Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
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自噬相关基因中的多态性作为多发性骨髓瘤的易感生物标志物：三个大同类群和功能表征的荟萃分析。
DOI：
10.3390/ijms24108500
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发表时间：
2023-05-09
影响因子：
5.6
通讯作者：
Sainz, Juan
中科院分区：
文献类型：
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作者：
Clavero, Esther;Sanchez-Maldonado, Jose Manuel;Macauda, Angelica;Ter Horst, Rob;Sampaio-Marques, Belem;Jurczyszyn, Artur;Clay-Gilmour, Alyssa;Stein, Angelika;Hildebrandt, Michelle A. T.;Weinhold, Niels;Buda, Gabriele;Garcia-Sanz, Ramon;Tomczak, Waldemar;Vogel, Ulla;Jerez, Andres;Zawirska, Daria;Watek, Marzena;Hofmann, Jonathan N.;Landi, Stefano;Spinelli, John J.;Butrym, Aleksandra;Kumar, Abhishek;Martinez-Lopez, Joaquin;Galimberti, Sara;Eugenia Sarasquete, Maria;Subocz, Edyta;Iskierka-Jazdzewska, Elzbieta;Giles, Graham G.;Rybicka-Ramos, Malwina;Kruszewski, Marcin;Abildgaard, Niels;Garcia Verdejo, Francisco;Sanchez Rovira, Pedro;Inacio da Silva Filho, Miguel;Kadar, Katalin;Razny, Malgorzata;Cozen, Wendy;Pelosini, Matteo;Jurado, Manuel;Bhatti, Parveen;Dudzinski, Marek;Druzd-Sitek, Agnieszka;Orciuolo, Enrico;Li, Yang;Norman, Aaron D.;Zaucha, Jan Maciej;Reis, Rui Manuel;Markiewicz, Miroslaw;Rodriguez Sevilla, Juan Jose;Andersen, Vibeke;Jamroziak, Krzysztof;Hemminki, Kari;Berndt, Sonja I.;Rajkumar, Vicent;Mazur, Grzegorz;Kumar, Shaji K.;Ludovico, Paula;Nagler, Arnon;Chanock, Stephen J.;Dumontet, Charles;Machiela, Mitchell J.;Varkonyi, Judit;Camp, Nicola J.;Ziv, Elad;Vangsted, Annette Juul;Brown, Elizabeth E.;Campa, Daniele;Vachon, Celine M.;Netea, Mihai G.;Canzian, Federico;Foersti, Asta;Sainz, Juan
我们通过对来自三个独立研究人群(包括13387名欧洲血统的受试者(6863名MM患者和6524名对照))234个自噬相关基因的种系遗传数据的荟萃分析，研究了自噬相关变异在调节多发性骨髓瘤(MM)风险中的影响，并研究了观察到的关联背后的功能机制。我们在6个与MM风险相关的CD46、IKBKE、PARK2、ULK4、ATG5和CDKN2A基因座中发现了SNPs，并观察到它们对疾病风险的影响是由特定的免疫细胞亚群以及维生素D3、MCP-2和IL20依赖的机制介导的。多发性骨髓瘤(MM)是由于骨髓浆细胞恶性增殖，分泌大量的特异性单抗免疫球蛋白或轻链，导致大量未折叠或错误折叠蛋白的产生而引起的。自噬可以在肿瘤发生中起双重作用，通过消除这些异常蛋白来避免癌症的发展，同时也确保MM细胞的存活和促进对治疗的耐药性。迄今为止，还没有研究确定自噬相关基因的遗传变异对多发性骨髓瘤风险的影响。我们对来自三个独立研究人群的234个自噬相关基因的种系遗传数据进行了荟萃分析，其中包括13,387名欧洲血统的受试者(6,863名MM患者和6,524名对照)，并检验了具有统计学意义的单核苷酸多态(SNPs；p<；1×10−9)与全血、外周血单核细胞和单核细胞来源的巨噬细胞的免疫反应的相关性。我们发现CD46、IKBKE、PARK2、ULK4、ATG5和CDKN2A6个基因座与MM相关(p=4.47×10−4−5.79×10−14)。在机制上，我们发现ULK4rs6599175SNP与循环维生素D3浓度相关(p=4.0×10−4)，而IKBKErs17433804SNP与CD2 4+CD38+B细胞数(p=4.8×10−4)和循环血清单核细胞趋化蛋白2浓度(p=3.6×10−4)相关。CD46rs1142469SNP与CD19+B细胞、CD19+CD3−B细胞、CD5+IgD−细胞、−细胞、−−细胞和CD4−CD8−−细胞数量相关(p=4.9×10−4−8.6×10−4)和循环中IL-20的浓度(p=0.00082)。最后，我们观察到CDKN2Ars2811710SNP与CD_4+EMCD_45RO+CD_(27)−细胞水平相关(p=9.3×10~(−)4)。这些结果表明，这六个基因座内的遗传变异通过调节特定的免疫细胞亚群以及维生素D3−、单核细胞趋化蛋白-2−和白介素20依赖的途径来影响多发性骨髓瘤的风险。
We investigated the influence of autophagy-related variants in modulating Multiple Myeloma (MM) risk through a meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined the functional mechanisms behind the observed associations. We identified SNPs within the six CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A loci associated with MM risk and observed that their effect on disease risk was mediated by specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent mechanisms. Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.
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影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
4.2
作者：
Cross, HS;Lipkin, M;Kállay, E
通讯作者：
Kállay, E
影响因子：
--
作者：
Folkersen, Lasse;van't Hooft, Ferdinand;Eriksson, Per
通讯作者：
Eriksson, Per
影响因子：
5
作者：
Desantis V;Saltarella I;Lamanuzzi A;Mariggiò MA;Racanelli V;Vacca A;Frassanito MA
通讯作者：
Frassanito MA
DOI：
10.4049/jimmunol.1202493
发表时间：
2013-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Heuck CJ;Mehta J;Bhagat T;Gundabolu K;Yu Y;Khan S;Chrysofakis G;Schinke C;Tariman J;Vickrey E;Pulliam N;Nischal S;Zhou L;Bhattacharyya S;Meagher R;Hu C;Maqbool S;Suzuki M;Parekh S;Reu F;Steidl U;Greally J;Verma A;Singhal SB
通讯作者：
Singhal SB