Allelic Variants Within the ABO Blood Group Phenotype Confer Protection Against Critical COVID-19 Hospital Presentation

Introduction: Coronavirus disease 2019 (COVID-19) disease severity differs widely due to numerous factors including ABO gene-derived susceptibility or resistance. The objective of this study was to investigate the association of the ABO blood group and genetic variations of the ABO gene with COVID-19 severity in a heterogeneous hospital population sample from the United Arab Emirates, with the use of an epidemiological and candidate gene approach from a genome-wide association study (GWAS).Methods: In this cross-sectional study, a total of 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited from multiple hospitals and population-based (quarantine camps) recruitment sites from March 2020 to February 2021. The participants were divided into two groups based on the severity of COVID-19: noncritical (n = 453) and critical [intensive care unit (ICU) patients] (n = 193), as per the COVID-19 Reporting and Data System (CO-RADS) classification. The multivariate logistic regression analysis demonstrated the association of ABO blood type as well as circulating anti-A antibodies and anti-B antibodies as well as A and B antigens, in association with critical COVID-19 hospital presentation. A candidate gene analysis approach was conducted from a GWAS where we examined 240 single nucleotide polymorphisms (SNPs) (position in chr9: 136125788-136150617) in the ABO gene, in association with critical COVID-19 hospital presentation.Results: Patients with blood group O [odds ratio (OR): 0.51 (0.33, 0.79); p = 0.003] were less likely to develop critical COVID-19 symptoms. Eight alleles have been identified to be associated with a protective effect of blood group O in ABO 3'untranslated region (UTR): rs199969472 (p = 0.0052), rs34266669 (p = 0.0052), rs76700116 (p = 0.0052), rs7849280 (p = 0.0052), rs34039247 (p = 0.0104), rs10901251 (p = 0.0165), rs9411475 (p = 0.0377), and rs13291798 (p = 0.0377).Conclusion: Our findings suggest that there are novel allelic variants that link genetic variants of the ABO gene and ABO blood groups contributing to the reduced risk of critical COVID-19 disease. This study is the first study to combine genetic and serological evidence of the involvement of the ABO blood groups and the ABO gene allelic associations with COVID-19 severity within the Middle Eastern population.

De impact van CYP2D6-polymorfisme op een behandeling met aripiprazol bij kinderen en jongeren: een systematische review

Impact of CYP2D6 polymorphism on children and adolescents treated with aripiprazole: a systematic review Psychotropic drugs show a significant individual variability in efficacy and adverse events. To explain these differences, there is a promising focus on studies which examine the genetic variants of the cytochrome P450 enzyme 2D6 (CYP2D6). The CYP2D6 gene has a large genetic variability with over 100 known allelic variants encoding this protein. These variants contain predictive value for the function of the CYP2D6 enzyme. Aripiprazole is metabolized by the CYP2D6 enzyme, thereby CYP2D6 allelic variants potentially affect the pharmacokinetics of the drug. This systematic literature review summarizes research on that potential influence of CYP2D6 polymorphism on the treatment outcomes of aripiprazole in minors, in terms of pharmacokinetic changes, efficacy and adverse events. Relevant articles were selected according to PRISMA guidelines (‘preferred reporting items for systematic reviews and meta-analyses’) using Embase and PubMed. After applying the inclusion and exclusion criteria, 10 relevant research articles were retained. The available research shows a possible link between genetic variants of the CYP2D6 enzyme on the one hand, and efficacy and adverse events such as hyperprolactinemia or weight gain on the other hand, in minors treated with aripiprazole. However, the number and quality of studies are low. Recommendations for future studies are made since this systematic review offers insight into the relevance of CYP2D6 genotyping in children and adolescents treated with aripiprazole.

POLYMORPHISM OF TAGLGAP MICROSATELITE LOCUS AND ITS CONNECTION WITH ALLELELIC VARIETIES OF GLIADINS OF BREAD WHEAT

Introduction. Gliadins are monomeric and highly polymorphic storage proteins of wheat endosperm, which together with glutenins form a gluten complex that determines the breadmaking properties of wheat. Allelic variants of gliadins are an important feature in the selection of material for breeding, but their determination by electrophoresis in acid PAGE is quite difficult. Aim. The aim of this study was to investigate the polymorphism of the Taglgap microsatellite locus and to analyze its correspondence to the polymorphism of allelic variants of gliadins that have been revealed by acid PAGE electrophoresis. Methods. 140 cultivars and lines of bread wheat of Ukrainian and foreign selection were analyzed. Electrophoresis of storage proteins was performed in an acid PAGE according to the method of F. O. Poperellia (1989), allelic variants were designated according to the international nomenclature (Metakovsky et al., 2018). DNA was isolated by CTAB method and PCR was performed with primers to the Taglgap microsatellite (Devos et al., 1995). PCR products were fractionated in 7% PAGE and stained with silver staining method. Nucleotide sequences were searched by BLAST and aligned by MAFT methods. The main results. 19 allelic variants of gliadins and 11 alleles of the Taglgap locus were identified. In the collection of Ukrainian varieties there were Gli-B1b, Gli-B1c, Gli-B1d, Gli-B1e, Gli-B1f, Gli-B1g, Gli-B1h, Gli-B1l and Gli-B1o allelic variants and alleles of Taglgap 216 bp, 237 bp, 246 bp, 248 bp, 252 bp, 267 bp, 270 bp and null. In the foreign collection of varieties − Gli-B1a, Gli-B1b, Gli-B1c, Gli-B1d, Gli-B1e, Gli-B1f, Gli-B1g, Gli-B1h, Gli-B1i, Gli-B1j, Gli-B1k, Gli -B1l, Gli-B1m, Gli-B1n, Gli-B1o, Gli-B1p, Gli-B1q, Gli-B1r, Gli-B1s and 213 bp, 216 bp, 237 bp, 246 bp, 248 bp, 250 bp, 252 bp, 270 bp, 285 bp and null. Nucleotide sequence analysis in the NCBI database showed the presence of a number of other alleles of the Taglgap microsatellite not only in bread wheat but also in some species of the Triticum L. and Aegilops L. genus. Conclusions. The detected polymorphism correlates with the polymorphism of allelic variants of gliadins of Gli-B1 locus and makes it possible to identify Gli-B1a, Gli-B1d, Gli-B1h and Gli-B1l allelic variants, and for Ukrainian varieties with high probability also Gli-B1b allelic variant. However, this marker does not allow identifying Gli-B1c, which is important for selection.

Role of mutations in MTHFR gene and hyperhomocysteinemia in occurrence of ischemic stroke

The objective of the study is review and analyze scientific publications devoted to the problems of stroke, its relationship with the most common mutations in the MTHFR gene and their individual allelic variants and serum homocysteine levels.Materials and methods. Analyzing foreign and domestic publications, the relationship of the strongest mutations in the MTHFR gene with an increase in the level of serum homocysteine, which is a predictor of the development of vascular accidents, including acute circulatory disorders of the brain, was revealed.Results. Stroke is a socially significant disease. All risk factors for acute cerebral stroke are subdivided into modifiable and non-modifiable. To a non-modifiable factor that predisposes to the development of ischemic and hemorrhagic stroke, hereditary factors, including genetic mutations in a number of genes. MTHFR is a genome carrying individual allelic variants that can affect the level of homocysteine in blood serum, causing it to increase, and hyperhomocysteinemia, according to a number of studies, is a likely predictor of diseases of the cardiovascular system, including severe cerebrovascular accidents. At the same time, a large number of studies use the services of the protective role of reducing the elevated level of serum homocysteine using various forms of folic acid and B vitamins. The authors of the article attempted to process, analyze and summarize the data of modern research issues on the topic under consideration.Conclusions. The relationship between the occurrence of ischemic and hemorrhagic stroke and the most common mutations in the MTHFR gene has been revealed. Hyperhomocysteinemia, separate and developing as a result of these mutations, is an independent risk factor for the development of acute cerebral ischemia. Normalization of elevated serum homocysteine levels is required for all patients as stroke prevention, and includes not only the use of foods enriched with folic acid, but also pharmacological correction of folates and B vitamins.

THE USE OF ARCHIVED GIEMSA-STAINED BLOOD SMEARS AND RDT FOR PCR-BASED GENOTYPING OF Plasmodium vivax MEROZOITE SURFACE PROTEIN-1 IN CENTRAL KALIMANTAN PROVINCE, INDONESIA: PCR-Based Genotyping of Pvmsp-1 in Central Kalimantan Province, Indonesia

Background: Plasmodium vivax is transmitted most across the country of Indonesia. The country has set out a malaria elimination program by 2030. The information on genetic diversity of malarial parasites relates to malaria transmission in an endemic area may provide the information that can help the malaria control program to achieve the target. Therefore, the purpose of this study was to determine the genetic diversity of the Pvmsp-1 gene in Central Kalimantan Province. Materials and Methods: Samples were 140 of archived Giemsa-stained blood smear and rapid detection test. Samples were divided into the indigenous and migrant populations. After confirmation by single-step PCR, only P. vivax and mixed infection samples were amplified to nested PCR for genotyping of Pvmsp-1 allelic variation in segments F1, F2, and F3. Results: Genotyping of 23 PCR positive samples resulted in 13 genotypes. In segment F1, three allelic variants type A containing subtype A1 (1,050 bp), A2 (350 bp), A3 (150 bp), and type B (100 bp). In segment F2, mono genotypes were detected as variant type A (1,050 bp) and type B3 (150 bp), multiple genotypes were detected as type B containing subtype B1 (250 bp), B2 (200 bp), and B3 (150bp). In segment F3, three allelic variants generated from four mono genotypes were type A (350 bp), type B (300 bp), and two type C (250 bp). Conclusion: The low allelic variation of Pvmsp-1 gene may reflect the actual situation of the low malaria endemic status of the study sites.

POLYMORPHISM OF PROLACTIN AND SOMATOTROPIN GENES IN DAIRY CATTLE OF THE REPUBLIC OF TATARSTAN

Изучен полиморфизм и определена частота встречаемости аллельных вариантов по генам пролактина (PRL) и соматотропина (GH) у коров в условиях двух племенных хозяйств Республики Татарстан. Объектом исследования были животные черно-пестрой породы первого (n=151) и третьего (n=168) отелов и холмогорской породы первого (n=160) и третьего (n=143) отелов. Проведено генотипирование коров по генам PRL и GH методом ДНК-диагностики. Установлено, что среди молочного скота преимущественно встречаются особи с генотипом PRL АА (70,0—77,5%), с частотой аллеля А гена пролактина — 0,83—0,87, аллеля В — 0,13—0,17. Встречаемость аллеля В была выше среди холмогорских коров (0,16—0,17). В стаде полновозрастных животных черно-пестрой породы имеется сдвиг генетического равновесия в сторону генотипов PRL AA и PRL BB (χ2=3,97; Р<0,05). В исследуемых стадах крупного рогатого скота выражено преимущество генотипа GH LL с частотой встречаемости 51,0—79,2%. Встречаемость генотипа GH VV у черно-пестрого скота составила 2,0—2,4%, у холмогорского — 5,6—7,0%. Аллель L гена соматотропина преобладает над аллелем V в обеих породах. При этом чаще встречаемость аллеля L GH среди коров холмогорской породы (0,28—0,29). У холмогорских коров больше представлены редкие и желательные аллели генов PRL и GH. Чтобы повысить встречаемость «предпочтительных» в хозяйственном отношении генотипов и аллелей ДНК-маркеров, необходимо в большей степени использовать быков-производителей с желательными аллелями PRL и GH, а именно В и V соответственно. The polymorphism was studied and the frequency of occurrence of allelic variants for the genes of prolactin (PRL) and somatotropin (GH) was determinedin cows in two bred livestock farms of the Republic of Tatarstan. The object of the study were animals of the black-and-white breed of the first (n=151) and third (n=168) calving and the Kholmogory breed of the first (n=160) and third (n=143) calving. Genotyping of cows for PRL and GH genes was carried out using method of DNA diagnostics. It was revealed that there were mainly individuals with the PRL AA genotype (70,0–77,5%)among dairy cattle, the frequency of the A allele of the prolactin gene was 0,83–0,87, the B allele was 0,13–0,17. The frequency of allele B was higher among Kholmogory cows (0,16–0,17). There was a shift in the genetic balance towards the PRL AA and PRL BB genotypes (χ2=3,97; Р<0,05) in the herd of full-age animals of the black-and-white breed. The advantage of the GH LL genotype was expressed with a frequency of occurrence 51,0–79,2% in the studied cattle herds. The occurence of the GH VV genotype was 2,0–2,4%in black-and-white cattle, 5,6–7,0% was in Kholmogorycattle. The L allele of the somatotropin gene predominated over the V allele in both breeds. Moreover, the occurrence of the L GH allele among cows of the Kholmogory breed (0,28–0,29) was more often. Rare and desirable alleles of the PRL and GH genes are more represented in Kholmogory cows. In order to increase the occurrence of economically “preferred” genotypes and alleles of DNA markers, it is necessary to use more stud bulls with the desired PRL and GH alleles, namely B and V, respectively.

Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia

Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G &gt; T:p. V555F), and a homozygous variant in FANCM (c. 1972C &gt; T:p. R658X) in a sporadic case with NOA, respectively. H&amp;E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.

The Role of HLA in the Association between IgA Deficiency and Celiac Disease

Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB 1 ∗ 02 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB 1 ∗ 02 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB 1 ∗ 02 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.

Frequency of CYP2D6*3 and *4 and metabolizer phenotypes in three mestizo Peruvian populations

Wild type genotypes (CYP2D6) and their allelic variants have been described in a sample of a Peruvian mestizo population. The global allele frequency was 0.015 for CYP2D6*3 and 0.051 for CYP2D6*4. The percentages of genotypes described were 97% CYP2D6*1/*1 and 3.0% CYP2D6*1/*3; 90.60% for CYP2D6*1/*1, 8.55% CYP2D6*1/*4 and 0.85% CYP2D6*4/*4. The allelic frequencies of CYP2D6*3 in the Lima subpopulations were 0.022 and 0.010 for Junin; CYP2D6*4 of 0.048, 0.060, and 0.050 for residents of Lima, Junín, and Tacna, respectively. The Hardy-Weinberg equilibrium test for the studied population showed that both frequencies are in equilibrium, p &lt;.05. The metabolizer phenotype was inferred according to the genotypes: 11.54% were classified as intermediate metabolizers (*1/*3 or *1/*4) and 0.85% as poor metabolizers (*4/*4). It is concluded that the frequencies of the CYP2D6*3 and CYP2D6*4 alleles are low for the Peruvian mestizo population compared to the Latin American and tricontinental population, due to their natural population evolution, which is manifested by their decreased metabolic activity, the same that is relevant in clinical practice.