The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.
Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.
Laki
Judit
J
3rd Department of Medicine, Semmelweis University, and Buda Children's Hospital, Budapest, Hungary.
Kiszel
Petra
P
Vatay
Agnes
A
Blaskó
Bernadett
B
Kovács
Margit
M
Körner
Anna
A
Madácsy
László
L
Blatniczky
László
L
Almássy
Zsuzsa
Z
Szalai
Csaba
C
Rajczy
Katalin
K
Pozsonyi
Eva
E
Karádi
István
I
Fazakas
Adám
A
Hosszúfalusi
Nóra
N
Pánczél
Pál
P
Arason
Gudmundur J
GJ
Wu
Yee-Ling
YL
Zhou
Bi
B
Yang
Yan
Y
Yu
C-Yung
CY
Füst
George
G
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*
D006442:Glycated Hemoglobin; D006680:HLA Antigens; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic