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Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.

ABSTRACT: HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10^-20), "DQAA-YYARD" (OR = 3.34, 2.69*10^-72) and "DQDA-YYARD" (OR = 3.71, 1.53*10^-6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.

SUBMITTER: Zhao LP

PROVIDER: S-EPMC8065060 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.

Zhao Lue Ping LP Papadopoulos George K GK Moustakas Antonis K AK Bondinas George P GP Carlsson Annelie A Larsson Helena Elding HE Ludvigsson Johnny J Marcus Claude C Persson Martina M Samuelsson Ulf U Wang Ruihan R Pyo Chul-Woo CW Geraghty Daniel E DE Lernmark Åke Å

Scientific reports 20210423 1

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSAR ...[more]

PMID: 33893332

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Project description:ObjectiveType 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI).DesignThe type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized.SubjectsA total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated.ResultsOverall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (P<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1)03:02 genotype decreased with increasing BMI (P<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (P<0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing BMI (P<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased BMI was significant (P<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21-2.61; P<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age.ConclusionsSusceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.

Dataset Information

Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.

Publications

Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.

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