The connection between HLA microsatellites and HLA-B*27 gene in patients with psoriatic arthritis in Croatian population

The polymorphism at HLA microsatellites (D6S248, D6S2674, D6S2811 and D6S273) among patients with psoriatic arthritis (PsA) (N = 22) and healthy control subjects (K; N = 94), as well as haplotypic associations between tested loci were analysed in this study. All subjects were previously typed for HLA-A and -B by PCR-SSP method and were HLA-B*27 positive. HLA microsatellites were analysed using PCR-STR method and electrophoresis in an ALFexpress sequencer. The results demonstrated statistically significant P value for following alleles: D6S273-3 (PsA-21.1% vs. K-4.9%; P = 0.0013) and D6S273-4 (PsA-15.8% vs. K-32.1%; P = 0.0180). Analysis of haplotypic associations showed the only statistically significant difference for combination HLA-B*27/D6S273-4 (PsA-10.5% vs. K-40.2%; P = 0.0164). The results presented in this study lead to the assumption that some other gene/s involved in ethiology of PsA are located in the proximity of D6S273 microsatellite, but in order to reach a final conclusion, an increase in the number of patients is necessary.     

Distribution of HLA-B*27 subtypes in Tunisians and their association with ankylosing spondylitis

ObjectiveThe human leukocyte antigen HLA-B27 is a class I antigen of the major histocompatibility complex strongly associated with ankylosing spondylitis (AS) and other related spondyloarthropathies (SpAs). The mechanism of this association remains unknown. HLA-B27 is a serologic specificity that represents a family of at least 25 different HLA-B27 alleles (2701–2725). These alleles are closely related by nucleotide sequence homology, but differ in ethnic distribution. The purpose of the present study is to investigate the distribution of HLA-B27 alleles in healthy controls and in patients with ankylosing spondylitis (AS).MethodsWe selected 160 HLA-B27-positive individuals (39 controls and 121 patients with ankylosing spondylitis). Typing of HLA-B27, and Cw alleles were performed by polymerase chain reaction amplification with sequence specific primers (PCR–SSP), and by serological typing (microlymphocytotoxicity).ResultsSeven B27 subtypes were identified: B*2702, 03, 04, 05, 07, 09 and B*2714. The distribution of these alleles in the population of patients was B*2702 (47.1%) and B*2705 (47.1%). These subtypes were also detected in 16 (41%) and 16 (41%), respectively of the 39 control subjects. HLA-B*2707 was detected in 4 (3.31%) patients and in 3 (7.6%) controls. B*2704, 09 and B*2714 were relatively rare and were detected in one subject each. No significant differences were noticed in the frequencies and distribution of HLA-B27 alleles between patients and controls.ConclusionsOur results show a restricted number of HLA B27 subtypes associated with AS. B*2702 and B*2705 were equally common in patients and controls. The most prominent B27/Cw haplotypes in the patient groups and controls were B*2702/Cw02022 and B*2705/Cw02022.     

HLA-A, -B, -DRB1 Allele and Haplotype Frequencies and Comparison With Blood Group Antigens in Dialysis Patients in the East Anatolia Region of Turkey

Aim

The first aim of that study was to investigate HLA class I and class II allele and haplotype frequencies in renal dialysis patients who live in East Anatolia in Turkey. Our second aim was to investigate whether there was a relationship between ABO and D blood group antigens and HLA alleles and haplotypes for the study group.

Materials and methods

HLA class I and II polymorphisms in 408 renal dialysis patients were studied using sequence-specific primers (SSP) and sequence-specific oligonucleotides (SSO). Blood group antigens were detected by agglutination methods on microplates.

Results

A total of 16 HLA-A, 34 HLA-B, and 15 HLA-DRB1 alleles were identified. The most frequent HLA-A alleles were HLA-A*02, HLA-A*24, and HLA-A*11. The most frequent HLA-B alleles were HLA-B*35, HLA-B*51, and HLA-B*44. In case of HLA-DRB1; HLA-DRB1*11, HLA-DRB1*04, and HLA-DRB1*13 were first 3 alleles with higher frequency, in order. In the combination of those 3 alleles, the most frequent HLA-A-B-DRB1 haplotypes were HLA-A*02-B*51-DRB1*11, HLA-A*11-B*35-DRB1*11, A*24-B*35-DRB1*11. The frequency of ABO, D blood group antigens were observed as 0.168 for A Rh(+), 0.019 for A Rh(−), 0.057 for B Rh(+), 0.013 for B Rh(−), 0.123 for O Rh(+), 0.014 for O Rh(−), 0.018 for AB Rh(+), and 0.001 for AB Rh(−). While A Rh(+) samples with HLA-A*02 and HLA-DRB1*11 had the highest frequencies (0.067 and 0.088, respectively), O Rh(+) samples with HLA-B*51 had the highest frequency (0.06).

Conclusion

According to haplotype frequencies HLA-A*02-B*51-DRB1*11 is also found at higher frequencies in Bulgarian and Armenian populations. In case of HLA-associated diseases, the east Anatolian population could be susceptible to myastenia gravis, Behçet's disease, and systemic sclerosis due to the high frequencies of HLA-A*24, HLA-B*51, and HLA-DRB1*11 respectively. We did not observe a correlation between blood group antigens and HLA alleles or haplotypes in renal dialysis patients.     

HLA alleles and haplotypes in the east Black Sea Turkish population

HLA class I and class II alleles were studied for the first time in 234 unrelated individuals inhabiting the East Black Sea region in Turkey. This region is on the historic silk road and close to Georgia. HLA class I (A* and B*) and class II DRB1* typing was done by the PCR-SSP method. A total of 17 HLA-A* alleles, 34 HLA-B* alleles, and 15 HLA-DRB1* alleles were detected. HLA-A*-B*, A*-DRB1*, and B*-DRB1* two-loci linkage disequilibrium data show that two specific combinations (A2-B35, A2-DRB1*11, and B35-DRB1*13) had the highest frequency (more than three or four times) compared with the other two-loci combinations, possibly reflecting an ancient founder effect. A*24 B*18 DRB1*13 and A*32 B*27 DRB1*11 were the most common haplotypes in the east Black sea Turkish population. HLA-B* showed the highest heterozygosity (94%) among the samples. The observed diversity in the HLA-A* and HLA-DRB1* loci was quite similar, ranging from 79% to 84%. We suggest that the east Black Sea Turkish population is characterized by the features of the Turkish anthropological type with some influence of other groups, such as Caucasians, Asians, and Mediterraneans.     

The distribution of HLA alleles class I and class II among patientes with psoriatic arthritis in Croatia

The aim of the present study was to analyze the distribution of HLA-A, -B, -Cw, and -DRB1 alleles among patients with psoriatic arthritis (PsA) in Croatia. DNA was isolated from peripheral blood of 58 PsA patients (28 male and 30 female) and tested by PCR-SSP (Polymerase Chain Reaction - Sequence Specific Primers) method for polymorphism of the above mentioned HLA loci. The strongest association between psoriatic arthritis and HLA in the Croatian population was observed for alleles at HLA-B locus (B*39 and B*57), while the association of B*27 and B* 13 alleles with PsA reached significance only before correction of p value with the number of tested alleles. Higher frequency of Cw*02 and DRB1*16 alleles is a result of linkage disequilibrium between these alleles and HLA-B alleles associated with PsA in Croatia. We also observed lower frequency of B*0702, B*18 and B*38 alleles in our group of patients.     

Association of Human Leukocyte Antigen Haplotypes With End-Stage Renal Disease in Vietnamese Patients Prior to First Transplantation

IntroductionThe prevalence of chronic kidney failure is significantly increasing in Vietnam, causing a burden for health care. This study assessed the relationship of HLA-A, -B, and –DRB1 alleles with end-stage renal disease (ESRD).MethodA retrospective, cross-sectional study and a comparative study using secondary data analysis were conducted on 196 ESRD patients and 187 controls from 2009 to 2017. The patient and donor profiles were collected from medical records, including age, sex, etiology of renal failure, and HLA phenotypes. HLA-A*, -B*, and -DRB1* typing were done by polymerase chain reaction-sequence specific primers.ResultThe most frequent HLA alleles in Vietnamese patients with ESRD were HLA-A*02, -A*11, -B*15, -B*46, -DRB1*04, -DRB1*09, and -DRB1*12. The haplotypes HLA-A*0233 (odds ratio [OR] = 0.40, 95% CI: 0.15–0.98) had a negative association for ESRD. The haplotypes HLA-B*1515 (OR = 4.14, 95% CI: 1.52–11.26) and HLA-DRB1*1212 (OR = 2.01, 95% CI: 1.06–3.81) had a positive association for ESRD. The haplotypes HLA-B*1515 (OR = 4.69, 95% CI: 1.69–13.03) and -DRB1*1212 (OR = 2.15, 95% CI: 1.10–4.21) had a positive association for ESRD related to glomerulonephritis. The HLA-B*1557 (OR = 17.34, 95% CI: 2.70–11.49) had a positive association for ESRD related to hypertension.ConclusionThe haplotypes of HLA class I and II had significant relationships with ESRD. The results of our study should be confirmed in further investigations.     

"Extended" A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk

To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk.     

The probability of HLA-C matching between patient and unrelated donor at the molecular level: estimations based on the linkage disequilibrium between DNA typed HLA-B and HLA-C alleles.

BACKGROUND: Recent evidence suggests a more significant role of HLA-C as a target of alloreactions after bone marrow transplantation than previously suspected. Although linkage disequilibrium (LD) between HLA-B and -C serogroups is well documented, the level of LD at the allelic level is not known. In this study, we determine the LD between HLA-B and -C alleles and estimate the probability of molecular HLA-C matching between unrelated individuals who match for both HLA-B alleles. METHODS: The study included 727 haplotypes from 849 individuals who were HLA-A, -B, -C and -DRB1 typed by high-resolution PCR-SSOP technique. Zelterman's statistic was used to test for global LD between HLA loci. LD between specific HLA-B and -C allelic combinations was calculated from their observed and expected frequencies in the study haplotypes. The probability of HLA-C matching for specific HLA-B allele was estimated from contingency table generated from the HLA-B and -C haplotypes. RESULTS: HLA-C was found to exist in LD with HLA-A and -B, as well as -DRB1, loci; however, it was strongest between HLA-B and -C loci. A marked variability in the level of LD between specific HLA-B and -C alleles was noticed. A strong LD was seen in some allele pairs like B*0702-C*w0702, B*3501-Cw*0401, and B*0801-Cw*0701. The overall estimated probability of HLA-C matching between unrelated individuals that match for both HLA-B alleles is 42.25%. For 237 (72.9%) of 325 combinations involving the 25 commonest HLA-B alleles, the estimated probability that the HLA-B-matched unrelated individuals will match for both HLA-C alleles is less than 50%. In addition, a 100% probability of matching for both HLA-C alleles is expected only if both individuals bear either B*0801/ B*0801 or B*4901/B*4901 or B*0801/B*4901. Probability tables for common alleles are presented. CONCLUSIONS: We conclude that, despite matching for both HLA-B alleles by high resolution DNA typing and the presence of a strong LD between HLA-B and HLA-C loci, unrelated individuals are more likely to mismatch rather than match for one or both HLA-C alleles.     

Distribution of HLA class II (DRB1/DQB1) alleles and haplotypes among Bahraini and Lebanese Arabs

The genetic relationship between Bahraini and Lebanese Arabs in terms of HLA class II (DRB1 and DQB1) gene and haplotype frequencies was investigated in a group of 90 Lebanese and 52 Bahraini Arabs. Subjects of both sexes were unrelated and HLA-DRB1 and DQB1 genes were genotyped using the polymerase chain reaction-sequence specific primer (PCR-SSP) technique. Analysis of the HLA-DRB1 alleles showed that the DRB1*040101 and DRB1*110101 alleles were more common among Lebanese, whereas DRB1*030101, DRB1*130701/1327, and DRB1*160101 alleles were more common among Bahrainis. Similarly, of the 7 HLA-DQB1 alleles analyzed, the presence of DQB1*0201 was higher among Bahrainis, whereas DQB1*030101 was higher among Lebanese. The DRB1*160101-DQB1*050101 (23.08%) and DRB1*030101-DQB1*0201 (21.15%) haplotypes were more frequent among Bahrainis, while the DRB1*110101-DQB1*030101 (56.67%), DRB1*040101-DQB1*0302 (28.89%) and DRB1*040101/DQB1*030101 (25.56%) haplotypes were more frequent in Lebanese subjects. Our results underline significant differences between these two populations in HLA class II distribution, and provide basic information for further studies of MHC heterogeneity among Arab-speaking countries, and as a reference for further anthropologic studies.     

Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B

Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)- and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association.     

Genetic Mechanisms Involved in the Generation of HLA Alleles in Brazilians: Description and Comparison of HLA Alleles

Background

The HLA genes show high levels of diversity as indicated by the number of HLA alleles. There are almost 11,000 classical HLA-A, -B, -DRB1 alleles in populations around the world, making the search for compatible donors difficult. HLA diversity is generated by different genetic mechanisms, such as point mutations, which result in single nucleotide polymorphisms, insertion and deletion, and recombination. The aim of this study was to describe genetic mechanisms involved in the generation of HLA alleles in Brazilians.

Strong linkage disequilibrium between HLA-B*3913 and DRB1*0807 in Brazilians

The purpose of this research was to study the HLA-B39 distribution in 2560 healthy, unrelated, randomly selected individuals living in the southeastern region of Brazil (the states of Rio de Janeiro and S?o Paulo). Molecular methods were used to type HLA class I and II polymorphism: PCR-SSP, PCR-SSO, and PCR-SBT. HLA-B*39 was found in 7% (n = 182) of these individuals. HLA-B*3901, B*3906, and B*3913 were the most common alleles in this group (n = 57, 36, and 24, respectively). B*3913 was found associated with DRB1*0807 and DQB1*0402 in 16 of the 24 individuals and 13 of these were also associated with A*31012. This haplotype segregation was confirmed by family studies. Furthermore, in 5 of the 13 individuals carrying the A*31012, B*3913, DRB1*0807, and DQB1*0402 haplotype, HLA-DPB1*2701 was also present, suggesting that these alleles were found preferentially in cis association. DRB1-DPB1 linkage disequilibrium analysis was performed in 420 of the 2560 individuals and the association of DRB1*0807 with the uncommon DPB1*2701 was found to be highly significant (P <.0001). Because HLA-B*3913 and HLA-DRB1*0807 have been observed only in South American populations, it is possible that interlocus association has been selected to act on the same haplotype to collaborate in the class I and II restricted immune response to local pathogens and functional adaptation. Although numbers are small to predict which ethnic groups of the Brazilian population display this haplotype prevalently, it is possible to speculate that these data may have clinical application, such as in the selection of unrelated donors for bone marrow transplantation.     

No independent association between HSP70 gene polymorphism and IDDM.

A role for heat shock proteins (HSPs) in autoimmunity has recently been suggested by several authors. Autoantibodies against HSPs have been associated with such autoimmune diseases as systemic lupus erythematosus, polymyositis, and the NOD mouse model of diabetes. Moreover, genes for the major 70,000-M(r) HSP (HSP70) are located within the MHC. To investigate a potential association of an HSP70-2 gene polymorphism with insulin-dependent diabetes mellitus (IDDM), we analyzed restriction-fragment-length polymorphism (RFLP) of this gene in 29 families with one or more member affected by IDDM. With the enzyme PstI, as reported previously, two HSP70-2 alleles of 8.5- and 9.0-kb were found. The 8.5-kb allele was found more frequently on diabetic haplotypes compared with control haplotypes (41 of 66 [62%] vs. 20 of 46 [43%], P = 0.03). This association was due to the conservation of alleles on extended haplotypes we previously reported to be associated with diabetes on initial analysis of families. Twenty-three of 26 diabetic DR3 haplotypes and 3 of 3 normal DR3 haplotypes and all instances of [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] had the 8.5-kb allele, whereas 0 of 9 normal DR2 haplotypes and 0 of 2 diabetic DR2 haplotypes had the 8.5-kb allele (P = 8 x 10(-7) DR3 vs. DR2 haplotypes). The alleles were equally distributed among DR4 haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of HLA-A, -B, -Cw, and -DRB1 alleles frequency in Turkish patients with nasal polyposis

OBJECTIVE: To evaluate whether there is a relationship between HLA-A, -B, -Cw, and -DRB1 alleles and developing nasal polyposis (NP). STUDY DESIGN: Data from 66 patients with NP were compared with data from 100 healthy randomly selected controls. Asthma, ASA (acetylsalicylic acid) triad, polyp score, and previous sinonasal surgery were also recorded. SUBJECTS AND METHODS: Genotyping of the HLA-A, -B, -Cw, and -DRB1 alleles were performed with polymerase chain reaction (PCR) with the sequence-specific primer (SSP) method. Data were analyzed by using a Pearson chi(2) test. RESULTS: The HLA-B*07 and -Cw*12 alleles were found to be significantly higher in the NP patients compared with the control group, whereas the HLA-B*57 and HLA-Cw*04 alleles were significantly lower (P < 0.05). The HLA-A*24, HLA-Cw*12, and HLA-DRB1*04 alleles were determined to be significantly higher in the NP patients with asthma and ASA triad (P < 0.05). CONCLUSIONS: Our results show that some of the HLA alleles seem to be associated with the genetic susceptibility to develop NP in the Turkish population.     

Association between type 1 diabetes age of onset and HLA among sibling pairs.

In this study, we report type 1 diabetes age-of-onset association with HLA class II (DRB1, DQB1, and DPB1) and class I (A) genes in 222 multiplex families from the Human Biological Data Interchange. Linear regression showed a small (R2 = 0.26) but significant correlation in the ages of onset among sib pairs. A strong association in age of onset between members of sib pairs was observed when the analysis was performed using contingency tables that split sibs into three age-at-onset ranges (0-10, 11-20, and 21-36 years). The association is strongest for sib pairs that share both haplotypes and is nonsignificant for sib pairs that do not share any DR-DQ haplotypes. A goodness-of-fit test revealed that DR-DQ haplotype sharing cannot account for all the association in age of onset among sib pairs. The age-of-onset distribution of DR-DQ haplotypes is affected by the DPB1 and A alleles present. The strongest associations were found with the A locus: DR3/DR4 genotype frequency decreases with age of onset in this data set only among A*0101- individuals, and A*2402 is strongly associated with younger age of onset in many DR-DQ haplotypes.     

Identification of HLA‐DR4‐restricted immunogenic peptide derived from xenogenic porcine major histocompatibility complex class I molecule

Park C‐S, Kim K‐H, Im S‐A, Song S, Lee C‐K. Identification of HLA‐DR4‐restricted immunogenic peptide derived from xenogenic porcine major histocompatibility complex class I molecule. Xenotransplantation 2012; 19: 317–322. © 2012 John Wiley & Sons A/S. Abstract: Indirect recognition of xenoantigens has been implicated as the major mechanism underlying xenospecific CD4⁺ T‐cell activation in chronic rejection. We identified swine leukocyte antigen (SLA)‐derived immunogenic peptides that are presented in the context of human HLA‐DR4 molecules. The SLA class I‐derived peptides that bind HLA‐DRB1*0401, a representative of the DR4 supertype, were predicted using a computer‐assisted algorithm. The candidate peptides were synthesized, and their binding capacities to HLA‐DRB1*0401 were compared in a competitive ELISA using biotinylated hemagglutinin reporter peptides [HA_307‐319]. Peptide‐11 (LRSWTAADTAAQISK) was determined to exhibit the most potent binding capacity to HLA‐DRB1*0401 in vitro and thus selected for in vivo immunization. Immunization of HLA‐DRB1*0401‐transgenic mice with peptide‐11 elicited potent CD4⁺ Th1 responses. Peptide‐11 shares homology to α2 domains of three SLA‐1 alleles, six SLA‐2 alleles, and 14 SLA‐3 alleles. Thus, this study has important implications not only for the identification of an immunogenic indirect epitope shared by diverse SLA class I alleles, but also for the development of epitope‐specific immunoregulation strategies.     

Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1*0401 (DR4) and DRB1*0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class II haplotypes may be associated with the onset age of type 1 diabetes.     

HLA extended haplotypes in steroid-sensitive nephrotic syndrome of childhood

Idiopathic nephrotic syndrome has been postulated to have an immunopathogenic basis. To determine whether steroid-sensitive nephrotic syndrome is associated with greater than expected frequencies of specific extended haplotypes of the major histocompatibility complex, we studied genetic markers (Class I, II, III HLA alleles and glyoxalase I) in 173 subjects in 42 families of patients with nephrotic syndrome of childhood. The single allele, DQW2, was found in 72% of steroid sensitive patients compared with only 35% of the controls (P = 0.003). In half of 32 steroid sensitive, but not 10 steroid resistant, patients, one or both of two specific extended haplotypes (alleles that segregate together) were identified. The first, [HLA-A1, B8, DR3, DRW52, SCO1], occurred in 11 of 64 haplotypes, or 17%, compared to 5% of controls (P = 0.017). The other, [HLA-B44, DR7, DRW53, FC31], occurred in 10 of 64 haplotypes, 16% compared to 3.8% of controls (P = 0.014). Five patients had both haplotypes. Patients with these specific extended haplotypes had a greater frequency of relapses than did those with other haplotypes. These data provide additional support for the hypothesis that steroid-sensitive nephrotic syndrome has an immunogenetic basis.     

Role of Major Histocompatibility Complex and Ethnicity in Acute Renal Graft Rejection

Background

The major histocompatibility complex (MHC) plays a main role in antigen presentation. Class I, II, and III genes form defined “blocks” of conserved DNA sequences (conserved extended haplotypes) that are useful to follow the ancestry of a population. Each variant encodes a specific peptide that determines a particular individual's immune response. In addition, differential expression of HLA antigens in certain physiological and pathological conditions may participate in the pathogenesis of allograft rejection versus tolerance.

Objectives

The aim of this study was to determine whether the specific HLA ancestry was associated with acute renal graft rejection among the Mexican mestizo population.

Materials and Methods

We studied 544 Mexican mestizo renal donors and their respective recipients for their serologically determined HLA and based on antigens haplotype assignments. The acute rejection group was compared with the nonrejection group among donors and recipients, correspondingly.

Results

Frequent Mexican alleles were observed in this study. Moreover, HLA-B*61/-DR*04, HLA-A*35/-DR*06 (Amerindian ancestry), HLA-A*68/-DR*01, HLA-A*28/-B*65/-DR*01 (African ancestry), and HLA-A*33/-B*65 (Caucasian ancestry) in donors were associated with acute renal graft rejection episodes.

Conclusion

Knowing the ancestry of a donor's HLA molecules may help to individualize immunosuppressive therapy for postransplant surveillance, because they may be more membrane-exposed in parenchymal cells, making them more susceptible of being recognized by the recipient's immune system.     

HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes: Analysis of the Type 1 Diabetes Genetics Consortium Families

OBJECTIVE

To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.

RESEARCH DESIGN AND METHODS

The frequency of DPA1 and DPB1 alleles and haplotypes in type 1 diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on HLA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined.

RESULTS

Eight DPA1 and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed; nineteen DPB1 alleles were associated with multiple DPA1 alleles. Following both analyses, type 1 diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes. Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype.

CONCLUSIONS

HLA DP allelic and haplotypic diversity contributes significantly to the risk for type 1 diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection. Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes.Insulin-dependent autoimmune or type 1 diabetes is a common autoimmune disorder of unknown etiology which results in the destruction of the insulin-secreting pancreatic β-cells. The concordance rate in monozygotic twins is estimated to be 30 to 50% with an average risk to sibs of 6% (1) and an overall genetic risk ratio (λ-s) of about 15 (2). The increasing incidence of type 1 diabetes in a genetically homogeneous population, however, clearly indicates that environmental factors also play a key role (3,4).Multiple association studies and genome linkage and association scans have confirmed that the greatest genetic risk is associated with variation within the HLA region located on chromosome six with evidence for modest associations at other regions in addition to HLA (5,6). In particular allelic, haplotypic or genotypic differences at the HLA class II DRB1, DQA1 or DQB1 loci have been shown in many studies, including a subset of this dataset (7), to have the greatest association.The most plausible mechanism explaining the association with genes of the HLA class II region is their role in presentation of peptides derived from exogenous protein to CD4+ T-helper cells which, in the case of type 1 diabetes, may result in an inappropriate T cell immune response against self-antigens on the pancreatic β-cells. Allelic differences at the DRB1, DQA1 and DQB1 loci have been shown to influence the peptide binding and T cell stimulatory capacities of the individual HLA molecules (8), suggesting that such differences contribute to the association of individual or groups of alleles with autoimmune diseases. Genetic polymorphisms at other loci, both within and outside the HLA region may, in addition, contribute to and influence the magnitude of the immune response.The HLA DPA1 and DPB1 genes are the third set of classical HLA class II loci which code for the DP antigen and have been associated with a lower immunostimulatory capacity and level of expression (9,10) although differences at individual DPB amino acids have been associated with an increased proliferative response in the mixed lymphocyte reaction (11,12). Similarly, a single DPB amino acid, glutamic acid at position 69, has been shown to contribute to graft versus host disease in otherwise HLA identical sibling bone marrow transplantation (13) and susceptibility to Beryllium disease (14).Association studies of HLA-DPB1 and type 1 diabetes have shown multiple associations with conflicting results. The following have been reported as susceptibility alleles in populations of different ethnic backgrounds: DPB1*0201, *0202, *0301, *0401, *0402, *1701 and the following as protective alleles; DPB1*0101, *0202, *0401, *0402, *1701 (15–23). Other studies have reported weak or no association with HLA DPB1 alleles (24,25). The conflicting nature of these association studies may be a reflection of population specific differences, inconsistent typing approaches, differences in study design or inadequately powered studies.The HLA DPA1 and DPB1 loci are highly polymorphic with 28 DPA1 and 136 DPB1 alleles defined as of October, 2009 (http://www.ebi.ac.uk/imgt/hla/). Association analyses in the HLA region are complicated by the occurrence of extensive linkage disequilibrium between loci such that the classical HLA loci, A, B, C, DR, DQ and DP, as well as other genes in this region, are often inherited as a “block”. The DR/DQ recombination frequency per meiosis between DR-DQ and DP has been estimated to range between 1–3% (13,26). Estimates of the relative contribution of HLA DP to susceptibility or protection against type 1 diabetes must therefore consider the potential influence of co-inherited loci, some of which are strongly associated with type 1 diabetes.The Type 1 Diabetes Genetic Consortium (T1DGC) is a large worldwide collaborative study of type 1 diabetes families that have been collected in a highly standardized fashion from various populations (27). High resolution HLA typing has been performed at eight loci at four genotyping centers using standardized typing protocols and reagents (28). The large sample size and addition of DPA1 typing permits, for the first time, an association analysis of the DPA1 locus in addition to DPB1 and DPA1-DPB1 haplotypes, which encode the antigen presenting alpha and beta chain heterodimer with type 1 diabetes.