Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

Zhao, Lue Ping; Papadopoulos, George K.; Kwok, Bill; Xu, Bryan; Kong, Matthew; Moustakas, Antonis K.; Bondinas, George P.; Carlsson, Annelie; Larsson, Helena Elding; Ludvigsson, Johnny; Marcus, Claude; Persson, Martina; Samuelsson, Ulf; Wang, Ruihan; Pyo, Chul‐Woo; Nelson, Wyatt C.; Geraghty, Daniel E.; Lernmark, Åke

doi:10.2337/db19-0273

Cited by 14 publications

(22 citation statements)

References 53 publications

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“…To reduce the challenges of excessive polymorphisms and strong associations with HLA loci (e.g. HLA-DRB1 ), we used a “virtual reference” of the null association, and computed odds ratio (OR) as the ratio of a case frequency over a control frequency of the same residue [6] . To evaluate the significance of the estimated odds ratio (OR), we computed haplotype-based score statistic (Z-score) that was used to compute p-values under the assumption of normality.…”

Section: Methodsmentioning

confidence: 99%

The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

et al. 2021

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Background HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. Methods We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions. Findings Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The “KAG” motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10 −64 ). Three less frequent motifs (“EAV”, OR = 2.55, p = 0.025; “RAG”, OR = 1.93, p = 0.043; and “RAV”, OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs (“REG” and “REV”) were equally protective (OR = 0.11, p = 4.23 × 10 −4 ). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the “KAG” motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10 −14 ) after adjusting potential confounders. Interpretations DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65. Funding National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.

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Section: Methodsmentioning

confidence: 99%

The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

et al. 2021

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“…HLA-DQ genes are known to significantly contribute to susceptibility to islet autoimmunity and further to the progression to clinical onset of T1D, independently or jointly with HLA-DRB1 . The major finding through exploration of the protein sequences of DQA1 and DQB1 12 , 13 was that we identified, respectively, three and seven critical amino acid residues associated with T1D onset 14 , 15 . Integrating both sets of critical residues resulted in four alpha residues (αa1, α44, α157, α196) and five beta residues (β9, β30, β57, β70, β135) forming motifs that was associated with either susceptibility or resistance to T1D.…”

Section: Discussionmentioning

confidence: 94%

“…As expected, the ratio of its corresponding haplotype frequency among patients over that among controls equals one. Hence, the expected odds ratio for any given haplotype is thus computed as the ratio of two observed haplotype frequencies among patients and controls 14 .…”

Section: Methodsmentioning

confidence: 99%

“…Conventionally, DQ molecules exhibit stronger empirical associations with T1D. Our recent effort focused on identification of specific DQ risk residues among subjects with high-risk HLA-DQ haplotypes (DQ2.5 and DQ8.1) 12 as well as those resistant residues among subjects with low risk HLA-DQ haplotypes 13 , complementing earlier works on HLA-DR molecules 14 , 15 .…”

Section: Introductionmentioning

confidence: 92%

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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

Papadopoulos

Moustakas

et al. 2021

Sci Rep

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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.

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“…When computing haplotype-specific odds ratios, a "virtual null haplotype" under the null hypothesis is chosen as the reference haplotype, as explained earlier (7). Table S1 list individual DQ haplotypes in those selected DQ clusters, with respect to their polymorphic residues within clusters.…”

Section: Supplementary Description To Statistical Analysis and Softwarementioning

confidence: 99%

Next generation HLA sequence analysis uncovers seven HLA-DQ amino acid residues and six motifs resistant to childhood type 1 diabetes

Admin¹,

Zhao²,

Papadopoulos³

et al. 2020

Preprint

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HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif “DAAFYDG”, “DAAYHDG” and “DAAYYDR” have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif “DAAYHDG” to “DAAYHSG” (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher’s p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, b167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

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Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

Cited by 14 publications

References 53 publications

The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

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

Next generation HLA sequence analysis uncovers seven HLA-DQ amino acid residues and six motifs resistant to childhood type 1 diabetes

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