Breast cancer risk-associated variants at 6q25.1 influence risk of hepatocellular carcinoma in a Chinese population

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of estrogens in HCC pathogenesis. In this study, we conducted a case–control study to investigate whether breast cancer risk-associated single nucleotide polymorphisms (SNPs) located at estrogens loci identified by genome-wide association studies (GWASs) also predispose to HCC in a Chinese population. Three candidate SNPs at 6q25.1 were genotyped in 2025 HCC cases and 2032 healthy controls. Differential expression analyses and expression quantitative trait loci (eQTL) analyses were conducted to further explore the potential function of significant SNPs and genes they reside in. Two of the three candidate SNPs (rs9383951 and rs9485372) were observed to be significantly associated with HCC risk. Under a dominant model, the odds ratios (OR) for rs9383951 and rs9485372 were 1.28 (95% CI: 1.10–1.49, <span style="font-style:italic;">P</span> = 0.002) and 1.34 (95% CI: 1.17–1.53, <span style="font-style:italic;">P</span> = 2.75 × 10^–5), respectively. We also found a significant accumulative effect of these two SNPs and there was a gradual increase in OR with a greater number of hazard genotypes. Moreover, the association between rs9383951 and HCC risk was specific in males. Lower <span style="font-style:italic;">ESR1</span> and <span style="font-style:italic;">TAB2</span> expressions were investigated in hepatic tumor tissues than adjacent normal tissues. We found a significant association between rs9383951 and <span style="font-style:italic;">ESR1</span> expression (<span style="font-style:italic;">P</span> = 0.047). Besides, <span style="font-style:italic;">ESR1</span> expression was significantly correlated with the expression of <span style="font-style:italic;">TAB2</span>. Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting <span style="font-style:italic;">ESR1</span> and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.</span>

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