Distribution Of HLA Haplotypes Research Articles

An intermediate-sized donor registry experience: HLA barriers in matching procedures.

The data enabling the estimation of the possibility of finding a matched unrelated donor (MUD) within a relatively short time is important for the success of hematopoietic stem cell transplantation (HSCT). In the present study, 738 unrelated Croatian patients in the program of unrelated HSCT were retrospectively analyzed for gender matching, donor origin (national or international), the distribution of HLA alleles and haplotypes, as well as for the probability of finding a 9-10/10 MUD. Almost 70% of the patients in our study group had a 10/10 MUD, while among the patients with a 9/10 MUD, a 1st field resolution level mismatched donor was selected for 55.0% of patients. The majority of pairs were HLA-A mismatched (33.8%). A comparison of HLA allele frequencies between two subgroups of patients revealed significant differences for 13 alleles. However, after p value correction, the difference in frequency remained significant only for four alleles; three HLA alleles (B*08:01, C*07:01, and DRB1*03:01) demonstrated a significantly higher frequency among patients with a 10/10 MUD (Pcorr < 0.0001, Pcorr = 0.0096, and Pcorr < 0.0001, respectively), while the B*35:08 allele was significantly more present among patients with a 9/10 MUD (Pcorr = 0.0328). The comparison of the distribution of HLA haplotypes between patients with a 10/10 MUD and patients with a 9/10 MUD showed significant differences for a number of two-locus and three-locus haplotypes, as well as for one five-locus haplotype (HLA-A*01:01~B*08:01~C*07:01~DRB1*03:01~DQB1*02:01), which was significantly more present in the group of patients with a 10/10 MUD. At least one HLA haplotype from the group of non-frequent HLA haplotypes (positions >1000) was carried by patients with a 9/10 MUD. The data obtained by the present study will contribute to a better estimation of the probability of finding a suitable 9-10/10 MUD for Croatian patients in need of HSCT.

HLA-based banking of induced pluripotent stem cells in Saudi Arabia

BackgroundHuman iPSCs' derivation and use in clinical studies are transforming medicine. Yet, there is a high cost and long waiting time associated with autologous iPS-based cellular therapy, and the genetic engineering of hypo-immunogenic iPS cell lines is hampered with numerous hurdles. Therefore, it is increasingly interesting to create cell stocks based on HLA haplotype distribution in a given population. This study aimed to assess the potential of HLA-based iPS banking for the Saudi population.MethodsIn this study, we interrogated the HLA database of the Saudi Stem Cell Donor Registry (SSCDR), containing high-resolution HLA genotype data from 64,315 registered Saudi donors at the time of analysis. This database was considered to be a representative sample of the Saudi population. The most frequent HLA haplotypes in the Saudi population were determined, and an in-house developed iterative algorithm was used to identify their HLA matching percentages in the SSCDR database and cumulative coverage. Subsequently, to develop a clinically relevant protocol for iPSCs generation, and to illustrate the applicability of the concept of HLA-based banking for cell therapy purposes, the first HLA-based iPS cell line in Saudi Arabia was generated. Clinically relevant methods were employed to generate the two iPS clones from a homozygous donor for the most prevalent HLA haplotype in the Saudi population. The generated lines were then assessed for pluripotency markers, and their ability to differentiate into all three germ layers, beating cardiomyocytes, and neural progenitors was examined. Additionally, the genetic stability of the HLA-iPS cell lines was verified by comparing the mutational burden in the clones and the original blood sample, using whole-genome sequencing. The standards set by the American College of Medical Genetics and Genomics (ACMG) were used to determine the clinical significance of identified variants.ResultsThe analysis revealed that the establishment of only 13 iPSC lines would match 30% of the Saudi population, 39 lines would attain 50% coverage, and 596 lines would be necessary for over 90% coverage. The proof-of-concept HLA-iPSCs, which cover 6.1% of the Saudi population, successfully demonstrated pluripotency and the ability to differentiate into various cell types including beating cardiomyocytes and neuronal progenitors. The comprehensive genetic analysis corroborated that all identified variants in the derived iPSCs were inherently present in the original donor sample and were classified as benign according to the standards set by the ACMG.ConclusionsOur study sets a road map for introducing iPS-based cell therapy in the Kingdom of Saudi Arabia. It underscores the pragmatic approach of HLA-based iPSC banking which circumvents the limitations of autologous iPS-based cellular therapies. The successful generation and validation of iPSC lines based on the most prevalent HLA haplotype in the Saudi population signify a promising step toward broadening the accessibility and applicability of stem cell therapies and regenerative medicine in Saudi Arabia.

Immunogenetic characteristics of hematopoietic stem cell donors representing the most numerous ethnic groups in Russia

Development of criteria for the optimal donor selection based on the analysis of the allo-HSCT results, high-resolution HLA typing for the donor and recipient resulted in decreased incidence of immunological complications, primarily an acute «graft-versus-host reaction». However, due to the pronounced allelic polymorphism of the main histocompatibility complex (MHC) genes, the search for an optimal donor is ineffective in a number of patients. To increase the chances of selecting a donor for patients with rare HLA genotypes, the hematopoietic stem cell donor registries recruit the persons of various nationalities. An increased number of donors from different ethnic groups provide a broader immunogenetic diversity of the donor cohort. Currently, the registry of hematopoietic stem cell donors at the Russian Research Institute of Hematology and Transfusiology includes representatives of 49 nationalities, most of which, are considered themselves Russians. The third largest ethnic group in the registry comprises Tatars. The purpose of this study is a comparative analysis of immunogenetic characteristics of potential hematopoietic stem cells donors in the registry, who have self-identified as Russians and Tatars. As a result of the study, we have not found significant differences in frequencies of HLA allelic groups in the compared cohorts, a trend for higher frequency of the HLA-B*27 group was noted in Tatars. However, significant differences have been revealed for the distribution of HLA haplotypes in Russians and Tatars. The most common HLA haplotype among Tatars was A*02-B*44-DRB1*07, being much less common in Russians (4.61% vs 0.55%, p = 0.002). HLA haplotype A*03-B*13-DRB1*07, belonging to the ten most common among Tatars, was significantly less frequently detected in Russians (1.62% vs 0.08%, p = 0.026). HLA haplotype A*03-B*08-DRB1*03 was also significantly more common in Tatars compared to Russians (1.42% vs 0.06%, p = 0.026). HLA haplotypes A*02-B*18-DRB1*11, A*02-B*15-DRB1*04, A*02-B*15-DRB1*13, presented in Russians at a frequency of &gt; 1%, were not determined among the tested Tatars. HLA haplotypes A*31-B*58-DRB1*04, A*24-B*44-DRB1*01, presented in Tatars at a frequency of &gt; 1%, were not detectable in Russians. The results of our study indicate a need for recruiting more representatives of the Tatar ethnicity to the registry, thus increasing immunogenetic diversity of the donor pool and resulting into increased chances of compatible unrelated donor selection for the patients with HLA haplotypes, which are now underrepresented in our registry.

Multilocus HLA haplotypes &lt;i&gt;(A-B-C-DRB1-DRB3/DRB4/DRB5-DQA1-DQB1-DPA1-DPB1)&lt;/i&gt; in families of patients scheduled for allogeneic hematopoietic stem cell transplantation

HLA haplotype is a block of HLA genes located on the same chromosome. Highly polymorphic HLA genes display strong linkage disequilibrium, which results in conserved multilocus HLA haplotypes. Assessment of HLA haplotypic diversity of a specific population is important, particularly for allogeneic hematopoietic stem cell transplantation. Family pedigrees remain the gold standard for studying HLA haplotype segregation. HLA haplotypes, obtained by observations of the segregation of HLA alleles within the family, really exist in the human population. The aim of this work has been to establish the frequencies of HLA haplotypes A-B-C-DRB1-DRB3/DRB4/DRB5-DQA1-DQB1-DPA1-DPB1 in families of patients with assignment to HLA-typing for allogeneic hematopoietic stem cell transplantation. The study included 109 families of patients, in which patients and their potential relative donors of allogeneic hematopoietic stem cell were subjected to HLA-typing. Patients and members of their families were typed by the NGS method in the Laboratory of Tissue Typing at the National Medical Research Center for Hematology for 11 HLA genes – A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1 and DPB1. The genotyping was performed by the NGS method using the AllType NGS 11 Loci Amplification Kits (One Lambda, USA) on the MiSeq sequencing platform (Illumina, USA). The sequences were analyzed using the TypeStream Visual Software (TSV) (One Lambda, USA) and the IPD-IMGT/HLA database 3.44. 360 copies of HLA-haplotypes were found in the studied families. The frequencies of HLA haplotypes were determined by direct counting. The most common 7-locus haplotype was A*01:01-B*08:01-C*07:01-DRB1*03:01-(DRB3*01:01-DQA1*05:01)-DQB1*02:01/163N, the most common 9-locus haplotype was A*03:01-B*07:02-C*07:02-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02-DPA1*01:03-DPB1*04:01P. These HLA haplotypes (in brief, A-B-C-DRB1-DQB1) are the first and second most common HLA haplotypes in most Russian registries of bone marrow donors. Despite several differences, the distribution of HLA haplotypes in families of the patients and in donor registries is similar, and the probability of finding a compatible donor for patients with common HLA-haplotypes in Russian registries is quite high. Most of 7-locus haplotypes are associated with different alleles of the HLA-DP locus in the 9-locus haplotypes, due to presence of a recombination hot spot. The study revealed strong linkage disequilibrium between the HLA alleles DRB1*03:01 and DPB1*01:01P (D’ = 0.579), DRB1*07:01, and DPB1*17:01 (D’ = 0.808), DRB1*09:01 and DPB1*04:02P (D’ = 0.502). The information obtained about real 7- and 9-locus HLA-haplotypes in families may be used in clinical practice as a reference for analyzing the results of HLA-typing and predicting the expected HLA-haplotypes. It has been shown that, despite recombination hot spot between the HLA-DP locus and the rest of the HLA complex, there is strong linkage disequilibrium between some alleles of the DRB1 and DPB1 genes.

Computationally Optimized SARS-CoV-2 MHC Class I and II Vaccine Formulations Predicted to Target Human Haplotype Distributions.

SummaryWe present a combinatorial machine learning method to evaluate and optimize peptide vaccine formulations for SARS-CoV-2. Our approach optimizes the presentation likelihood of a diverse set of vaccine peptides conditioned on a target human-population HLA haplotype distribution and expected epitope drift. Our proposed SARS-CoV-2 MHC class I vaccine formulations provide 93.21% predicted population coverage with at least five vaccine peptide-HLA average hits per person (≥ 1 peptide: 99.91%) with all vaccine peptides perfectly conserved across 4,690 geographically sampled SARS-CoV-2 genomes. Our proposed MHC class II vaccine formulations provide 97.21% predicted coverage with at least five vaccine peptide-HLA average hits per person with all peptides having an observed mutation probability of ≤ 0.001. We provide an open-source implementation of our design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in our design efforts here: https://github.com/gifford-lab/optivax.

HLA Haplotype Association with Celiac Disease in Albanian Pediatric Patients from Kosovo.

Genetic predisposition to celiac disease (CD) is strongly associated with the presence of HLA alleles in the individual genotype encoding HLA-DQ2 and/or HLA-DQ8 heterodimers. The main aim of this study was to analyze the HLA-A, -B, -DRB1, and -DQ allele and five-locus haplotype frequencies in 60 Albanian pediatric CD patients and 124 non-CD children from Kosovo. The most prevalent haplotype in patients was the ancestral AH 8.1 haplotype present in 22.5% of the cases compared to 2.8% of the controls (P < 0.0001). Additionally, two other haplotypes were also overrepresented in patients (HLA-A∗02~B∗50~DRB1∗07~DQA1∗02:01~DQB1∗02:02 and HLA-A∗68~B∗44~DRB1∗07~DQA1∗02:01~DQB1∗02:02). Analysis showed that 95.0% of CD patients and 43.3% of controls were carriers of HLA-DQ2 and/or HLA-DQ8 heterodimers. The most frequent CD-predisposing HLA-DQ haplotypes in patients were HLA-DQ2.5 (46.7%) and HLA-DQ2.2 (11.6%), while the most prevalent genotypes were HLA-DQ2.5/DQX (58.3%) and HLA-DQ2.5/DQ2.2 (20.0%). The frequency of the HLA-DQ8 heterodimer among CD patients (4.2%) compared to the control group (8.1%) was without statistical significance. The given data demonstrate differences in the distribution of HLA haplotypes among Albanian CD patients from Kosovo in comparison to other European and non-European populations, as well as provide additional population data to supplement the thus far undisputed importance of the role of HLA-DQ2 and HLA-DQ8 heterodimers in the development of CD.

Next Generation Sequencing in HLA haplotype distribution among Telugu speaking population from Andhra Pradesh, India

HLA A:B:C:DRB1:DQB1 allele and haplotype frequencies were determined among India, Andhra Pradesh, Telugu speaking population from South India by Next Generation Sequencing. 180 bone marrow registry donors and 6 cord blood units from Jeevan Stem Cell Foundation (part of Be The Cure Registry), Chennai, Tamilnadu state were included in the study.

The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME).

The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indígena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies.

Is HLA the cause of the high incidence of type 1 diabetes in the Canary Islands? Results from the Type 1 Diabetes Genetics Consortium (T1DGC)

IntroductionIncidence of childhood-onset type 1 diabetes mellitus in the Canary Islands is the highest reported so far in Spain, and among the highest worldwide. The HLA region accounts for approximately half the genetic risk of type 1 diabetes. Our aim was to assess distribution of high-risk and protective HLA haplotypes in the Canarian families included in the T1DGC, as compared to the rest of Spain. MethodsThe T1DGC study, an international project to study the genetics and pathogenesis of type 1 diabetes, enrolled more than 3000 families with type 1 diabetes worldwide. Spain provided 149 of these families, of whom 42 were from Tenerife and Gran Canaria. HLA was genotyped centrally using a PCR-based, sequence-specific oligonucleotide probe system. Haplotypes were reconstructed using the deterministic algorithm alleHap in the R programming environment. Based on prior T1DGC results in Caucasian population, haplotypes DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB1*0302, DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0402-DQA1*0301-DQB1*0302 and DRB1*0404-DQA1*0301-DQB1*0302 were considered high-risk. DRB1*0701-DQA1*0201-DQB1*0303, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*1104-DQA1*0501-DQB1*0301, DRB1*1303-DQA1*0501-DQB1*0301, DRB1*1301-DQA1*0103-DQB1*0603 and DRB1*0403-DQA1*0301-DQB1*0302 were considered protective. The distribution of protective, high-risk, and other haplotypes in the (first two) affected siblings and unaffected parents from Canarian and non-Canarian Spanish families was compared (Chi-square test). ResultsNo significant differences were found between the regions in distribution of the HLA haplotypes in the affected siblings or in the non-affected parents. ConclusionsThe high incidence of childhood-onset type 1 diabetes in the Canarian population does not appear to be explained by a greater prevalence of high-risk class II HLA haplotypes in families with the disease. However, sample size limits the differences that can be detected in this study.

Is HLA the cause of the high incidence of type 1 diabetes in the Canary Islands? Results from the Type 1 Diabetes Genetics Consortium (T1DGC)

IntroductionIncidence of childhood-onset type 1 diabetes mellitus in the Canary Islands is the highest reported so far in Spain, and among the highest worldwide. The HLA region accounts for approximately half the genetic risk of type 1 diabetes. Our aim was to assess distribution of high-risk and protective HLA haplotypes in the Canarian families included in the T1DGC, as compared to the rest of Spain. MethodsThe T1DGC study, an international project to study the genetics and pathogenesis of type 1 diabetes, enrolled more than 3000 families with type 1 diabetes worldwide. Spain provided 149 of these families, of whom 42 were from Tenerife and Gran Canaria. HLA was genotyped centrally using a PCR-based, sequence-specific oligonucleotide probe system. Haplotypes were reconstructed using the deterministic algorithm alleHap in the R programming environment. Based on prior T1DGC results in Caucasian population, haplotypes DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB1*0302, DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0402-DQA1*0301-DQB1*0302 and DRB1*0404-DQA1*0301-DQB1*0302 were considered high-risk. DRB1*0701-DQA1*0201-DQB1*0303, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*1104-DQA1*0501-DQB1*0301, DRB1*1303-DQA1*0501-DQB1*0301, DRB1*1301-DQA1*0103-DQB1*0603 and DRB1*0403-DQA1*0301-DQB1*0302 were considered protective. The distribution of protective, high-risk, and other haplotypes in the (first two) affected siblings and unaffected parents from Canarian and non-Canarian Spanish families was compared (Chi-square test). ResultsNo significant differences were found between the regions in distribution of the HLA haplotypes in the affected siblings or in the non-affected parents. ConclusionsThe high incidence of childhood-onset type 1 diabetes in the Canarian population does not appear to be explained by a greater prevalence of high-risk class II HLA haplotypes in families with the disease. However, sample size limits the differences that can be detected in this study.

Cord blood banking in Europe and worldwide: factors of organization and sustainability

BackgroundIn the public sector, currently almost 600,000 cord blood units (CBU's) in over 150 public cord blood banks (CBB's), and an estimated 1,000,000 CBU's is stored in over 200 private CBB's.Aims &amp; MethodsAn overview on current international state of public and private CB Banking including an outlook on different concepts of hybrid banking (public and private CB Banking combined) is given. Possible factors influencing financial sustainability and economic viability of CB Banks, i.e. cell count TNC, and HLA haplotype distribution) are taken into consideration.ConclusionsBanking CBU's with predominantly high TNC figures is one way to improve the business model of a public CB Bank, with regard to the establishment of financially sustainable operations. Current recruitment practices of storing low TNC count CBU's with rare HLA haplotypes for the sake of HLA diversity should be carefully scrutinized in this context.

Analysis of the adequate size of a cord blood bank and comparison of HLA haplotype distributions between four populations

The number of units and especially the number of different HLA haplotypes present in a cord blood (CB) bank is a crucial determinant of its usefulness. We generated data relevant to the development of our national CB in Finland. The HLA haplotype distribution was examined between specific populations. We developed graphical ways of data presentation that enable easy visualization of differences. First, we estimated the optimal size of a CB bank for Finland and found that approximately 1700 units are needed to provide a 5/6 HLA-matched donor for 80% of Finnish patients. Secondly, we evaluated HLA haplotype distributions between four locations, Finland, Japan, Sweden and Belgium. Our results showed that the Japanese Tokyo Cord Blood Bank differs in both the frequency and distribution of haplotypes from the European banks. The European banks (Finnish Cord Blood Registry, The Swedish National Cord Blood Bank, and Marrow Donor Program-Belgium) have similar frequencies of common haplotypes, but 26% of the haplotypes in the Finnish CB bank are unique, which justifies the existence of a national bank. The tendency to a homogenous HLA haplotype distribution in banks underlines the need for targeting recruitment at the poorly represented minority populations.

Primary sclerosing cholangitis in two brothers: report of a family with special emphasis on molecular HLA and MICA genotyping

Immune mechanisms play a role in the pathogenesis of primary sclerosing cholangitis (PSC), as suggested by its association with certain HLA haplotypes. Genetic predisposition is supported by its occurrence in families, but data are scarce. Our aim is to report on two brothers with PSC, and to investigate HLA and MICA alleles in this family. The clinical, biochemical, radiological, and pathological findings in two brothers with PSC as well as in their sister and parents were reviewed. Molecular genotyping of HLA class II and MICA alleles was performed in all five family members. In two brothers, p-ANCA positive PSC was found. The youngest also had ulcerative colitis, and had evolved into cirrhosis at the age of 17 years. Their mother had positive p-ANCA and mild cholestatic changes. Their father and sister were unaffected. Both brothers were homozygous for the MICA*00801 allele, and were positive for the susceptibility HLA haplotypes DR3-DQ2 and DR6-DQ6. Their unaffected father and sister both carried the protective DR4 allele. The presence of PSC in two brothers, and the distribution of HLA haplotypes and MICA alleles, adds supportive evidence for an immunogenetic origin of PSC.

HLA haplotypes in Koreans based on 107 families.

There are marked differences in the distribution of HLA haplotypes among different populations, and multilocus HLA haplotypes can best be studied by family analysis. In the present study, 107 Korean families were analyzed for HLA-A, B, C, DR, and DQ antigens and haplotypes. Allele frequencies of more than 10% for class I antigens were A2, A24, A33, B44, B62, Cwl, Cw7, Cw9, Cw10, and C blank (CBL) and those for class II antigens were DR4, DR8, DR13, DR15, DQ1, DQ3, DQ4 and DQ7. In the analysis of HLA haplotypes, 18 kinds of A-B-DR and 11 kinds of A-C-B-DR-DQ haplotypes occurred at frequencies of more than 1%, comprising 34% and 24% of the total theoretical haplotypes, respectively. The five most common A-B-DR haplotypes were exclusively related with the five most common A-C-B-DR-DQ haplotypes (frequency>2%). These remarkably conserved five-locus haplotypes in Koreans were A33-CBL-B44-DR13-DQ1 (5.4%), A24-Cw7-B7-DR1-DQ1 (3.5%), A33-Cw7-B44-DR7-DQ2 (3.0%), A33-Cw10-B58-DR13-DQ1 (2.3%), and A30-Cw6-B13-DR7-DQ2 (2.3%). Comparison of the distribution of A-B-DR haplotypes among East Asian populations revealed that Koreans are closest to Japanese, but show a higher degree of polymorphism in the distribution of HLA haplotypes compared to Japanese. The results obtained in this study will be useful as basic data on Koreans for anthropology and organ transplantation.

Analysis of nuclear families with two and more diabetic siblings with insulin dependent condition

HLA haplotype distribution was analyzed in nuclear families of patients with insulin-dependent diabetes mellitus. Sixteen families with two or more diabetic siblings were examined, a total of 69 subjects, 33 of these diabetic siblings and 36 normal subjects (siblings and parents). The data were processed using the involved sibling pairs method based on a mixed model making use of a conditional probability approach. The ratio of diabetic sibling pairs concordant by 2 haplotypes, 1 haplotype, and discordant by 2 haplotypes was 9:5:2 vs. 1:2:1 expected according to Mendels accidental distribution (p 0.025). Increased incidence of siblings concordant by 2 haplotypes proves the presence in the HLA domain of one or several genes responsible for the development of diabetes mellitus. Siblings identical by two HLA haplotypes with the diabetic proband are at a higher risk of developing this disease.

RHEUMATOID ARTHRITIS IN THYROID DISEASE POSITIVE AND NEGATIVE SAME-SEXED SIBSHIPS

A total of 249 rheumatoid arthritis (RA) same-sexed sibships were clinically documented, HLA-typed and had auto-antibody screens performed. Sibships with a history of thyroid disease (TD) or significant thyroid antibodies were categorized as 'thyroid' sibships and the rest 'non-thyroid'. TD was more common in the female RA sibships than controls, particularly in the RA probands. The presence of thyroid microsomal antibody, but not thyroglobulin antibody, was significantly higher in all members of the female sibships, and in the probands and non-RA siblings of the male sibships. Comparing the thyroid and non-thyroid sibships, there was no significant difference in the distribution of HLA haplotypes in RA-RA sibling pairs, and HLA-DR status, clinical or immunological characteristics of the probands. These data do not support the concept that predisposition to RA in thyroid sibships might be non-DR4 or non-HLA linked.

Testicular germ cell tumors in HLA-genotype non-twin brothers

The diagnosis of metastatic testicular carcinoma in a thirty-three-year-old man and his nineteen-year-old brother is reported. Histologically, the tumor of the older brother consisted predominantly of embryonal carcinoma with minor components of seminoma and adult teratoma; the tumor of the younger brother consisted entirely of embryonal carcinoma. Since previous reports suggest the possibility that the HLA genotype may be a factor in the etiology of testicular cancer, we typed the parents and four children of this family. The two affected brothers shared a paternal HLA-A3,Cω-,B7,DR2 haplotype that had not been transmitted to the two other living siblings. Analysis of the distribution of HLA haplotypes of the affected non-twin brothers of this family and those of three other non-twin pairs of brothers that have been reported showed that the affected pairs in each family shared one HLA haplotype. The differences between the expected and the observed distribution of HLA haplotypes in the four sibling pairs is not statistically significant, perhaps because of the small number of patients typed. Two of the four pairs shared a common haplotype. Additional family studies are required to establish a genetic origin of testicular tumors and to determine whether or not a “testicular carcinoma disease” gene is linked to the HLA complex. A large number of multicase families will be required for linkage analysis.

Can the high risk of type I diabetes in Finland be explained by familial aggregation and by HLA haplotype distribution? Study Group on Childhood Diabetes in Finland.

Finland is the country which has the highest incidence of Type I (insulin dependent) diabetes in the world. The age-adjusted annual incidence in 1977 to 1984 was 30 per 100,000 in the age group 0–15 years (1). Finland is also one of the countries in the world where the incidence of Type I diabetes is rapidly increasing. The latest data from 1986 to 1987 indicate that the incidence is now about 40 per 100,000 which means about 350 new cases per year.

The genetics of Graves' disease: HLA and disease susceptibility.

To relate genetic variation in Graves' disease (GD) susceptibility to polymorphism at MHC loci, clinical and family studies were undertaken in eastern Hungary. Among 1980 relatives of 534 index patients, 2.9% of siblings, 2.7% of offspring, and 3.0% of parents had GD. HLA haplotype combinations in affected sibling pairs were determined in the present data and combined with data in the literature (12 sibling pairs from Farid 1981, 12 from Chan et al. 1980, and 15 from Sasazuki et al. 1983); 43, 23, and 1 affected sibling pairs shared, respectively, 2, 1, and 0 HLA haplotypes. This distribution is inconsistent with simple dominant inheritance, but is consistent with simple recessive inheritance of HLA-related susceptibility over a range of gene frequencies (0.2-0.4). A frequency of 0.3 gives the best fit and is consistent with penetrance of 7.1% for the recessive susceptibility genotype; the data, however, can accommodate penetrance values up to 16%. The distribution of HLA haplotypes in 33 families related disease susceptibility more strongly to DR than to other loci. The distribution of HLA-B8 genotypes in 256 patients was in close agreement with Hardy-Weinberg equilibrium proportions, also favoring recessive inheritance of MHC-related susceptibility. The probability that an individual will be affected with GD can be predicted, based on sex, HLA genotype, and family history. For example, 14.9% of DR3-positive women with an affected first degree relative are likely to be affected. These predictions can be tested as family data accumulate.

Genetics of HLA-associated disease; rheumatoid arthritis.

An association between rheumatoid arthritis (RA) and the HLA antigen DR4 supports the view that genes in the HLA region are important in susceptibility to this disease. To further define the basis for genetic susceptibility to RA, we analyzed HLA haplotype sharing among affected and unaffected individuals in 29 multiple-case families with definite or classic RA. We have observed a non-random distribution of HLA haplotypes to unaffected as compared with affected offspring in sibships containing two or more affected individuals having 3 of 4 parental haplotypes. These data support the view that susceptibility to RA is determined, at least in part, by genes in the HLA region of chromosome 6.