KIR haplotypes are associated with late-onset type 1 diabetes in European-American families.
Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups.
Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.|Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
J A
JA
Traherne
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
W
W
Jiang
Academic Rheumatology, University of Nottingham, City Hospital, Nottingham, UK.
A M
AM
Valdes
Department of Neurology, University of California San Francisco School of Medicine, San Francisco, CA, USA.
J A
JA
Hollenbach
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
J
J
Jayaraman
Children's Hospital Oakland Research Institute, Oakland, California, USA.
J A
JA
Lane
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
C
C
Johnson
Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.|Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
J
J
Trowsdale
Children's Hospital Oakland Research Institute, Oakland, California, USA.
J A
JA
Noble
D017668:Age of Onset; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D054340:Receptors, KIR / Q000235:genetics* / Q000378:metabolism; D044465:White People
D006680:HLA Antigens; D054340:Receptors, KIR