A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes

Fabrice Danjou, Claudio Fozza, Magdalena Zoledziewska, Antonella Mulas, Giovanna Corda, Salvatore Contini, Fausto Dore, Antonio Galleu, Anna Angela Di Tucci, Giovanni Caocci, Eleonora Gaviano, Giancarlo Latte, Attilio Gabbas, Paolo Casula, Lucia Gemma Delogu, Giorgio La Nasa, Emanuele Angelucci, Francesco Cucca, Maurizio Longinotti

Research output: Contribution to journalArticlepeer-review


Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 (p = 1.16 × 10−12), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10−6 and 3.34 × 10−6, are situated in the methylene tetrahydrofolate reductase (MTHFR) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.

Original languageEnglish (US)
Pages (from-to)1034-1038
Number of pages5
JournalExperimental Hematology
Issue number11
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research


Dive into the research topics of 'A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes'. Together they form a unique fingerprint.

Cite this