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.

Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome.

OBJECTIVE: Nonclassic congenital adrenal hyperplasia (NCAH) is common among Ashkenazi Jews (1:400). It is associated with various degrees of postnatal virilization, irregular menses and infertility. Therapy of symptomatic subjects consists of physiologic doses of glucocorticoids. The objective of this study was to evaluate the effect of glucocorticoid treatment on fertility and on pregnancy outcome in women with NCAH. DESIGN, SETTING AND PATIENTS: This retrospective study included 75 women diagnosed with NCAH who were followed in our clinic and sought fertility between 2008 and 2015. RESULTS: Seventy-two women succeeded in conceiving (187 pregnancies). Time to conception was 4.0 ± 7 months without and 3.3 ± 3 months with glucocorticoid therapy (P = .43). Seventeen pregnancies were achieved by glucocorticoid therapy after failure to conceive spontaneously. Time to conception before therapy initiation was 10.2 ± 11.4 months compared to 3.3 ± 3.4 months after therapy initiation (P = .02). Of 187 pregnancies, 135 (72%) resulted in live births, 38 (20.3%) ended in spontaneous miscarriages during the first trimester, seven (3.7%) were electively terminated, three (1.6%) were ectopic and four (2.1%) were ongoing during the study with similar rate in glucocorticoid treated and untreated pregnancies. CONCLUSIONS: The 96% pregnancy rate among our cohort of NCAH females was similar to the 95% rate reported for the normal population. Glucocorticoid therapy may shorten the time to conceive in a subgroup of women with NCAH. Glucocorticoid therapy did not affect the rate of first trimester miscarriage. Our 77% live birth rate was similar to the 72% live birth rate in the current healthy US population.

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.

An SNX10 mutation causes malignant osteopetrosis of infancy.

BACKGROUND: Osteopetrosis is a life-threatening, rare disorder typically resulting from osteoclast dysfunction and infrequently from failure to commitment to osteoclast lineage. Patients commonly present in infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, and bone marrow failure. In ∼70% of the patients there is a molecularly defined failure to maintain an acid pH at the osteoclast-bone interface (the ruffled border) which is necessary for the bone resorptive activity. METHODS AND RESULTS: In eight patients with infantile osteopetrosis which could be cured by bone marrow transplantation, the study identified by homozygosity mapping in distantly related consanguineous pedigrees a missense mutation in a highly conserved residue in the SNX10 gene. The mutation segregated with the disease in the families and was carried by one of 211 anonymous individuals of the same ethnicity. In the patients' osteoclasts, the mutant SNX10 protein was abnormally abundant and its distribution altered. The patients' osteoclasts were fewer and smaller than control cells, their resorptive capacity was markedly deranged, and the endosomal pathway was perturbed as evidenced by the distribution of internalised dextran. CONCLUSIONS: SNX10 was recently shown to interact with vacuolar type H(+)-ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. Mutations in TCIRG1, the gene encoding a subunit of the V-ATPase complex, account for the majority of cases of osteopetrosis. It is speculated that SNX10 is responsible for the vesicular sorting of V-ATPase from Golgi or for its targeting to the ruffled border. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna. Determination of the sequence of the SNX10 gene is warranted in molecularly undefined patients with recessive 'pure' osteopetrosis of infancy.

Adult height of subjects with nonclassical 21-hydroxylase deficiency.

AIM: To determine whether nonclassical 21-hydroxylase deficiency (NC21OHD) compromises adult height (AH), and to establish the clinical parameters affecting AH in subjects with NC21OHD. METHODS: This is a multicenter, retrospective review of medical records for clinical and biochemical parameters. The corrected height (CH) standard deviation score (SDS), defined as AH SDS minus mean parental height (MPH) SDS, was calculated for each patient, where MPH SDS is the average of the father's height SDS and the mother's height SDS. RESULTS: The study group consisted of 122 NC21OHD subjects whose median age at diagnosis was 8.7 years (range, 0.1-36). Seventy-two patients had two mild mutations, 22 had one mild and one severe mutation, 10 were heterozygous for one mild mutation, and 18 did not undergo molecular analysis. The CH SDS of the 66 patients who initiated hydrocortisone treatment during childhood was significantly lower than those who presented after achieving AH (p = 0.03). However, there was a negative correlation between age at diagnosis and AH SDS in the former group (R = -0.7, p = 0.03). Being heterozygous for one mild and one severe mutation (R = -0.7, p < 0.02) and age at diagnosis (R = -0.7, p = 0.03) were negatively associated with CH SDS. The CH SDS was significantly lower in those who had bone age advancement at diagnosis compared to those who did not (p = 0.04). CONCLUSION: The main determinants of AH in patients with NC21OHD are apparently age at diagnosis and initiation of therapy, and genotype. Early diagnosis and initiation of glucocorticoids therapy may improve height outcome in those presenting during childhood.

The prevalence of non-classic adrenal hyperplasia among Turkish women with hyperandrogenism.

The prevalence of non-classic adrenal hyperplasia (NCAH) among Turkish women with hirsutism has not been established so far. Thus, we aimed to evaluate the prevalence of 21-hydroxylase (21-OH) deficiency by ACTH stimulation test among hirsute women. The study population consisted of 285 premenopousal women, aged 16-46 years (mean: 23.2 ± 0.3). All were hirsute and hyperandrogenic. Androgen secreting tumors of the ovaries and the adrenal glands were excluded as well as thyroid dysfunction and hyperprolactinemia. All the patients were evaluated by 0.25 mg (i.v.) ACTH stimulation test and 17-OHP responses were obtained at 30 and 60 min. The diagnosis of NCAH due to 21-OH deficiency was considered in patients with the poststimulation 17-OHP level exceed 10 ng/ml. Six (2.1%) of the patients had NCAH due to 21-OH deficiency confirmed by genotyping. The rest of the patients were polycystic ovary syndrome (n = 166, 58.2%) and idiopathic hyperandrogenemia (n = 113, 39.7%). There were no patients with idiopathic hirsutism because patients with normal serum androgen levels were excluded. This first and most extensive national study investigating NCAH prevalence among Turkish population showed that NCAH is not prevalent in this population.

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.

Immunogenetics of HLA class II in Israeli patients with adult-onset type 1 diabetes mellitus.

The distribution of HLA class II alleles and genotypes in Israelis of different ethnic origin with adult-onset type 1 diabetes (T1D) was examined. The results were compared with published findings in healthy Israelis and childhood-onset T1D Israelis. An additional comparison was made between subgroups of patients with rapidly and slowly progressive adult-onset T1D (LADA). A DNA-based low-resolution analysis was performed for DRB1* and DQB1* alleles and a high-resolution analysis for DRB1*04 and DQB1*1 alleles. In all, 87% of the study group was positive for DRB1*03 or DRB1*04 compared with 36% of the healthy controls. The main alleles accounting for susceptibility to T1D were DRB1*0402, found in 77.9% of carriers of DRB1*04 and DQB1*0302, found in 74.6% of carriers of DQB1*03. The DQB1*0602 was not detected in any patient. The distribution was similar to that reported in Israeli children with T1D and significantly different from healthy Israelis. There was no significant difference in the distribution of HLA class II alleles between patients with rapidly progressive T1D or LADA. It may be concluded that the different ages of onset of T1D and its different forms of development in Israeli patients are apparently not caused by a different prevalence of HLA class II alleles.

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.

Validation of two commercial real-time PCR assays for rapid screening of the HLA-B*57:01 allele in the HIV clinical laboratory.

The pharmacogenetics approach to screen for the presence of the HLA-B*57:01 allele in HIV-1 infected patients is mandatory to prevent the potential development of hypersensitivity reaction to abacavir treatment. Given the limitations of current genotype methodologies, commercial real-time PCR assays were specifically developed for this purpose, but have not been sufficiently validated and are still not widely used. Here, in the context of the HIV laboratory, we assessed the ability of two commercial kits, the LightSNiP rs2395029 HPC5 assay (TIB Molbiol) and the DuplicαReal-TimeHLA-B*5701 Genotyping kit (Euroclone), to retrospectively detect HLA-B*57:01 positive and negative samples of Israeli HIV-1 infected patients. The LightSNiP rs2395029 HPC5 assay had false-positive results, whereas the DuplicαReal-Time HLA-B*5701 Genotyping kit was highly accurate and could be readily implemented into clinical practice. It is hoped that this study will facilitate the assessment of additional commercial kits for HLA-B*57:01 detection and expand their use in the clinical laboratory. Such studies can likely help the use of abacavir treatment in HIV-1 infected patients.

Increased occurrence of anti-AQP4 seropositivity and unique HLA Class II associations with neuromyelitis optica (NMO), among Muslim Arabs in Israel.

BACKGROUND: Previous studies have revealed different human leukocyte antigen (HLA) associations in multiple sclerosis (MS) and neuromyelitis optica (NMO), further discriminating these two demyelinating pathological conditions. In worldwide analyses, NMO and opticospinal MS are represented at higher proportions among demyelinating conditions in African, East-Asian and Latin American populations. There are currently no data regarding the prevalence of NMO in Middle East Muslims. The population in Israel is diverse in many ways, and includes subpopulations, based on religion and ethnicity; some exhibit genetic homogeneity. In Israel, the incidence of MS is lower in the Muslim population than the Jewish population and Muslims carry different allele frequency distribution of HLA haplotypes. OBJECTIVE: To evaluate the occurrence of anti-AQP4 seropositivity in the Israeli Muslim population among patients with central nervous system (CNS) demyelinating conditions; and to identify the HLA DR and DQ profiles of Muslim Arab Israeli patients with NMO spectrum of diseases (NMOSD). METHODS: The prevalence of anti-AQP4 seropositivity was analyzed in 342 samples, obtained from patients with various CNS demyelinating conditions and in a validation set of 310 samples. HLA class II alleles (HLA-DRB1 and DQB1) were examined in DNA samples from 35 Israeli Muslim Arabs NMO patients and compared to available data from 74 Israeli Muslim controls. RESULTS: Our data reveal a significantly increased prevalence of anti-AQP4 seropositivity, indicative of NMOSD, in Muslim Arab Israeli patients with initial diagnosis of a CNS demyelinating syndrome. In this population, there was a positive association with the HLA-DRB1*04:04 and HLA-DRB1*10:01 alleles (p=0.03), and a strong negative association with the HLA-DRB1*07 and HLA-DQB1*02:02 alleles (p=0.003, p=0.002). CONCLUSIONS: Our findings indicate a possibly increased prevalence of NMOSD in Muslim Arabs in Israel with distinct (positive and negative) HLA associations. Further studies in patients with similar genetic backgrounds worldwide could help to confirm our findings and identify more genetic susceptibility factors for NMO, contributing to our general understanding of the pathogenesis of NMOSD.

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.

Late-onset congenital adrenal hyperplasia with Cushing syndrome.

Although hirsutism is classically part of the clinical presentation of polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia and Cushing's syndrome (CS), CS associated with underlying late-onset congenital adrenal hyperplasia (LCAH) in an adult has not been previously reported. We herein present the case of a 25-year-old woman who was followed for PCOS for seven years. After undergoing detailed tests described within the text, she received the diagnosis of LCAH and was found to have point mutations. Interestingly, she later had diagnosis of endogenous CS that regressed folowing excision of an adrenal adenoma found on MRI. The present patient thus exhibited the coexistence of two paradoxical endocrine pathologies.

Lack of association between the C2 allele of transferrin and age-related macular degeneration in the Israeli population.

BACKGROUND: Altered iron metabolism and transferrin expression were associated with neurodegenerations including age-related macular degeneration (AMD) and Alzheimer's disease (AD). Carriers of transferrin C2 allele alone or in combination with the hemochromatosis C282Y variant may have increased risk for developing AD. We aim to assess if these alleles also predispose to AMD. METHODS: DNA was collected from 290 AMD patients and 157 unaffected, age-matched, controls. Genotyping was performed for transferrin C1/C2 alleles and hemochromatosis C282Y allele, and association with AMD was evaluated. RESULTS: There was no association between the C1/C2 transferrin alleles and AMD. Hemochromatosis C282Y variant was identified in four individuals; one was an AMD patient and three were unaffected. CONCLUSION: Transferrin C2 and hemochromatosis C282Y alleles are not associated with increased risk for developing AMD in Israel.

TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.

Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.