title: Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency.
abstract: Variation in clinical phenotype is a hallmark of many complex diseases. The cause of this clinical heterogeneity is unknown, but it may be determined by genetic factors distinct from those conferring disease susceptibility. Common variable immunodeficiency (CVID) is a complex disease of unknown aetiology and diverse clinical manifestations. We have developed a unified polymerase chain reaction and sequence-specific primer (PCR-SSP) method to simultaneously genotype multiple polymorphisms under identical conditions, and have used this method to test the hypothesis that the clinical phenotype of CVID is determined by immunoregulatory gene polymorphism. Twenty-three polymorphisms in 13 genes were studied in 163 CVID patients. Vitamin D receptor and IL-6 alleles were associated with immunophenotypic abnormalities characteristic of more severe disease; and tumour necrosis factor and IL-10 alleles conferred susceptibility to the granulomatous form of CVID in an interacting fashion. These findings demonstrate that different clinical features of a disease may have unique pathogenetic abnormalities, determined by multiple interacting genetic factors. The ease of application of this efficient, robust genotyping technique to polymorphisms throughout the genome will make it a powerful tool in the investigation of the genetic basis of phenotypic variability in a wide variety of diseases.
authors.affiliation: Transplantation Immunology, Nuffield Department of Surgery, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
authors.forename: C G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: S E
authors.initials: SE
authors.lastname: Marshall
authors.forename: M
authors.initials: M
authors.lastname: Bunce
authors.forename: K I
authors.initials: KI
authors.lastname: Welsh
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D015331:Cohort Studies; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology; D017931:DNA Primers; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D018796:Immunoconjugates; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D019713:Receptors, CCR5 / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D006680:HLA Antigens; D018796:Immunoconjugates; D019713:Receptors, CCR5; D000069594:Abatacept