Zhao Jing, Zhu Xiangzhu, Shrubsole Martha J, Ness Reid M, Hibler Elizabeth A, Cai Qiuyin, Long Jirong, Chen Zhi, Jiang Ming, Kabagambe Edmond K, Zhang Bing, Hou Lifang, Smalley Walter E, Edwards Todd L, Giovannucci Edward L, Zheng Wei, Dai Qi
Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Department of Veterans Affairs, Tennessee Valley Healthcare System, Geriatric, Research, Education and Clinical Center (GRECC), Nashville, Tennessee.
Mol Carcinog. 2017 Oct;56(10):2258-2266. doi: 10.1002/mc.22678. Epub 2017 Jun 15.
The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na /Ca exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (P = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1, and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg/day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.
编码钠/钙交换蛋白的SLC8A1（溶质载体家族8成员1）基因在调节钙重吸收和体内平衡方面至关重要。钙稳态在细胞增殖和凋亡中起关键作用。我们推测，五个钙调节基因（SLC8A1、ATP2B1、CALB1、CALB2和CABP1）的多态性与钙摄入量相互作用，与结直肠肿瘤发生风险相关。在田纳西州结直肠息肉研究中进行了一项两阶段（发现和验证）研究，共纳入1275例病例和2811例对照。在第一阶段，我们在135个单核苷酸多态性（SNP）中鉴定出6个与钙摄入量显著相互作用且与腺瘤风险相关的SNP。在第二阶段，rs4952490（SLC8A1）与钙摄入量的相互作用得到了验证（P = 0.048）。我们发现，在rs4952490的G等位基因携带者中，钙摄入量（1000 - 2000毫克/天）与结直肠腺瘤之间呈负相关，尤其是对于多发性/晚期腺瘤，但在常见变异（A）的纯合子携带者中未观察到这种相关性。在SLC8A1、KCNJ1和SLC12A1 SNP的联合分析中，至少两个基因携带变异等位基因且钙摄入量高于膳食参考摄入量（DRI，1000毫克/天）的携带者患腺瘤的可能性比钙摄入量低于DRI的携带者低约30 - 57%。这种关联在多发性/晚期腺瘤中更强。当钙摄入量低于2500毫克/天时，在这些基因中未携带任何变异等位基因的人群中未发现关联。这些发现若得到证实，可能为结直肠腺瘤和癌症的个性化预防提供新途径。
