Elsevier

Gene

Volume 561, Issue 1, 25 April 2015, Pages 63-67
Gene

Replication the association of 2q32.2–q32.3 and 14q32.11 with hepatocellular carcinoma

https://doi.org/10.1016/j.gene.2015.02.006Get rights and content

Highlights

  • We replicate the locus 2q32.2–q32.3 (STAT4) associated with HCC.

  • The locus 14q32.11 (EFCAB11) is first reported to have association with HCC in Chinese population.

  • STAT4 and EFCAB11 generate evidence for interaction in association with HCC.

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor. The morbidity and mortality of HCC tend to ascend and become a serious threat to the population health. Genetic studies of HCC have identified several susceptibility loci of HCC. In this study, we aim to replicate the association of these loci in our samples from Chinese population and further investigate the genetic interaction. We selected 16 SNPs within 1p36.22, 2q32.2–q32.3, 3p21.33, 8p12, 14q32.11 and 21q21.3 and genotyped in 507 HCC patients and 3014 controls by using Sequenom MassARRAY system. Association analyses were performed by using PLINK 1.07. We observed that the STAT4 (2q32.2–q32.3) at rs7574865 (P = 1.17 × 10 3, OR = 0.79) and EFCAB11 (14q32.11) at rs8013403 (P = 1.54 × 10 3, OR = 0.80) were significantly associated with HCC in this study. In 3p21.33, genetic variant rs6795737 within GLB1 was also observed with suggestive evidence (P = 9.98 × 10 3, OR = 0.84). In the interaction analysis, the pair of associated SNPs (rs7574865 within STAT4, rs8013403 within EFCAB11) generated evidence for interaction (P = 4.10 × 10 3). In summary, our work first reported the association of 14q32.11 (EFCAB11) with HCC in Chinese Han population and revealed the genetic interaction between STAT4 (2q32.2–q32.3) and EFCAB11 (14q32.11) in HCC.

Introduction

Hepatocellular carcinoma (HCC) is a malignant tumor with a high incidence, which ranks as fifth most common malignant tumors and the second leading cause of cancer mortality (Yang and Roberts, 2010). There are more than 600,000 new cases worldwide each year according to the latest statistic, especially in the Asia-Pacific region (Parkin et al., 2005). HCC is a disease with high morbidity in China, which develops mainly from hepatitis B cirrhosis. Meanwhile the gradual increase of hepatitis C virus infection is also the predisposing factor (El-Serag and Rudolph, 2007, Tanaka et al., 2011). In China, the HCC patients account for 55% of the whole number worldwide (Parkin et al., 2005). Nearly 230,000 patients died from HCC per year, which is 18.8% within the cancer death, just behind gastric carcinoma. The morbidity and mortality of HCC tend to ascend and HCC has become a serious health threat (Yang and Roberts, 2010). With the development of molecular biology and genetic engineering, the genetic study of HCC is becoming a research hotspot to explore the pathogenesis and improve the clinical efficiency as well as survival rate of HCC.

Recently, several GWASs in Asian populations have identified at least 8 susceptibility loci for HCC, including 1p36.22 (KIF1B, UBE4B, PGD) (Zhang et al., 2010), 2q32.2–q32.3 (STAT4) (Jiang et al., 2013), 3p21.33 (GLB1) (Clifford et al., 2010), 8p12 (Chan et al., 2011), 14q32.11 (EFCAB11) (Clifford et al., 2010), 21q21.3 (GRIK1) (Sun et al., 2012), 22q12.2 (DEPDC5) (Miki et al., 2011) and MHC region (Jiang et al., 2013, Clifford et al., 2010, Sun et al., 2012, Kumar et al., 2011).

In this study, we selected tag-SNPs within the above loci (non-MHC region) to validate in Chinese population and further investigate the interactions associated with disease between these genetic variants.

Section snippets

Subjects

A total of 507 HCC patients and 3014 health controls were enrolled in this study (Table 1). All samples were unrelated and Chinese Han in origin from the same region of Anhui Province. Patients with HCC were recruited from No. 1 Hospital of Anhui Medical University in China. Diagnosis with HCC was based on (i) positive findings on cytological or pathological examination and/or (ii) positive images on angiogram, ultrasonography, computed tomography and/or magnetic resonance imaging, combined

Results

Totally, 16 SNPs were genotyped in 507 HCC cases and 3014 controls (Table 2). We replicated the association of STAT4 (2q32.2–q32.3) with HCC at rs7574865 (P = 1.17 × 10 3, OR = 0.79) and observed that the variant rs8013403 within 14q32.11 (EFCAB11) was significantly associated with HCC in this study (P = 1.54 × 10 3, OR = 0.80) (Table 2). In 3p21.33, genetic variant rs6795737 within GLB1 was also observed with suggestive evidence (P = 9.98 × 10 3, OR = 0.84) (Table 2). Those SNPs located within loci 1p36.22,

Discussion

In this study, we carried a replication study on previously reported 7 susceptibility loci for HCC in 507 HCC cases and 3014 controls of Chinese Han.

We replicated the association of STAT4 (2q32.2–q32.3) at rs7574865, which has been reported as a genetic factor for the susceptibility to various autoimmune diseases including primary biliary cirrhosis (Remmers et al., 2007, Hirschfield et al., 2009), systemic lupus erythematosus (Han et al., 2009), rheumatoid arthritis (Zhernakova et al., 2011),

Conclusions

In summary, our work first reported the association of 14q32.11 (EFCAB11) with HCC in Chinese Han population and found the genetic interaction between STAT4 (2q32.2–q32.3) and EFCAB11 (14q32.11) in HCC. Considering the small sample size of cases in this study, further study will be needed to investigate the association within other loci and then gain a better understanding on HCC genetic pathogenesis.

Conflict of interest

The authors declare no conflict of interest.

Author contributions

Conceived and designed the experiments: WC and LDS. Sample selection: WC, MQW, ZZ, XLM, MX, FD, HW, MFW, and SXC. Performed the experiments: FSZ, BL, JPG, JZ, JF, and YZ. Analyzed the data: XBZ, THY, and WC. Wrote the paper: WC, HYT, and LDS.

Acknowledgments

We are most grateful to all the members who have so willingly participated in this study, which made this study possible. We also thank the funding of Anhui Provincial Natural Science Foundation (1508085MH175) and the Local Universities Characteristics and Advantages of Discipline Development Program of the Ministry of Finance of China.

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    These authors contributed equally to this work.

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