Pine Sharon R, Mechanic Leah E, Ambs Stefan, Bowman Elise D, Chanock Stephen J, Loffredo Christopher, Shields Peter G, Harris Curtis C
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
J Natl Cancer Inst. 2007 Sep 19;99(18):1401-9. doi: 10.1093/jnci/djm128. Epub 2007 Sep 11.
The relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms.
We used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non-small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided.
We found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (P(interaction) = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients.
The functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.
慢性炎症、先天免疫与癌症之间的关系已得到充分证实。甘露糖结合凝集素（MBL）是先天免疫中的关键因子。MBL2基因启动子和第一外显子中的五个多态性改变了MBL在人体内的表达和功能，并与炎症相关疾病易感性有关。这五个多态性产生了六个特征明确的单倍型，导致血清MBL浓度较低（即LYB、LYC、HYD和LXA）或较高（即HYA和LYA）。我们研究了肺癌患者的生存是否与这些多态性相关。
我们使用多变量Cox比例风险模型，研究了马里兰州巴尔的摩地区558名白人和173名非裔美国非小细胞肺癌患者中MBL2多态性及其单倍型和双倍型与肺癌死亡率之间的关联。吸烟史和种族通过访谈获得，肿瘤分期通过病历获得，死亡原因通过国家死亡指数获得。所有统计检验均为双侧检验。
我们发现，启动子Y/X多态性的X等位基因（导致血清MBL浓度较低）与白人患者肺癌生存率提高之间存在统计学显著关联（X/X或X/Y基因型患者死于肺癌的风险比[RR]与Y/Y基因型相比=0.61，95%置信区间[CI]=0.46至0.81），但在非裔美国患者中未发现此关联（RR=1.11，95%CI=0.69至1.77）。白人患者中的关联在重度吸烟者中最强，且与分期无关。我们还发现Y/X多态性与种族之间在肺癌生存方面存在统计学显著的相互作用（P（相互作用）=0.019）。同样与低血清MBL水平相关的MBL2 LXA单倍型和XA/B双倍型与白人患者肺癌生存率提高在统计学上显著相关。
先天免疫基因MBL2的功能性Y/X多态性以及MBL2单倍型和双倍型似乎与白人患者的肺癌生存相关。
