Abstract
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.
Highlights
The 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
Not all HLA-DR3 or -DR4 positive haplotypes are predisposing [3,4]. This might suggest the role of other Major Histocompatibility Complex (MHC) loci responsible for modifying the susceptibility to diabetes conferred by class II genes, but their search has been difficult due to the strong linkage disequilibrium (LD) present in this chromosomal region
We first aimed to corroborate in the Spanish population the published increased risk to autoimmune diabetes of the AH 18.2, as compared to other DR3-positive haplotypes [6]
Summary
The 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. Among the genetic determinants of susceptibility, with more than 18 putative loci identified to date, a region in chromosome 6p21 (IDDM1) containing the Major Histocompatibility Complex (MHC) is the only one consistently associated with T1D in genome-wide screenings. More than 90% of Caucasoid type 1 diabetic patients have at least one copy of the class II HLA-DR3 or DR4 allele, as compared to the 45% present in the general population and the genotype frequency of the DR3/DR4 heterozygote in T1D patients is 40% vs 3% in controls [2]. Not all HLA-DR3 or -DR4 positive haplotypes are predisposing [3,4] This might suggest the role of other MHC loci responsible for modifying the susceptibility to diabetes conferred by class II genes, but their search has been difficult due to the strong linkage disequilibrium (LD) present in this chromosomal region. Additional MHC haplotypes question the paradigm of class II genes as sole responsible for the association and open up the possibility that class III susceptibility factors would be involved
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