title: A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes.
abstract: 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 × 10-6and 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.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Danjou
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy. Electronic address: cfozza@uniss.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fozza
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Corda
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Contini
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Dore
authors.affiliation: King's College London, London, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Galleu
authors.affiliation: UO Ematologia e Centro Trapianti Ospedale Oncologico di Riferimento Regionale Armando Businco, Azienda Ospedaliera Brotzu, Cagliari, Italy.
authors.forename: Anna Angela
authors.initials: AA
authors.lastname: Di Tucci
authors.affiliation: Dipartimento di Scienze Mediche Internistiche, Università di Cagliari, Cagliari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Caocci
authors.affiliation: Ematologia, Ospedale San Francesco, Nuoro, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gaviano
authors.affiliation: Ematologia, Ospedale San Francesco, Nuoro, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Latte
authors.affiliation: Ematologia, Ospedale San Francesco, Nuoro, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Gabbas
authors.affiliation: Servizio di Ematologia, ASL Oristano, Oristano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Casula
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Sassari, Italy.
authors.forename: Lucia Gemma
authors.initials: LG
authors.lastname: Delogu
authors.affiliation: Dipartimento di Scienze Mediche Internistiche, Università di Cagliari, Cagliari, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: La Nasa
authors.affiliation: UO Ematologia e Centro Trapianti Ospedale Oncologico di Riferimento Regionale Armando Businco, Azienda Ospedaliera Brotzu, Cagliari, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Angelucci
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy; Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Sassari, Sassari, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Longinotti
mesh_terms: D000483:Alleles; D019295:Computational Biology / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D056747:Immunomodulation / Q000235:genetics*; D015201:Meta-Analysis as Topic; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide