title: Killer immunoglobulin-like receptor locus polymorphisms in multiple sclerosis.
abstract: OBJECTIVE
  The objective of this study was to analyze whether inhibitory and activating killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I alleles defined by their KIR binding motifs are associated with multiple sclerosis (MS) susceptibility or severity.
  
  
  METHODS
  We performed a population-based case-control study in 321 patients with clinically isolated syndrome (CIS) and clinically definite MS (CDMS) and 156 healthy blood donors (HD). Inhibitory and activating KIRs and HLA class I alleles were genotyped using polymerase chain reaction (PCR) sequence-specific primers. Allelic frequencies were correlated with prevalence, age of onset, disability and disease duration of CIS and CDMS.
  
  
  RESULTS
  The frequency of the inhibitory KIR2DL3 gene was significantly reduced in patients with CIS and CDMS (p = 3.1 × 10(-5)). KIR2DL3-dependent risk reduction remained significant after elimination of patients carrying MS-associated DRB1*15, DRB1*03, DRB1*01 alleles. In addition, individuals carrying two copies for KIR2DL2/KIR2DS2 but lacking KIR2DL3 were overrepresented in the CIS/CDMS cohort. However, both genes did not affect disease risk in presence of KIR2DL3. We did not detect any association between the presence or absence of KIR genes with clinical disease parameters.
  
  
  CONCLUSIONS
  Absence of the inhibitory KIR2DL3 gene is associated with the development of CIS/CDMS. These findings, if confirmed in larger cohorts, suggest that KIR-mediated recognition of HLA class I molecules should be further explored as potential disease mechanism in MS.
authors.affiliation: Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ilijas
authors.initials: I
authors.lastname: Jelcić
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.forename: Kristina
authors.initials: K
authors.lastname: Kakalacheva
authors.forename: Petra
authors.initials: P
authors.lastname: Breiden
authors.forename: Bo
authors.initials: B
authors.lastname: Dupont
authors.forename: Markus
authors.initials: M
authors.lastname: Uhrberg
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Jan D
authors.initials: JD
authors.lastname: Lünemann
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D054340:Receptors, KIR / Q000235:genetics; D054344:Receptors, KIR2DL3 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D015236:HLA-C Antigens; C515078:KIR2DL3 protein, human; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3