Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

TY - JOUR

T1 - Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

AU - Kristiansen, O P

AU - Karlsen, A E

AU - Larsen, Z M

AU - Johannesen, J

AU - Pociot, F

AU - Mandrup-Poulsen, Thomas

AU - Danish IDDM Epidemiology and Genetics Group and Danish Study Group of IDDM in Childhood

PY - 2004/6/1

Y1 - 2004/6/1

N2 - CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(-1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.

AB - CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(-1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.

KW - Adolescent

KW - Antigens, CD4

KW - Child

KW - Denmark

KW - Diabetes Mellitus, Type 1

KW - Female

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Mutation

KW - Polymerase Chain Reaction

KW - Polymorphism, Genetic

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Tandem Repeat Sequences

U2 - 10.1111/j.1365-3083.2004.01444.x

DO - 10.1111/j.1365-3083.2004.01444.x

M3 - Journal article

C2 - 15182254

SN - 0301-6323

VL - 59

SP - 582

EP - 591

JO - Scandinavian Journal of Immunology, Supplement

JF - Scandinavian Journal of Immunology, Supplement

IS - 6

ER -