Polymorphisms of CXCR3-binding chemokines in type 1 diabetes.
Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease. Although the precise mechanisms leading to the destruction of islet beta cells are unknown, diverse studies support a role of the CXCR3-binding chemokines. A combination of a case (n = 447)-control (n = 300) and family (n = 221) analysis was performed to investigate the role of the CXCL9 (rs10336, rs3733236) and CXCL10 (rs3921, rs35795399 and rs8878) polymorphisms and their interaction with HLA high-risk haplotypes DQ2(DQA*0501-DQB*0201)-DQ8(DQA*0301-DQB*0302) in T1D. In addition, the mRNA expression of these genes and of the CXCR3 in peripheral blood mononuclear cells (PBMCs) of T1D patients was studied. In the family analysis, an overtransmission of the allele T and G of the polymorphisms rs35795399 and rs8878 in the whole group (p = 0.0520 and p = 0.0290, respectively) as well as in combination with the HLA-high risk haplotypes (p = 0.0209 and 0.0340, respectively) were observed. In addition, the haplotype rs8878G-rs35795399T was more often transmitted from parents to affected offspring, whereas the haplotype rs8878A-rs35795399C was less often transmitted (p = 0.0130 and p = 0.0201, respectively). Nevertheless these associations did not remain significant after correction for multiple testing, and they could not be corroborated in the case-control analysis. Although we did not find an association of the CXCL9 and CXCL10 polymorphisms with type 1 diabetes in the German population, we cannot discard their role in other populations or other autoimmune diseases.
Department of Internal Medicine IV, Division of Haematology and Oncology, University Hospital Giessen and Marburg, Germany.
Patrick
P
Brück
Wiebke
W
Bartsch
Marissa
M
Penna-Martinez
Heinrich
H
Kahles
Christian
C
Seidl
Angelika
A
Böhme
Klaus
K
Badenhoop
Elizabeth
E
Ramos-Lopez
D000328:Adult; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000235:genetics* / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D005858:Germany; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C053186:HLA-DQ2 antigen; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D012333:RNA, Messenger; D054367:Receptors, CXCR3