Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity
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Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity. / Kristiansen, O P; Karlsen, A E; Larsen, Z M; Johannesen, J; Pociot, F; Mandrup-Poulsen, Thomas; Danish IDDM Epidemiology and Genetics Group and Danish Study Group of IDDM in Childhood.
I: Scandinavian Journal of Immunology, Bind 59, Nr. 6, 01.06.2004, s. 582-91.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 59
SP - 582
EP - 591
JO - Scandinavian Journal of Immunology, Supplement
JF - Scandinavian Journal of Immunology, Supplement
SN - 0301-6323
IS - 6
ER -
ID: 33902644