Cytokine Genetic Polymorphisms and Risk of Hepatocellular Carcinoma

背景/目的：慢性B與C型肝炎病毒(HBV, HCV)感染是肝細胞癌(hepatocellular carcinoma, HCC)的重要危險因子。HBV, HCV持續感染導致肝細胞發炎、壞死是誘導HCC發展的主要致癌機轉，細胞激素在免疫與發炎反應過程中扮演重要角色。本研究目的在利用病例對照研究分析細胞激素基因多形性和HCC的關係，由於男女性的病因有可能不同，我們特別對男女性的HCC進行個別分析。

材料與方法：研究個案包括989名男性新發病病例和956名男性對照，所有的男性個案均為HBsAg帶原者；女性有362名新發病病例和426名對照進入研究。我們分析14種細胞激素的單一核苷酸基因多形性(single nucleotide polymorphism, SNP)與HCC的關係，這些SNP所在基因牽涉pro-inflammation(IL12Rβ1+641、IL12Rβ1+1094 )、anti-inflammation(IL4-590、IL4R+50、IL6-174、IL10-592、IL10-819、IL10-627) 、fibrosis與apoptosis(Fas-1377、Fas-670、FasL-844)、影響α-interferon治療效果(MxA-88)，或chemokines(SDF1-3’、CCR2-190)的功能。利用非條件式羅吉斯迴歸模式進行危險比(odds ratio, OR)與95%信賴區間(95% confidence interval, 95%CI)的估計。

結果：對於男性，多重檢定校正後，沒有一個SNP或haplotype和HCC顯著相關。對於女性，在多重檢定校正後，只有Fas-670和HCC呈顯著相關(P=0.0012)，Fas-1377和Fas-670具強連鎖不平衡現象(D’=0.91)，分析這兩個基因所組成之haplotype，發現帶有兩條 Fas haplotype 3 [-1377G; -670A]者相對於不帶Fas haplotype 3者，其HCC的OR值在調整後為1.8(95% CI = 1.2-2.8)。我們也發現Fas-1377和Fas-670所組成的haplotype和FasL-844具顯著的交互作用(P=0.0176)，對帶有兩條Fas haplotype 3者，其FasL-844為TT, TC和CC調整後的OR值各為1.0, 4.33(95% CI= 1.24-15.09), 3.02(95% CI= 0.88-10.42)；在帶一條或不帶Fas haplotype 3者，FasL-844的TC和CC基因型則不增加HCC危險性。

結論：Fas-1377和-670所組成haplotype與FasL-844對於女性HCC發生的危險性具交互作用。

Background Chronic infection with hepatitis B or C virus is an important risk factor for hepatocellular carcinoma (HCC). Persistent viral infection leads to hepatic inflammation and then necrosis, which is the main mechanism causing HCC. Cytokine plays an important role in immunity and the production of inflammatory response. We conducted a case-control study to analyze the association between cytokine polymorphisms and HCC risk.

Materials and Methods Genotyping was performed for a total of 1351 (989 males and 362 females) case patients and 1382 (956 males and 426 females) control subjects. We analyzed 14 single nucleotide polymorphisms (SNPs) in the genes involving proinflammation (IL12Rβ1+641, IL12Rβ1+1094 ), anti-inflammation (IL4-590, IL4R+50, IL6-174, IL10-592, IL10-819, IL10-627), apoptosis (Fas-1377, Fas-670, FasL-844), anti-viral effect (MxA-88), or chemokines (SDF1-3’, CCR2-190). Unconditional logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (CIs).

Results For males, none of the 14 SNPs were significantly associated with HCC after adjusting multiple comparisons. For females, Fas-670 was significantly associated with HCC (P=0.0012). Fas-1377 was in linkage disequilibrium (D’=0.91) with Fas-670. Haplotype analysis also revealed that homozygosity for the Fas-1377G-670A haplotype was significantly associated with HCC, showing an adjusted OR of 1.8 (95% CI=1.2-2.8), when compared with individuals carrying zero copy of this haplotype. The Fas-1377G-670A haplotype modified the association between FasL-844 and HCC (P for interaction=0.0176). Among homozygotes of the Fas-1377G-670A haplotype, the ORs of HCC associated with the TT, TC, and CC genotype of the FasL-844 were 1.00, 4.33 (95% CI=1.24-15.09), and 3.02 (95% CI=0.88-10.42), respectively. By contrast, no association between FasL-844 and HCC was observed among individuals carrying zero or one copy of the Fas-1377G-670A haplotype.

Conclusion Fas-1377G-670A haplotype modified the effect of the FasL-844 on the development of HCC in females.