Genetic Basis of Delayed Hypersensitivity Reactions to Drugs in Jewish and Arab Populations.

Genetic variation can affect drug pharmacokinetics and pharmacodynamics and contribute to variability between individuals in response to medications. Specifically, differences in allele frequencies among individuals and ethnic groups have been associated with variation in their propensity to develop drug hypersensitivity reactions (HSRs). This article reviews the current knowledge on the genetic background of HSRs and its relevance to Jewish and Arab populations. The focus is on human leukocyte antigen (HLA) alleles and haplotypes as predictive markers of HSRs ("immunopharmacogenetics"), but other genes and alleles are described as well. Also discussed is the translation of the pharmacogenetic information to practice recommendations.

Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.

Identification of 33 novel HLA alleles in Arab potential bone marrow donors.

Between 2008 and April 2018, we recruited more than 37 000 potential Arab donors to the Hadassah Bone Marrow Donor Registry, all of whom were typed for high resolution HLA-A, -B, and -DRB1. In addition, more than 22% of them were also typed for their HLA-C and -DQB1 alleles. A comparison of the sequences obtained from these donors with the IPD-IMGT/HLA Database showed 33 novel alleles from five loci (HLA-A, -B, -C, -DR, -DQ). All of these novel HLA alleles were detected in the local Arab communities; 79% of these alleles have not been described in other groups yet and remain unique to the local Arab communities.

High resolution HLA allele and haplotype frequencies for Arab donors in the Hadassah bone marrow donor registry.

Five locus allele-level HLA-A, -B, -C, -DRB1, -DQB1 allele and haplotype frequencies have been calculated for almost 29,000 people from three Arab populations that live in Israel and were recruited as donors to the Hadassah bone marrow donor registry. These groups are of Muslim, Christian and Bedouin Arab descent which represent more than 90% of the Arabs that live in Israel. The goal of the study was to describe the HLA genetic profiles of the Hadassah Arab registry donors and investigate the utility of these donors for the local and international hematopoietic stem-cell transplant community. The results demonstrate that the analyzed Arab populations share at least seven of the top ten most frequent alleles. Comparison with other populations confirmed the proximity of the three Arab populations to each other and to the Be The Match® Middle Eastern population. Despite these similarities, some alleles are private to each of the three groups, possibly because of historical, environmental or societal events. Clinical data showed that Arab donors were HLA matched with Arab and international patients. This analysis indicates the value added by the Hadassah Arab donors to the local and global transplant community.

Distribution of the V281L mutation of the CYP21 gene in Israeli congenital adrenal hyperplasia patients and its association with HLA- B14.

The V281L mutation in the CYP21 gene, responsible for non classical CAH, was studied in patients of different Israeli ethnic groups and compared to the data on healthy population. The Israeli population consists of many ethnic groups which can be divided into three main entities: Ashkenazi, Non Ashkenazi and Israeli Arabs. The frequency of V281L mutation in the patients of the different ethnic groups varied and was a reflection of the frequency found in the healthy population namely: very high in the Ashkenazi (74%) , lower in the non Ashkenazi (39%) and very low in the Israeli Arabs (2.9%) . The phenomenon of strong association between the HLA B14 allele and the V281L mutation found in our population study, as well as in other studies, confirmed by linkage found in patient families, can be used to distinguish between homozygote and hemizygote carrying the V281L mutation, when no family study is available. The relevance of this finding is especially important in cases of genetic counseling when a carrier of a severe mutation is involved.

The region of 150 kb telometic to HLA-C is associated with psoriasis in the Jewish population.

The HLA-Cw*0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case-control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw*0602 nor the allele CDSN*TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1_4_4 (OR = 2.6, 95% CI = 1.4-4.7, p(c) = 0.018) the octamer transcription factor (OTF)-3 gene (OR = 2.6, 95% CI = 1.6-4.3, p(c) = 0.0001) and the alpha-helix coiled-coil rod homologue (HCR) gene (OR = 2.5, 95% CI = 1.3-4.5, p(c) = 0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene.

Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome.

The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression.

Is presensitization relevant to liver transplantation outcome?

The impact of anti-HLA antibodies and crossmatch (CM) on liver transplantation (LT) outcome is still controversial. In this retrospective study we analyzed LT outcome according to pretransplant pre-formed anti-HLA antibodies and CM status. Serum anti-HLA antibodies were screened by ELISA assay, utilizing One Lambda antigen tray-mixed (LAT-M). CMs were performed by the complement dependent cytotoxicity test using Dithiotreitol treated sera. Anti-HLA antibodies were studied in 80 recipients; 56/80 had positive LAT-M tests (PLAT-M), whereas the remaining 24 recipients tested negative for both classes I and II (NLAT-M). Rejection episodes were more frequent in PLAT-M compared with NLAT-M group in post-LT intervals of <1 week (p = 0.05), 1 week-3 months (p = 0.035), and 3-12 months (p = 0.076). Graft and patient survival rates were better, albeit not significantly, in the NLAT-M compared with PLAT-M recipients. CM status was investigated in 62/80 recipients, 18/62 recipients had positive CM (PCM), and 44 had negative CM (NCM). Five of 18 PCM recipients (28%) experienced early graft loss compared with 1/44 (2%) with NCM (p = 0.006). Rejection episodes were more frequent within first 3 months post-LT in PCM recipients compared with NCM (p = 0.015). One-year graft survival rate was better in NCM, compared with PCM recipients (graft loss of 2/44 vs 5/18). NCM PLAT-M had a higher incidence of rejection episodes compared with the NCM NLAT-M group (p = 0.031). The presence of anti-HLA antibodies suggests a deleterious effect on LT outcome, and was associated with an increased incidence of early graft loss and rejection episodes.

An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201.

A group of 18 Israeli, clozapine-treated, schizophrenia patients underwent molecular and serological HLA typing in order to determine whether the major histocompatibility complex is associated with the development of clozapine-induced agranulocytosis. While under treatment with clozapine, 2 of the 18 patients developed agranulocytosis (total white blood cell count <3000/mm(3) and absolute polymorphonuclear count <500/mm(3)) and 3 developed granulocytopenia (total white blood cell count <3500/mm(3) and absolute polymorphonuclear count <1000/mm(3)). HLA-DQB1*0201 was present in all five patients who developed agranulocytosis or granulocytopenia (5/5; 100%), but in only 54% (7/13) of the patients who did not develop those complications. These findings indicate that DQB1*0201 or a gene located nearby could be involved in clozapine-induced agranulocytosis.

DRB1*1502-DQB1*0601-DQA1*0103 and DRB1*04-DQB1*0302 in Jewish hypersomnolent patients.

OBJECTIVES: Narcolepsy is a sleep disorder with a genetic association with the haplotype DRB1*1501, DQA1*0102, DQB1*0602. This haplotype has been described in different ethnic groups suffering from narcolepsy (Japanese, Caucasian, African Americans, Jews). In a recent study we have found the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in three patients with hypersomnolence. The similarity of this haplotype to the narcoleptic haplotype DRB1*1501, DQB1*0602 and DQA1*0102 has raised the question of whether this haplotype is a marker for sleepiness, or rather indicates a variant of non-cataplectic narcolepsy. This study was conducted to further investigate this question. METHODS: HLA-DNA analysis was carried out in 20 healthy Jewish patients (age 23.9+/-6.3 years; 13 Ashkenazi, seven non-Ashkenazi) who had objective measures of hypersomnolence. All underwent whole-night polysomnography, multiple sleep latency test and tissue typing. RESULTS: HLA-DNA analysis revealed HLA-DR2 in eight patients of whom five (25%) carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103 (vs. 1.4% in the Israeli population, P<0.0001). Six patients were diagnosed as non-cataplectic narcoleptics. Five of them carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103. Forty percent of the patients carried the haplotype DRB1*04, DQB1*0302, which was not statistically different from its prevalence in the healthy Israeli population (25%). CONCLUSIONS: This is the first report describing the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in narcoleptic patients (non-cataplectic). This haplotype is close but different from the already known narcoleptic haplotype DRB1*1501, DQA1*0102, DQB1*0602. We assume that this haplotype represents a variant of non-cataplectic narcolepsy rather than association with hypersomnolence. However, in order to conclude whether this haplotype is a marker for the lack of cataplexy, or represents a variant of non-cataplectic narcolepsy, a larger group of patients should be investigated.

Decreased cortisol secretion in nonclassical 21-hydroxylase deficiency before and during glucocorticoid therapy.

OBJECTIVE: The cortisol response in patients with nonclassical 21-hydroxylase deficiency (NC21OHD) was assessed before and during hydrocortisone therapy and the findings were related to genotype. DESIGN: Comparative study. METHODS: The study sample comprised 41 patients (10 males) with NC21OHD, divided into two groups according to the genetic analysis of the CYP21 gene: Group A carried two mild mutations (n = 29), and Group B were compound heterozygotes for one mild and one severe mutation (n = 12). The 250 microg short ACTH test was performed at diagnosis. To evaluate the degree of treatment-induced suppression of adrenal function, 31 patients also underwent the 1 microg/1.73 m2 ACTH test during hydrocortisone therapy. Basal and stimulated cortisol levels and the increment in cortisol response were compared between Groups A and B and between the whole patient sample and healthy controls (32 subjects for the 250 microg test and 29 for the 1 microg/1.73 m2 test). RESULTS: The basal, stimulated, and incremental cortisol levels were similar in Groups A and B; therefore, all the patients were considered together. At diagnosis, the basal cortisol levels were similar in the patients and controls, but the stimulated and incremental cortisol levels were significantly lower in the patients (p <0.001 for both). During hydrocortisone therapy, the patients had slightly higher basal cortisol levels than the controls (p = 0.04), but significantly lower stimulated and incremental cortisol levels (p <0.001 for both). CONCLUSIONS: Cortisol levels in NC21OHD are similar in patients carrying two mild mutations and in compound heterozygotes for one mild and one severe mutation. Stimulated and incremental cortisol levels in response to the short ACTH test might be decreased not only during but also before hydrocortisone therapy. Therefore, coverage with a stress dose of hydrocortisone during serious intercurrent illness or surgery is recommended in patients with NC21OHD, especially those previously treated with corticosteroids.

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations.

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.