| 1. |
- Alshiekh, Shehab, et al.
(author)
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High-resolution genotyping indicates that children with type 1 diabetes and celiac disease share three HLA class II loci in DRB3, DRB4 and DRB5 genes
- 2021
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In: HLA: Immune Response Genetics. - : Wiley. - 2059-2302. ; 97:1, s. 44-51
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Journal article (peer-reviewed)abstract
- Type 1 diabetes (T1D) and celiac disease (CD) share common genetic loci, mainly within the human leukocyte antigen (HLA) class II complex. Extended genotyping of HLA class II alleles and their potential risk for developing both diseases remains to be studied. The present study compared extended HLA-class II gene polymorphisms in children with T1D, CD, and a subgroup diagnosed with both diseases (T1D w/CD). Next-generation targeted sequencing (NGTS) of HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1, and DPB1 alleles from DNA collected from 68 T1D, 219 CD, and seven T1D w/CD patients were compared with 636 HLA-genotyped Swedish children from the general population selected as controls. In comparison to controls, the DRB4*01:03:01 allele occurred more frequently in T1D w/CD (odds ratio (OR) = 7.84; 95% confidence interval (95% CI) = (2.24, 34.5), P = 0.0002) and T1D (OR = 3.86; 95% CI, (2.69, 5.55), P = 1.07 × 10−14), respectively. The DRB3*01:01:02 allele occurred more frequently in CD as compared to controls (OR = 7.87; 95% CI, (6.17, 10.03), P = 4.24 × 10−71), but less frequently in T1D (OR = 2.59; 95% CI, (1.76, 3.81), P = 7.29 × 10−07) and T1D w/CD (OR = 0.87; 95% CI, (0.09, 3.96), P ≤ 0.999). The frequency of the DRB4*01:03:01-DRB1*04:01:01-DQA1*03:01:01-DQB1*03:02:01 (DR4-DQ8) haplotype was higher in T1D w/CD (OR = 12.88; 95% CI (4.35, 38.14) P = 3.75 × 10−9), and moderately higher in T1D (OR = 2.13; 95% CI (1.18, 3.83) P = 0.01) compared with controls, but comparable in CD (OR = 1.45; 95% CI (0.94, 2.21), P = 0.08) and controls. Children with T1D and CD are associated with DRB4*01:03:01, DRB3*01:01:02, and DRB3*02:02:01 of which DRB4*01:03:01 confers the strongest risk allele for developing T1D w/CD.
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| 2. |
- Alshiekh, Shehab, et al.
(author)
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High-resolution genotyping of HLA class I loci in children with type 1 diabetes and celiac disease
- 2021
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In: HLA: Immune Response Genetics. - : Wiley. - 2059-2302. ; 97:6, s. 505-511
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Journal article (peer-reviewed)abstract
- Objectives: HLA-DQ2 and DQ8 contribute to the strongest risk haplotypes for type 1 diabetes (T1D) and celiac disease (CD). The variation in genetic risk association is likely linked to different HLA class II loci susceptibility, but association studies of HLA class I alleles are scarce. The aim was to investigate HLA class I A, B, and C alleles polymorphisms in children with only T1D, CD, and a subgroup with both T1D and CD (T1D w/CD). Materials and methods: HLA class I A, B, and C genes were genotyped using next-generation targeted sequencing. A conditional analysis was performed on 68 children with T1D, 219 children with CD and seven children with T1D w/CD enrolled from a birth cohort study at high genetic risk children from the South of Sweden. Results: Among 1764 HLA class I allele variants, A*29:02:01 in T1D w/CD was associated with both T1D (OR = 21.42 [1.05, 1322.4], p = 0.0231) and CD (OR = 35 [2.36, 529.12], p = 0.0051) along with C*05:01:01 with both T1D (OR = 5.54 [1.06, 24.8], p = 0.02) and CD (OR = 6.84 [1.46, 26.01], p = 0.0077). No independent effects of HLA-B allele associations were observed in T1D w/CD. Conclusion: Although the distribution of HLA class I alleles differs between children with T1D and CD, the A*29:02:01 and C*05:01:01 alleles showed shared risk association of both diseases.
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| 3. |
- Akel, Omar, et al.
(author)
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High-resolution HLA class II sequencing of Swedish multiple sclerosis patients
- 2022
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In: International Journal of Immunogenetics. - : Wiley. - 1744-3121 .- 1744-313X. ; 49:5, s. 333-339
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype. Here, high-resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls. The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA-DR-DQ genotypes were found. Three extended HLA-DR-DQ genotypes were found to be correlated to MS; HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype together with. (A) HLA-DRB4*01:01:01//DRB4*01:01:01:01-DRB1*07:01:01-DQA1*02:01//02:01:01-DQB1*02:02:01,. (B) HLA-DRBX*null-DRB1*08:01:01-DQA1*04:01:01-DQB1*04:02:01, and. (C) HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01. At the allelic level, HLA-DRB3*01:01:02 was considered protective against MS. However, when combined with HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes. In conclusion, with 69 genotypes presented among 100 patients, high-resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01.
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| 4. |
- Lind, Alexander, et al.
(author)
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HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy
- 2019
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:10, s. 1-13
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Journal article (peer-reviewed)abstract
- The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.
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| 5. |
- Ping Zhao, Lue, et al.
(author)
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Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes
- 2017
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In: Diabetes/Metabolism Research Reviews. - : WILEY. - 1520-7552 .- 1520-7560. ; 33:8
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Journal article (peer-reviewed)abstract
- AimIt is of interest to predict possible lifetime risk of type 1 diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. MethodsUtilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing technology to genotype class II genes and applied an object-oriented regression to build and validate a prediction model for T1D. ResultsIn the training set, estimated risk scores were significantly different between patients and controls (P=8.12x10(-92)), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a biological validation by correlating risk scores with 6 islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score=3.628, Pamp;lt;0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying approximately 20 000 high-risk subjects after testing all newborns, and this calculation would identify approximately 80% of all patients expected to develop T1D in their lifetime. ConclusionThrough both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.
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| 6. |
- Ping Zhao, Lue, et al.
(author)
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Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes
- 2016
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 65:3, s. 710-718
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Journal article (peer-reviewed)abstract
- The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1-18 years with islet autoantibody-positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10(-36)), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.
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| 7. |
- Zhao, Lue Ping, et al.
(author)
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An Object-Oriented Regression for Building Disease Predictive Models with Multiallelic HLA Genes
- 2016
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In: Genetic Epidemiology. - : Wiley. - 0741-0395. ; 40:4, s. 315-332
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Journal article (peer-reviewed)abstract
- Recent genome-wide association studies confirm that human leukocyte antigen (HLA) genes have the strongest associations with several autoimmune diseases, including type 1 diabetes (T1D), providing an impetus to reduce this genetic association to practice through an HLA-based disease predictive model. However, conventional model-building methods tend to be suboptimal when predictors are highly polymorphic with many rare alleles combined with complex patterns of sequence homology within and between genes. To circumvent this challenge, we describe an alternative methodology; treating complex genotypes of HLA genes as "objects" or "exemplars," one focuses on systemic associations of disease phenotype with "objects" via similarity measurements. Conceptually, this approach assigns disease risks base on complex genotype profiles instead of specific disease-associated genotypes or alleles. Effectively, it transforms large, discrete, and sparse HLA genotypes into a matrix of similarity-based covariates. By the Kernel representative theorem and machine learning techniques, it uses a penalized likelihood method to select disease-associated exemplars in building predictive models. To illustrate this methodology, we apply it to a T1D study with eight HLA genes (HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) to build a predictive model. The resulted predictive model has an area under curve of 0.92 in the training set, and 0.89 in the validating set, indicating that this methodology is useful to build predictive models with complex HLA genotypes.
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| 8. |
- Zhao, Lue Ping, et al.
(author)
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Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1
- 2022
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 45:7, s. 1610-1620
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.RESULTS: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10-4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10-3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10-3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.CONCLUSIONS: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex.
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| 9. |
- Zhao, Lue Ping, et al.
(author)
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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
- 2019
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In: Diabetes. - Arlington, VA, United States : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:8, s. 1692-1704
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Journal article (peer-reviewed)abstract
- Next-generation targeted sequencing of HLA-DRB1 and HLA-DRB3, -DRB4, and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity as a result of high polymorphisms and extended linkage disequilibrium among the DR loci, we applied a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease-associated DR sequences and identifies 11 residues of DRB1, sequences of which retain all significant associations observed by DR genes. Furthermore, all 11 residues locate under/adjoining the peptide-binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. The 15 residues of DRB345, located respectively in the beta 49-55 homodimerization patch and on the face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds that DRB1 residues significantly associated with ZnT8A and DRB345 residues with GADA. The strongest association is between four residues (beta 14, beta 25, beta 71, and beta 73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15, P = 10(-18)), and another sequence, ERKG, confers a protective association (odds ratio 0.59, P = 10(-11)), despite a difference of only one amino acid. Because motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.
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| 10. |
- Zhao, Lue Ping, et al.
(author)
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HLA Class II (DR, DQ, DP) Genes Were Separately Associated With the Progression From Seroconversion to Onset of Type 1 Diabetes Among Participants in Two Diabetes Prevention Trials (DPT-1 and TN07)
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In: Diabetes Care. - 1935-5548.
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression.RESULTS: 1) The current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10-3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10-3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). 2) After adjusting for DQ, DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10-3, respectively). 3) DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02, sharing the DRB1*03:01, had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). 4) Through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression.CONCLUSIONS: These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.
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