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.

Risk Alleles for Multiple Myeloma Susceptibility in ADME Genes

The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e., chemical agents) in MM onset. The inter-individual variability in the bioactivation, detoxification, and clearance of chemical carcinogens such as asbestos, benzene, and pesticides might increase the MM risk. This inter-individual variability can be explained by the presence of polymorphic variants in absorption, distribution, metabolism, and excretion (ADME) genes. Despite the high relevance of this issue, few studies have focused on the inter-individual variability in ADME genes in MM risk. To identify new MM susceptibility loci, we performed an extended candidate gene approach by comparing high-throughput genotyping data of 1936 markers in 231 ADME genes on 64 MM patients and 59 controls from the CEU population. Differences in genotype and allele frequencies were validated using an internal control group of 35 non-cancer samples from the same geographic area as the patient group. We detected an association between MM risk and ADH1B rs1229984 (OR = 3.78; 95% CI, 1.18–12.13; p = 0.0282), PPARD rs6937483 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), SLC28A1 rs8187737 (OR = 11.33; 95% CI, 1.43–89.59; p = 0.005), SLC28A2 rs1060896 (OR = 6.58; 95% CI, 1.42–30.43; p = 0.0072), SLC29A1 rs8187630 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), and ALDH3A2 rs72547554 (OR = 2.46; 95% CI, 0.64–9.40; p = 0.0293). The prognostic value of these genes in MM was investigated in two public datasets showing that shorter overall survival was associated with low expression of ADH1B and SLC28A1. In conclusion, our proof-of-concept findings provide novel insights into the genetic bases of MM susceptibility.

Balanced assessment of growth disorders using clinical, endocrinological, and genetic approaches

Determining the pathogenesis of pediatric growth disorders is often challenging. In many cases, no pathogenesis is identified, and a designation of idiopathic short stature is used. The investigation of short stature requires a combination of clinical, endocrinological, and genetic evaluation. The techniques used are described, with equal importance being given to each of the 3 approaches. Clinical skills are essential to elicit an accurate history, family pedigree, and symptoms of body system dysfunction. Endocrine assessment requires hormonal determination for the diagnosis of hormone deficiency and initiation of successful replacement therapy. Genetic analysis has added a new dimension to the investigation of short stature and now uses next-generation sequencing with a candidate gene approach to confirm probable recognizable monogenic disorders and exome sequencing for complex phenotypes of unknown origin. Using the 3 approaches of clinical, endocrine, and genetic probes with equal status in the hierarchy of investigational variables provides the clinician with the highest chance of identifying the correct causative pathogenetic mechanism in a child presenting with short stature of unknown origin.

Ischemic Stroke Genetics: What Is New and How to Apply It in Clinical Practice?

The etiology of ischemic stroke is multifactorial. Although receiving less emphasis, genetic causes make a significant contribution to ischemic stroke genesis, especially in early-onset stroke. Several stroke classification systems based on genetic information corresponding to various stroke phenotypes were proposed. Twin and family history studies, as well as candidate gene approach, are common methods to discover genetic causes of stroke, however, both have their own limitations. Genome-wide association studies and next generation sequencing are more efficient, promising and increasingly used for daily diagnostics. Some monogenic disorders, despite covering only about 7% of stroke etiology, may cause well-known clinical manifestations that include stroke. Polygenic disorders are more frequent, causing about 38% of all ischemic strokes, and their identification is a rapidly developing field of modern stroke genetics. Current advances in human genetics provide opportunity for personalized prevention of stroke and novel treatment possibilities. Genetic risk scores (GRS) and extended polygenic risk scores (PRS) estimate cumulative contribution of known genetic factors to a specific outcome of stroke. Combining those scores with clinical information and risk factor profiles might result in better primary stroke prevention. Some authors encourage the use of stroke gene panels for stroke risk evaluation and further stroke research. Moreover, new biomarkers for stroke genetic causes and novel targets for gene therapy are on the horizon. In this article, we summarize the latest evidence and perspectives of ischemic stroke genetics that could be of interest to the practitioner and useful for day-to-day clinical work.

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Genomic Analysis of Human Population Structure

<p>Recent developments in technology and computation have encouraged a shift towards a whole-genome approach to genetic analysis. Two key contributors to this shift, the Human Genome Project and the HapMap project, sparked an interest in studying the genetic patterns found in particular groups of individuals. The Maori population of New Zealand is an ideal, yet untapped, model for such studies due to recent partial mixture of two distinct population groups, and a culture of good documentation of genealogical information. A previous study carried out by the author found observable genetic differences between Maori and European populations in markers of forensic significance, yet no particular genetic patterns were found that were uniquely Maori. This study extends the previous work by developing methods to determine to what scale these differences exist, as well as demonstrating that a knowledge of these differences and methods could be used to improve current practices for clinical diagnosis. The current project began by taking a ‘candidate gene’ approach, studying two regions where there were known large genetic differences between Maori and European individuals: the region of Alcohol Dehydrogenase genes on Chromosome 4 (Chapter 2), and the Monoamine Oxidase A gene region on Chromosome X (Chapter 3). In both of these regions, large frequency differences were observed between Maori and non-Maori populations at both a single mutation level, and at a haplotype level. Despite the differences that were observed, no particular combinations of mutations could be considered uniquely Maori or uniquely non-Maori, so studies were expanded to the entire genome. This epansion was made possible due to the recent and continuing developments in genome-wide technology and advancements in computational speed and efficiency. Once it was possible to carry out a genome-wide study of genetic differences, the goal of research changed from determining whether or not Maori and European individuals were uniquely different at a genotype level, to how small a marker set could be produced while maintaining population-uniqueness at a genotype level. A method that uses bootstrap sub-sampling and other internal validation techniques has been developed for the generation of such a signature set for a Maori tribe (Ngati Rakaipaaka), and the generated set has been validated in other similar populations (Chapter 4). As a consequence of producing this set, the degree of European admixture was estimated in the tribe (28.7%), with over 15% of individuals within Rakaipaaka found to have no discernible European genomic ancestry. In a validation of the signature set generation method itself, the marker selection procedure was repeated for Type 1 Diabetes, a disease with high heritability. An analysis of case and control individuals using this signature set found that the generated set is able to perform better than a genome-wide reference set of mutations known to be associated with Type 1 Diabetes. This validation study, other potential uses, and a more detailed discussion of the signature set generation method are presented in Chapter 5.</p>

Genomic Analysis of Human Population Structure

<p>Recent developments in technology and computation have encouraged a shift towards a whole-genome approach to genetic analysis. Two key contributors to this shift, the Human Genome Project and the HapMap project, sparked an interest in studying the genetic patterns found in particular groups of individuals. The Maori population of New Zealand is an ideal, yet untapped, model for such studies due to recent partial mixture of two distinct population groups, and a culture of good documentation of genealogical information. A previous study carried out by the author found observable genetic differences between Maori and European populations in markers of forensic significance, yet no particular genetic patterns were found that were uniquely Maori. This study extends the previous work by developing methods to determine to what scale these differences exist, as well as demonstrating that a knowledge of these differences and methods could be used to improve current practices for clinical diagnosis. The current project began by taking a ‘candidate gene’ approach, studying two regions where there were known large genetic differences between Maori and European individuals: the region of Alcohol Dehydrogenase genes on Chromosome 4 (Chapter 2), and the Monoamine Oxidase A gene region on Chromosome X (Chapter 3). In both of these regions, large frequency differences were observed between Maori and non-Maori populations at both a single mutation level, and at a haplotype level. Despite the differences that were observed, no particular combinations of mutations could be considered uniquely Maori or uniquely non-Maori, so studies were expanded to the entire genome. This epansion was made possible due to the recent and continuing developments in genome-wide technology and advancements in computational speed and efficiency. Once it was possible to carry out a genome-wide study of genetic differences, the goal of research changed from determining whether or not Maori and European individuals were uniquely different at a genotype level, to how small a marker set could be produced while maintaining population-uniqueness at a genotype level. A method that uses bootstrap sub-sampling and other internal validation techniques has been developed for the generation of such a signature set for a Maori tribe (Ngati Rakaipaaka), and the generated set has been validated in other similar populations (Chapter 4). As a consequence of producing this set, the degree of European admixture was estimated in the tribe (28.7%), with over 15% of individuals within Rakaipaaka found to have no discernible European genomic ancestry. In a validation of the signature set generation method itself, the marker selection procedure was repeated for Type 1 Diabetes, a disease with high heritability. An analysis of case and control individuals using this signature set found that the generated set is able to perform better than a genome-wide reference set of mutations known to be associated with Type 1 Diabetes. This validation study, other potential uses, and a more detailed discussion of the signature set generation method are presented in Chapter 5.</p>

INDUCED MUTATIONS IN TaASN-A2 REDUCE FREE ASPARAGINE CONCENTRATION IN THE WHEAT GRAIN

Acrylamide is a neurotoxin and probable carcinogen formed as a processing contaminant during baking and production of different foodstuffs, including bread products. The amino acid asparagine is the limiting substrate in the Maillard reaction that produces acrylamide, so developing wheat varieties with low free asparagine concentrations in the grain is a promising approach to reduce dietary acrylamide exposure. A candidate gene approach was used to identify chemically-induced genetic variation in ASPARAGINE SYNTHETASE 2 (ASN2) genes that exhibit a grain-specific expression profile. In field trials, durum and common wheat lines carrying asn-a2 null alleles exhibited reductions in free asparagine concentration in their grains of between 9 and 34% compared to wild-type sister lines. These plants showed no significant differences in spikelet number, grain size and weight, germination or baking quality traits. These non-transgenic variants can be deployed without restriction in elite wheat germplasm to reduce acrylamide-forming potential with no negative impacts on quality or agronomic performance.

Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients

Background Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients. Methods This analysis is part of the European BioCog project (www.biocog.eu), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2). Results 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD. Conclusions We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD. Trial registration: ClinicalTrials.gov: NCT02265263.