for example the rs429358 polymorphism in apolipoprotein E , the rs72613567 HSD17B13 locus, and rs2242652 in TERT have been unravelled. [6] , [7] , [8] Knowledge of these factors may both lead to a better understanding of the molecular pathways underlying liver disease development and the identification of potential drug targets, but also facilitate risk stratification, for example for HCC screening programmes.…”