title: Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia.
abstract: Candidaemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidaemia may aid in designing adjunctive immunotherapeutic strategies. Here we hypothesize that variation in immune genes may predispose to candidaemia. We analyse 118,989 single-nucleotide polymorphisms (SNPs) across 186 loci known to be associated with immune-mediated diseases in the largest candidaemia cohort to date of 217 patients of European ancestry and a group of 11,920 controls. We validate the significant associations by comparison with a disease-matched control group. We observe significant association between candidaemia and SNPs in the CD58 (P = 1.97 × 10(-11); odds ratio (OR) = 4.68), LCE4A-C1orf68 (P = 1.98 × 10(-10); OR = 4.25) and TAGAP (P = 1.84 × 10(-8); OR = 2.96) loci. Individuals carrying two or more risk alleles have an increased risk for candidaemia of 19.4-fold compared with individuals carrying no risk allele. We identify three novel genetic risk factors for candidaemia, which we subsequently validate for their role in antifungal host defence.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.|Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek North Carolina, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.affiliation: Service des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudoises, Lausanne, Switzerland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wojtowicz
authors.affiliation: 4 Department of Internal Medicine, University of Athens, Medical School, Athens, Greece, and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Jos W M
authors.initials: JWM
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LAB
authors.lastname: Joosten
authors.affiliation: Service des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudoises, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: Service des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudoises, Lausanne, Switzerland.
authors.forename: Oscar
authors.initials: O
authors.lastname: Marchetti
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.|Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek North Carolina, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.affiliation: The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.|Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000368:Aged; D018968:CD58 Antigens / Q000235:genetics*; D058387:Candidemia / Q000235:genetics*; D016022:Case-Control Studies; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D018968:CD58 Antigens; D055233:Cornified Envelope Proline-Rich Proteins; D020690:GTPase-Activating Proteins; C524771:LCE4A protein, human; C557017:TAGAP protein, human