Genetic variants in STAT4 and their interactions with environmental factors for the incidence of hepatocellular carcinoma

Article type: Research Article

Authors: Zhong, Xuan^{a; b} | Luo, Meihua^c | Wu, Yanmei^b | Zhou, Xinfeng^b | Yu, Xinfa^c | Liu, Li^{b; *} | Chen, Sidong^b

Affiliations: [a] Department of Tumor, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong, China | [b] Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China | [c] Shunde Hospital of Southern Medical University, Foshan, Guangdong, China

Correspondence: [*] Corresponding author: Li Liu, Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, No. 283, Jianghai Avenue, Haizhu District, Guangzhou, Guangdong, China. Tel.: +86 20 34055123; E-mail: gdpu_liuli@gdpu.edu.cn.

Abstract: BACKGROUND: A recent genome-wide association study (GWAS) has posed STAT4 as a promising susceptibility gene for hepatocellular carcinoma (HCC). However, the most significant variant in this GWAS, rs7574865, yielded inconsistent results. OBJECTIVE: This study, in a Southern Chinese population, was aimed to clarify the roles in HCC incidence of the rs7574865 and other two potentially functional variants, rs897200 and rs1031507 in STAT4. METHODS: This study enrolled 631 new HCC cases and 631 cancer-free controls. The genetic association was estimated using the multivariate logistic regression model. The pairwise gene-environment interactions were assessed using the multiplicative term in regression model and the “Delta” method for the additive scale. RESULTS: In the multivariate analysis, the rs7574865 TT genotype conferred a decreased risk of HCC compared to the GG genotype (adjusted OR = 0.62, 95%CI = 0.38∼0.99). The significant association of rs7574865 was also observed under the additive genetic model, with an adjusted OR of 0.81 (95%CI = 0.65∼0.99). Nevertheless, other two variants alone showed no significant association, as well as the haplotypes and genetic risk scores. Further analysis indicated a potential interaction between the rs897200 and alcohol drinking (P= 0.048 and 0.072 for additive and multiplicative interactions, respectively). Drinkers with the rs897200 CT+CC genotypes presented an increased disease-risk, as compared with non-drinkers carrying the TT genotype (adjusted OR = 1.68, 95%CI = 1.11∼2.54). CONCLUSIONS: The variant in STAT4, rs7574865, serves as a potential marker for predicting incidence of HCC. The rs897200 variant possibly interplays with alcohol drinking to alter HCC risk in the Southern Chinese, but warrants further investigation.

Keywords: Hepatocellular carcinoma (HCC), signal transducer and activator of transcription 4 (STAT4), genetic variant, genotype, gene-environment interaction

DOI: 10.3233/CBM-203162

Journal: Cancer Biomarkers, vol. 32, no. 1, pp. 3-9, 2021