Polymorphic variation in the GC and CASR genes and associations with vitamin D metabolite concentration and metachronous colorectal neoplasia.
Polymorphic variation in the GC and CASR genes and associations with vitamin D metabolite concentration and metachronous colorectal neoplasia.
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DOI：
10.1158/1055-9965.epi-11-0916
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Jacobs ET
中科院分区：
文献类型：
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作者：
Hibler EA;Hu C;Jurutka PW;Martinez ME;Jacobs ET
维生素D水平和钙摄入量与大肠肿瘤的风险相关，维生素D途径基因的遗传变异可能影响循环中的维生素D代谢物浓度和/或大肠病变的风险。这项研究评估了GC球蛋白(GC)和钙敏感受体(CASR)的多态变异与异时性大肠肿瘤和维生素D代谢物浓度之间的关系。来自熊去氧胆酸(UDCA)和小麦麸皮纤维(WBF)试验的参与者(n=1439)使用单核苷酸多态(SNP)标记方法进行了分析，UDCA试验参与者的子集(n=404)也可以获得维生素D代谢物浓度。用多种统计方法对25个GC和35个CaSR标签SNP进行了分析。主成分分析没有揭示GC或CASR与大肠肿瘤之间的基因水平关联，然而，观察到GC和25(OH)D浓度之间存在显著的基因水平关联(p<；0.01)。在个体SNP水平上，经过多重比较调整后，观察到7个GC(rs7041、rs222035、rs842999、rs1155563、rs12512631、rs16846876、rs1746825)的多态和25(OH)D的循环指标(调整后p<；0.01)以及CaSR rs1042636与近端大肠肿瘤(调整后p=0.01)之间的显著关联。这些结果表明，CASR的变化与大肠肿瘤的发生几率之间可能存在关联，以及GC中25(OH)D循环浓度的变化可能起到的作用。有必要进行进一步的研究，以确定GC基因型影响25(OH)D浓度的机制，并进一步阐明CaSR在结直肠肿瘤中的作用。
Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D-pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and Calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations. Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n=1439) were analyzed using a single nucleotide polymorphism (SNP) tagging approach, with a subset (n=404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods. Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia, however, a significant gene-level association between GC and 25(OH)D concentrations (p < 0.01) was observed. At the individual SNP-level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted p < 0.01), and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted p = 0.01). These results demonstrate a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations. Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia.