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BMC Genomics

, 6:56

First Online: 20 April 2005Received: 15 November 2004Accepted: 20 April 2005


BackgroundThe Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes T1D; genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4.

ResultsGenetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls p = 0.0019; odds ratio OR 95% confidence interval CI = 2.26 1.3–3.93. This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals p = 0.001; OR = 2.09 and by using the Arlequin software to check the DR3-positive haplotypes p = 0.004;OR = 1.93. The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population.

Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6-DR3-DQ2-DR4-DQ8 negative population. Several genetic markers in both MHC class II DQA1*0101-DQB1*0501 p = 0.007;OR = 2.81, DQA1*0201-DQB1*0202 p = 0.03; OR = 2.35 and III TNFa2b1 p = 0.01 OR = 2.74, BAT-2*2 p = 0.004; OR = 3.19 were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2. Finally, we studied a T1D susceptibility-protection marker located in extended class I, D6S2223; however, no association was observed in our population.

ConclusionOur results suggest that other associated MHC haplotypes might present susceptibility factors in loci different from HLA-class II and that the class II molecules are not necessarily the universal etiologic factor in every MHC haplotype.

AbbreviationsT1Dtype 1 diabetes

MHCMajor Histocompatibility Complex

HLAhuman leukocyte antigen

AHancestral haplotype

LDlinkage disequilibrium

TNFtumor necrosis factor

ORodds ratio

LTAlymphotoxin alpha.


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Autor: Elena Urcelay - José L Santiago - Hermenegildo de la Calle - Alfonso Martínez - Julián Méndez - José M Ibarra - Carlo

Fuente: https://link.springer.com/article/10.1186/1471-2164-6-56

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