Linkage and association between a CD4 gene polymorphism and IDDM in Danish IDDM patients. The Danish IDDM Epidemiology and Genetics Group, and The Danish Study Group of Diabetes in Childhood.

CD4+ T-cells play a central role in IDDM pathogenesis (1). Hence, gene polymorphisms that modulate the CD4 T-cell response to antigen presentation may confer susceptibility to IDDM. The CD4 receptor augments the CD4 T-cell receptor-mediated response to antigen presentation by interacting with major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and the T-cell receptor, and by enhancing the antigen response through the CD4-associated tyrosine-protein kinase p56 (2). The CD4 receptor gene maps to chromosome 12pl2 in humans and to chromosome 6 in mice (3,4) close to the diabetes-linked locus Idd6 in the nonobese diabetic (NOD) mouse (5). Furthermore, a chromosome 6 locus conferring susceptibility to diabetes was found in the nonobese, nondiabetic (NON) mouse (6). Maximal linkage was found <6 cM from the CD4 gene. Random marker genome studies in humans have not linked loci on chromosome 12p to IDDM (7,8). However, in a Belgian case-control study an association between IDDM and the CD4*A4/A4 genotype of a pentanucleotide repeat polymorphism, 1250 bp upstream to the first exon, was demonstrated, suggesting the existence of an IDDM susceptibility locus in the CD4 gene or in a closely linked gene (9). Thus, several lines of evidence qualify the CD4 gene as a candidate gene in IDDM. The aim of the present study was therefore to investigate if the CD4*A4 allele is associated with and/or linked to IDDM in the Danish population. The study material comprised two types of IDDM multiplex families of Danish Caucasian origin: 115 sibpair families with 237 affected (110 female subjects, 129 affected sibpairs) and 91 unaffected (46 female subjects) offspring, and 105 parentoffspring families with a total of 105 affected (55 female subjects) and 112 unaffected (55 female subjects) offspring. Mean