title: Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis.
abstract: The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.
authors.affiliation: University of Florence, Florence, Italy.
authors.forename: A L
authors.initials: AL
authors.lastname: Zignego
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Wojcik
authors.affiliation: 1] Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France [2] INSERM, UMR_S 959, Paris, France [3] CNRS, FRE3632, Paris, France [4] AP-HP, Group Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Cacoub
authors.affiliation: Sapienza, University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Visentini
authors.affiliation: Sapienza, University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Casato
authors.affiliation: Liver Unity, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institution, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Latanich
authors.affiliation: Rockefeller University, New York City, NY, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Charles
authors.affiliation: University of Florence, Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gragnani
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Terrier
authors.affiliation: Liver Unity, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Piazzola
authors.affiliation: Rockefeller University, New York City, NY, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Dustin
authors.affiliation: University of Southampton, Southampton, UK.
authors.forename: S I
authors.initials: SI
authors.lastname: Khakoo
authors.affiliation: Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Busch
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Lauer
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Toulouse III University, CHU Purpan Hospital, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Alric
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institution, Baltimore, MD, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Thomas
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Duggal
mesh_terms: D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003449:Cryoglobulinemia / Q000209:etiology / Q000235:genetics; D003450:Cryoglobulins / Q000032:analysis*; D005260:Female; D005802:Genes, MHC Class II; D055106:Genome-Wide Association Study; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics; D014657:Vasculitis / Q000209:etiology / Q000235:genetics*
chemical_list: D003450:Cryoglobulins; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch