Publication Date:
2018-11-29
Description:
Background: Myelodysplastic Syndromes (MDS) are genetically and hematologically diverse stem cell malignancies pathogenetically linked to constitutive innate immune activation. Other than rare germline mutations and age, the only known predispositions to adult MDS include prior cytotoxic therapy, clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. Few studies investigating the genetic susceptibility to MDS have been performed owing to the limitations of SNP-array sample size. Here, we report the results from the first unbiased genome wide analysis of germline polymorphisms associated with non-del(5q) MDS using a multinational curated data set. Methods: Association analyses were performed on 2 sample sets (set 1: 555 cases, 2,964 controls; set 2: 352 cases, 2,640 controls) and combined by meta-analysis. Standard SNP- and sample-level QC was applied. Haplotype reference consortium (HRC) imputation was done by the Michigan imputation server (Rsq〉0.4) providing 23,278,269 markers for analysis. Gene expression sequencing was performed on an independent sample set from the National Taiwan University Hospital (213 MDS cases, 20 healthy donors; HumanHT-12 v4 Expression BeadChip; Chuang et al. Leukemia 2015). Functional analyses were performed as described. Results: Eight MDS associated loci were identified with lead variants, rs6683416, rs34539210, rs341274, rs1634783, rs7099032, rs2947170, rs4404050, and rs1206818, at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2), respctively. Odds ratio (OR) and p-values of each are listed in Table 1. Using gene expression profiling in an independent MDS sample set, we found expression of these five candidate genes was significantly increased in MDS vs controls (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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