Arizona Cancer Center, University of Arizona and Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona 85724-5024, USA.
Cancer Res. 2010 Feb 15;70(4):1496-504. doi: 10.1158/0008-5472.CAN-09-3264. Epub 2010 Feb 9.
Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH)(2)D(3), are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an approximately 30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (OR(proximal), 0.67; 95% CI, 0.52-0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions.
维生素 D 循环水平低会影响结直肠癌的风险。维生素 D 的激素形式 1,25(OH)(2)D(3)的生物学作用是通过维生素 D 受体 (VDR) 介导的，VDR 与视黄酸 X 受体 (RXR) 异二聚化。我们使用单核苷酸多态性 (SNP) 标记方法，评估了 RXRA 和 VDR 基因中的遗传变异与两项研究的 pooled 人群中复发性（异时性）结直肠新生物的几率之间的关联。共分析了 RXRA 中的 32 个标签 SNP 和 VDR 中的 42 个 SNP，涉及 1439 名参与者。RXRA 与任何（P = 0.04）或近端（P = 0.03）异时性新生物存在基因水平关联。VDR 未观察到基因水平关联，也未观察到 VDR 中的任何单个 SNP 在经过多次比较校正后与任何异时性腺瘤有关。相比之下，RXRA SNP rs7861779 与近端异时性新生物之间的关联具有边缘统计学意义[比值比（OR），0.68；95%置信区间（95%CI），0.53-0.86；未调整 P = 0.001；调整后 P = 0.06]，包括在每个单独的研究中独立观察时。RXRA 内连锁块内的单体型支持特定单体型携带者近端结肠发生异时性新生物的几率降低约 30%，携带 CGGGCA 单体型（rs1805352、rs3132297、rs3132296、rs3118529、rs3118536 和 rs7861779）的个体中这种相关性最强（OR(proximal)，0.67；95%CI，0.52-0.86）。我们的研究结果表明，RXRA 中的等位基因变异会影响异时性结直肠新生物，这可能对近端病变的发展尤为重要。
