Department of Biology, University of Pisa, Pisa, Italy.
Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Greenville, South Carolina, USA.
Int J Cancer. 2023 Jan 15;152(2):239-248. doi: 10.1002/ijc.34278. Epub 2022 Oct 1.
Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.
多效性是指一个基因或等位基因变异影响多个不相关的特征，这种现象在癌症中很常见，有证据表明，癌症和非癌症特征之间存在全基因组显著关联的位点。这一特征在多发性骨髓瘤（MM）中尤为重要，因为迄今为止已经确定了几个易感性位点是多效性的。因此，本研究旨在使用来自 GWAS Catalog 的 28684 个独立的单核苷酸多态性（SNP），这些 SNP 与各自的特征达到显著关联（P < 5 × 10 ），来识别与 MM 风险相关的新的多效性变异。从国际淋巴瘤流行病学联盟（InterLymph）中选择了 2434 例 MM 病例和 3446 例对照进行分析。在 InterLymph 中，与 MM 风险关联最强的 10 个 SNP 被选择用于在独立的 1955 例 MM 病例和 1549 例对照（来自国际多发性骨髓瘤 rESEarch [IMMEnSE] 联盟）和 418 例 MM 病例和 147282 例对照（来自 FinnGen 项目）中进行复制。这三个研究的综合分析确定了 DNAJB4-rs34517439-A 与 MM 发病风险增加之间的关联（OR = 1.22，95%CI 1.13-1.32，P = 4.81 × 10 ）。rs34517439-A 与 FUBP1 基因的表达改变有关，该基因编码一种多功能的 DNA 和 RNA 结合蛋白，研究观察到它影响了各种参与细胞周期调节的基因的调节，其中包括各种癌基因和抑癌基因。总之，通过多效性扫描方法，我们确定了 DNAJB4-rs34517439 作为一个潜在的新的 MM 风险位点。
