Thomsen Hauke, Campo Chiara, Weinhold Niels, da Silva Filho Miguel Inacio, Pour Luděk, Gregora Evžen, Vodicka Pavel, Vodickova Ludmila, Hoffmann Per, Nöthen Markus M, Jöckel Karl-Heinz, Langer Christian, Hajek Roman, Goldschmidt Hartmut, Hemminki Kari, Försti Asta
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Eur J Haematol. 2017 Jul;99(1):70-79. doi: 10.1111/ejh.12892. Epub 2017 May 24.
To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM).
We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS.
In GWAS, we identified 10 loci contributing to development of MGUS at P-value threshold of 10 . The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10 ), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS.
These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
确定导致意义未明的单克隆丙种球蛋白病（MGUS）发生的种系变异，MGUS是一种无症状的骨髓瘤（MM）癌前病变。
我们对243例德国患者进行了首例关于MGUS的全基因组关联研究（GWAS），并在294例捷克患者中进行了重复验证。在1508例德国MM患者中对鉴定出的基因座进行了进一步分析。最近在一项荟萃分析中报道的新MM基因座也在MGUS的GWAS中进行了检测。
在GWAS中，我们在P值阈值为10时鉴定出10个导致MGUS发生的基因座。捷克队列支持两个关联（6q26，rs6933936；7p21.3，rs10251201）。在GWAS中，rs974120（8p23.2）达到全基因组显著性（P = 2.94×10），在MM中具有名义显著性。根据ENCODE数据，rs974120基因座在白血病中显示出转录活性标记。rs10251201（7p第21.3）、rs9318227（13q第22.1）和rs10405859（19q第13.32）与白血病发生以及免疫和炎症反应相关的标志物有关。两个新鉴定出的MM候选基因座，rs1948915（8q第24.21）和rs8058578（16p第11.2），与MGUS存在名义关联。
这些数据首次谨慎地提出了MGUS的种系结构，其与白血病和自身免疫性疾病有关，后者与一项显示MGUS与自身免疫性疾病聚集的家族研究结果一致。
