scholarly journals SAT-412 Genetic Susceptibility to Graves’ Disease Conferred by HLA-DQβ1 Position 57

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Klaus Badenhoop ◽  
Sarah Bee ◽  
cand med ◽  
Marissa Penna-Martinez
Keyword(s):  
Amino Acid ◽  
Disease Risk ◽  
Human Leukocyte ◽  
Graves Disease ◽  
Amino Acid Residues ◽  
Gender Stratification ◽  
Leukocyte Antigen ◽  
Amino Acid Variability ◽  
Significant Difference ◽  
Chi Squared

Abstract Introduction: Human leukocyte antigen (HLA) locus is the major genetic risk factor for autoimmune endocrine diseases. The amino acid variability at the HLA-DQβ1 position 57 encoded by both DQB1 alleles was identified as critical risk residue for type 1 diabetes. We therefore investigated this amino acid residue at HLA-DQβ1 position 57 in Graves’ disease (GD). Subjects and methods: DNA samples were obtained from 572 healthy controls (HC, 262 females/310 males) and 299 patients with GD (255 females/44 males) and genotyped for HLA-DQB1 using a sequence specific primer (SSP, 13 primer pairs) approach. The PCR amplified products were analyzed by gel electrophoresis. The HLA-DQB1 alleles were defined with their corresponding amino acid residues at the DQß chain positon 57 as follows: Ala57 (DQB1*0201,*0302), Asp57 (DQB1*0301,*0303,*0401,*0402,*0503,*0601,*0602*,0603) Val57 (DQB1*0501,*0604) and Ser57 (DQB1*0502). Finally, the frequencies for amino acid variabilities and their combinations (Ala/Ala, Ala/non-Ala and non-Ala/non-Ala) were calculated and compared by Pearson-Mantel-Haenszel Chi-squared test. Results: The presence of Ala57 was significantly more frequent in patients with GD compared to HC (25% vs. 39%, OR: 1.77; p=7x10-4), whereas Val57 was less frequent (19% vs. 12%, OR: 0.59; p=0.04). In contrast, no difference in the distribution between GD and HC concerning the amino acids Asp57 and Ser57 was observable. Similar results were found in female (Ala57 23% vs. 38%, OR:2.01; p=1.2x10-3 and Val57 19% vs. 13%, OR:0.35; p=1.2x10-4) but not in males (p >0.5). Furthermore, homozygous HLA-DQB1 Ala (8% vs. 15%, OR:1.98; p=5x10-3) as well as heterozygous HLA-DQB1 Ala/non-Ala (34% vs. 45%, OR:1.58; pc=5x10-3) were significantly more prevalent, while non-Ala/non-Ala (58% vs. 40%, OR:0.49 pc=3x5x10-6) was found to be less frequent in patients than in HC. By gender stratification there was a significant difference between female patients with GD and female HC in the distribution of the mentioned amino acid combinations (Ala p=4.5x10-3, Ala/non-Ala pc=0.02, non-Ala/non-Ala p=1x10-5). Conclusion: We identify a strongly predisposing role for HLA-DQβ1 Ala5 7to GD, particularly in women, highlighting the gender specific disease risk. Immunogenetic testing may pave the way towards personalized treatment.

scholarly journals HATK: HLA analysis toolkit

2020 ◽  
Author(s):  
Wanson Choi ◽  
Yang Luo ◽  
Soumya Raychaudhuri ◽  
Buhm Han
Keyword(s):  
Amino Acid ◽  
Fine Mapping ◽  
Disease Susceptibility ◽  
Human Leukocyte ◽  
Amino Acid Sequences ◽  
Hla Typing ◽  
Amino Acid Residues ◽  
Leukocyte Antigen ◽  
Mapping Analysis ◽  
Visualization Tools

Abstract Summary Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities, such as various association tests, visualization tools and nomenclature conversion. Availability and implementation https://github.com/WansonChoi/HATK.

scholarly journals Regression Mapping of Association between the Human Leukocyte Antigen Region and Graves Disease

2005 ◽  
Vol 76 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Matthew J. Simmonds ◽  
Joanna M.M. Howson ◽  
Joanne M. Heward ◽  
Heather J. Cordell ◽  
Helen Foxall ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Graves Disease ◽  
Leukocyte Antigen ◽  
Human Leukocyte Antigen Region ◽  
Regression Mapping

scholarly journals Binding of Human Thyrotropin Receptor Peptides to a Graves’ Disease-Predisposing Human Leukocyte Antigen Class II Molecule

2000 ◽  
Vol 85 (3) ◽  
pp. 1176-1179 ◽  
Author(s):  
Yoshikuni Sawai ◽  
Leslie J. DeGroot
Keyword(s):  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Graves Disease ◽  
T Cell Repertoire ◽  
Thyrotropin Receptor ◽  
Cell Repertoire ◽  
Peptide Epitopes ◽  
Leukocyte Antigen

Abstract Abstract There are many reports that Graves’ disease (GD) is associated with certain human leukocyte antigen (HLA) molecules, in particular DR3. Here we examined the characteristics of binding of human TSH receptor (TSHR) peptides to this disease-associated HLA class II molecule. DR3 molecules bind TSHR immuonodominant peptide epitopes with intermediate affinity. On the contrary, DR3 binds nonimmunogenic peptides either with poor affinity or not at all, with one exceptional peptide that has extremely high affinity. These results suggest that susceptibility to GD associated with inheritance of a specific HLA class II gene is due to the influence of the HLA molecule-TSHR peptide complex on the T cell repertoire.

scholarly journals Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis

2008 ◽  
Vol 68 (1) ◽  
pp. 107-109 ◽  
Author(s):  
K A Guthrie ◽  
N R Tishkevich ◽  
J L Nelson
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte Antigen ◽  
Age Of Onset ◽  
Human Leukocyte ◽  
Paternal Allele ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
The North ◽  
Significant Difference ◽  
Hla Genotype

Objectives:Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.Methods:We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).Results:Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.Conclusions:Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

scholarly journals The Human Leukocyte Antigen HLA DRB3∗0202/DQA1∗0501 Haplotype Is Associated with Graves’ Disease in African Americans

2000 ◽  
Vol 85 (4) ◽  
pp. 1545-1549 ◽  
Author(s):  
Qiao-Yi Chen ◽  
David Nadell ◽  
Xian-Yang Zhang ◽  
Anjli Kukreja ◽  
Yao-Jin Huang ◽  
...  
Keyword(s):  
African Americans ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Graves Disease ◽  
Leukocyte Antigen

scholarly journals The unusual association of Graves' disease, chronic spontaneous urticaria, and premature ovarian failure: report of a case and HLA haplotype characterization

2013 ◽  
Vol 57 (9) ◽  
pp. 748-752 ◽  
Author(s):  
Rosaria Maddalena Ruggeri ◽  
Giuseppe Vita ◽  
Anna Grazia D'Angelo ◽  
Paolina Quattrocchi ◽  
Rosaria Certo ◽  
...  
Keyword(s):  
Premature Ovarian Failure ◽  
Genetic Background ◽  
Marked Improvement ◽  
Human Leukocyte ◽  
Ovarian Failure ◽  
Chronic Spontaneous Urticaria ◽  
Graves Disease ◽  
Leukocyte Antigen ◽  
Unusual Association ◽  
Symptoms And Signs

Chronic spontaneous urticaria (CSU), defined as the occurrence of spontaneous wheals for more than six weeks, has been associated with autoimmune diseases. Herein, we report the unusual association of CSU, Graves' disease, and premature ovarian failure. Human leukocyte antigen (HLA) studies were performed. A 36-year-old woman presented symptoms and signs of hyperthyroidism for three months. In the same period, the patient complained of widespread urticarial wheals, intensely itchy, and poorly responsive to therapy with antihistaminic agents. Hyperthyroidism was confirmed biochemically, and treatment with methimazole was started. As hyperthyroidism improved, a marked improvement in her urticaria was also observed. However, the patient continued to complain of amenorrhea. Endocrine evaluation, at the age 38, was consistent with premature ovarian failure. This is the first report of coexistence of GD, CSU, and POF. The genetic background of such unusual association is a specific combination of HLA.

Purification, structural characterization, and myotropic activity of endothelin from trout, Oncorhynchus mykiss

1999 ◽  
Vol 277 (6) ◽  
pp. R1605-R1611 ◽  
Author(s):  
Yuqi Wang ◽  
Kenneth R. Olson ◽  
Michael P. Smith ◽  
Michael J. Russell ◽  
J. Michael Conlon
Keyword(s):  
Amino Acid ◽  
Vascular Tissue ◽  
Molecular Form ◽  
Posttranslational Processing ◽  
Amino Acid Residues ◽  
Steelhead Trout ◽  
Cardinal Vein ◽  
Significant Difference ◽  
Myotropic Activity ◽  
Branchial Artery

Endothelin (ET) from a nontetrapod species has never been characterized, either structurally or biologically. A single molecular form of trout ET with 21-amino-acid residues was isolated in pure form from an extract of the kidney of the steelhead trout, Oncorhynchus mykissand its primary structure established as Cys-Ser-Cys-Ala-Thr-Phe-Leu-Asp-Lys-Glu10-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile20-Trp. This amino acid sequence shows only three substitutions (Ala4→Ser, Thr5→Ser, and Phe6→Trp) compared with human ET-2, demonstrating that the structure of the peptide has been well conserved during evolution and that the pathway of posttranslational processing of preproendothelin in the trout is probably similar to that in mammals. Synthetic trout ET produced concentration-dependent constrictions of isolated rings of vascular tissue from trout efferent branchial artery (EBA; pD2 = 7.90 ± 0.06, n = 5), caeliacomesenteric artery (pD2 = 8.03 ± 0.04, n = 4), anterior cardinal vein (ACV; pD2 = 8.57 ± 0.25, n = 4), and rat abdominal aorta (AO; pD2 = 8.86 ± 0.08, n = 7). Trout and rat vessels were more sensitive to mammalian ET-1 than to trout ET (pD2 for human ET-1 in: EBA = 9.12 ± 0.14; ACV = 9.90 ± 0.15; AO = 8.86 ± 0.08), but there was no significant difference in the maximum tension produced by either peptide in these vessels.

scholarly journals An Intronic HCP5 Variant Is Associated With Age of Onset and Susceptibility to Graves Disease in UK and Polish Cohorts

2020 ◽  
Vol 105 (9) ◽  
pp. e3277-e3284 ◽  
Author(s):  
Laura Claire Lane ◽  
Aleksander Kuś ◽  
Tomasz Bednarczuk ◽  
Artur Bossowski ◽  
Jacek Daroszewski ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Graves Disease ◽  
Ribonucleic Acids ◽  
Young Onset ◽  
Leukocyte Antigen ◽  
Genotype Frequencies ◽  
The Uk

Abstract Context The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. Objective We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. Design and Participants rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. Results The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10–9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (&lt;30 years) (P allele=1.70 × 10–10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10–5) and age of onset (P allele=5.63 × 10–8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. Conclusion The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

scholarly journals A One-Tube Polymerase Chain Reaction Protocol Demonstrates CC Chemokine Overexpression in Graves’ Disease Glands

1999 ◽  
Vol 84 (8) ◽  
pp. 2873-2882
Author(s):  
Yaqoub Ashhab ◽  
Orlando Dominguez ◽  
Mireia Sospedra ◽  
Carme Roura-Mir ◽  
Anna Lucas-Martín ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Needle Aspiration ◽  
Graves Disease ◽  
Tissue Samples ◽  
Autoimmune Thyroid ◽  
Leukocyte Antigen ◽  
Cc Chemokine ◽  
Inflammatory Protein ◽  
Cc Chemokines ◽  
Polymerase Chain

An adaptation of mixed oligonucleotide primed amplification of complementary DNA to detect the profile of CC chemokines in biological samples is presented. By introducing normalization, two correction coefficients, performing a single amplification reaction, and five parallel hybridizations, intrasample and intersample comparisons can be reliably made. This protocol of single tube PCR CC chemokine profiling was applied to tissue samples from an autoimmune thyroid condition, Graves’ disease, and from a nonautoimmune condition, multinodular goiter. Results demonstrate overexpression of CC chemokines in Graves’ disease, statistically significant for macrophage inflammatory protein-1α and -1β, which correlated with the aberrant human leukocyte antigen class II expression by thyrocytes, as assessed by flow cytometry. Overexpression of CC chemokines probably plays a major role in determining the characteristics of the lymphocytes migrating to the thyroid gland and influences the course of the disease. The study of chemokine profile should be more informative than the study of isolated chemokines and cytokines, and as it can be applied to fine needle aspiration biopsies, it may be useful to clinical research.

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