Association of COVID-19 Vaccines ChAdOx1-S and BNT162b2 with Circulating Levels of Coagulation Factors and Antithrombin.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is associated with increased risk of thrombosis and thromboembolism. Exposure to COVID-19 vaccines is also associated with immune thrombotic thrombocytopenia, ischemic stroke, intracerebral haemorrhage, and cerebral venous thrombosis, and it is linked with systemic activation of coagulation. METHODS: We assess the circulating levels of coagulation factors (factors XI, XII, XIII, and prothrombin) and antithrombin in individuals who completed two doses of either ChAdOx1-S or BNT162b2 COVID-19 vaccine, within the timeframe of two months, who had no previous history of COVID-19. RESULTS: Elevated levels of factors XI, XII, XIII, prothrombin, and antithrombin were seen compared to unvaccinated controls. Levels of coagulation factors, antithrombin, and prothrombin to antithrombin ratio were higher with BNT162b2 compared to ChAdOx1-S vaccine. CONCLUSIONS: The clinical significance of such coagulation homeostasis disruption remains to be elucidated but it is worthy of global scientific follow-up effort.

Impact of BNT162b2 mRNA Vaccination on the Development of Short and Long-Term Vaccine-Related Adverse Events in Inflammatory Bowel Disease: A Multi-Center Prospective Study.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been effective in protecting against severe COVID-19 infections and related mortality. It is recommended for all individuals including patients with inflammatory bowel disease (IBD). However, safety data are lacking in this group of patients. Therefore, we aim to evaluate the short- and long-term vaccine related adverse events (AEs) in patients with IBD. Methods: This is a prospective, observational cohort study investigating short- and long-term AEs related to the BNT162b2 vaccine in patients with IBD (study group) after the first and second dose compared to healthy participants (control group). Patients were recruited at the time of attendance to the clinic or infusion rooms. Short term (<3 weeks) localized and systemic AEs were assessed via questionnaire. Follow-up phone-based survey was made to collect data on long term (up to 24 weeks) AEs. Results: A total of 408 patients answered the questionnaires, 204 patients in each group, the study and control group. No serious adverse events were reported in either the study or the control group after the first or the second dose. Participants in the control group reported more frequent pain at the injection site than those in the study group after the first dose [58 (57%) vs. 38 (37%) respectively, P = 0.005]. After the second dose, tiredness was reported more frequently in the control group [49 (48%)] compared to the study group [25 (24%) (P < 0.001)]. At 20-24 weeks post vaccination, 386 out of 408 (94.6%) patients were willing to participate in the follow-up phone based questionnaire [196 (96.1%) in the study group vs. 190 (93.1%) in the control group]. In both groups, none of the patients reported local, systemic, or severe adverse events (0 out of 386) at week 20-24 post second dose. Conclusion: The BNT162b2 vaccine is safe in patients with IBD. No severe or long-term adverse events were reported in our study. The frequency of local and systemic adverse events after the second dose was generally higher among healthy participants compared to patients with IBD. Further studies including a larger cohort with a longer follow-up duration are needed to assess for possible rare adverse events.

Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula.

The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population.

PharmaKU: A Web-Based Tool Aimed at Improving Outreach and Clinical Utility of Pharmacogenomics.

With the tremendous advancements in genome sequencing technology in the field of pharmacogenomics, data have to be made accessible to be more efficiently utilized by broader clinical disciplines. Physicians who require the drug-genome interactome information, have been challenged by the complicated pharmacogenomic star-based classification system. We present here an end-to-end web-based pharmacogenomics tool, PharmaKU, which has a comprehensive easy-to-use interface. PharmaKU can help to overcome several hurdles posed by previous pharmacogenomics tools, including input in hg38 format only, while hg19/GRCh37 is now the most popular reference genome assembly among clinicians and geneticists, as well as the lack of clinical recommendations and other pertinent dosage-related information. This tool extracts genetic variants from nine well-annotated pharmacogenes (for which diplotype to phenotype information is available) from whole genome variant files and uses Stargazer software to assign diplotypes and apply prescribing recommendations from pharmacogenomic resources. The tool is wrapped with a user-friendly web interface, which allows for choosing hg19 or hg38 as the reference genome version and reports results as a comprehensive PDF document. PharmaKU is anticipated to enable bench to bedside implementation of pharmacogenomics knowledge by bringing precision medicine closer to a clinical reality.

Prognostic Genetic Markers for Thrombosis in COVID-19 Patients: A Focused Analysis on D-Dimer, Homocysteine and Thromboembolism.

COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus-2, which has infected over thirty eight million individuals worldwide. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, single-nucleotide polymorphisms (SNPs) in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with Heparin-induced Thrombocytopenia. In this study, we aimed to uncover the genetic basis of the above conditions by examining genome-wide associations and tissue-specific gene expression to build a molecular network. Based on gene ontology, we annotated various SNPs with five ancestral terms: pulmonary embolism, venous thromboembolism, vascular diseases, cerebrovascular disorders, and stroke. The gene-gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes. We propose that genotyping COVID-19 patients for SNPs examined in this study will help identify those at greatest risk of complications linked to thrombosis.

Assessment of coding region variants in Kuwaiti population: implications for medical genetics and population genomics.

Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. We sequenced 291 whole exomes of unrelated, healthy native Arab individuals from Kuwait to a median coverage of 45X and characterised 170,508 single-nucleotide variants (SNVs), of which 21.7% were 'personal'. Up to 12% of the SNVs were novel and 36% were population-specific. Half of the SNVs were rare and 54% were missense variants. The study complemented the Greater Middle East Variome by way of reporting many additional Arabian exome variants. The study corroborated Kuwaiti population genetic substructures previously derived using genome-wide genotype data and illustrated the genetic relatedness among Kuwaiti population subgroups, Middle Eastern, European and Ashkenazi Jewish populations. The study mapped 112 rare and frequent functional variants relating to pharmacogenomics and disorders (recessive and common) to the phenotypic characteristics of Arab population. Comparative allele frequency data and carrier distributions of known Arab mutations for 23 disorders seen among Arabs, of putative OMIM-listed causal mutations for 12 disorders observed among Arabs but not yet characterized for genetic basis in Arabs, and of 17 additional putative mutations for disorders characterized for genetic basis in Arab populations are presented for testing in future Arab studies.

Ketoacidosis at first presentation of type 1 diabetes mellitus among children: a study from Kuwait.

We examined the frequency and severity of diabetic ketoacidosis (DKA) in 679 children and adolescents (0-14 years) at diagnosis of Type 1 Diabetes Mellitus (T1DM) in Kuwait. Between 1(st) January 2011 and 31(st) December 2013, all newly diagnosed children with diabetes were registered prospectively in a population-based electronic register. DKA was diagnosed using standard criteria based on the levels of venous pH and serum bicarbonate. At the time of diagnosis, mild/moderate DKA was present in 24.8% of the children, while severe DKA was present in 8.8%. Incidence of ketoacidosis was significantly higher in young children less than 2 (60.7% vs 32.4% p = <0.005) compared to children 2-14 years old, and a higher proportion presented with severe DKA (21.4% vs 8.3% p = <0.05). No association was seen with gender. Significant differences were found in the incidence of DKA between Kuwaiti and non-Kuwaiti children (31.1% vs 39.8%; p < 0.05). Family history of diabetes had a protective effect on the occurrence of DKA (OR = 0.44; 95% CI = 0.27-0.71). Incidence of DKA in children at presentation of T1DM remains high at 33.6%. Prevention campaigns are needed to increase public awareness among health care providers, parents and school teachers in Kuwait.

Association between body mass index and onset of hypertension in men and women with and without diabetes: a cross-sectional study using national health data from the State of Kuwait in the Arabian Peninsula.

OBJECTIVE: Obesity contributes directly to the risk of diabetes and hypertension. Effective management of diabetes is essential to prevent or delay the onset of comorbid hypertension. In this study, we delineate the association body mass index (BMI) has with risk and age at onset of hypertension and explore how this association is modulated by sex and the pre-existing condition of diabetes. DESIGN: Cross-sectional study using retrospective data. SETTING: Kuwait Health Network that integrates primary health and hospital laboratory data into a single system. PARTICIPANTS: We considered 3904 native Kuwaiti comorbid individuals who had the onset of type 2 diabetes prior to that of hypertension, and 1403 native Kuwaiti hypertensive individuals with no incidence of diabetes. These participants have been regularly monitored for BMI, glycated haemoglobin and blood pressure measurements. Mean variance in BMI per individual over the period from registration is seen to be low. MAIN OUTCOME MEASURES: Association between age at onset of hypertension and BMI (as measured at hypertension diagnosis); HRs for developing hypertension. RESULTS: Risk of hypertension increases with obesity levels, and is higher in patients with diabetes than in patients without diabetes but of similar obesity levels. Age at onset of hypertension is inversely related to BMI; this relationship is seen to be stronger in men compared to women (slope estimate in men, -0.62 years per unit increase in BMI; in women -0.18) and in individuals (particularly women) with diabetes compared to those without (slope estimate in women, -0.39 vs -0.18, p<0.001; in men -0.66 vs -0.62; p=0.66). CONCLUSIONS: The observation that the presence of diabetes doubles the slope of inverse relationship between hypertension onset age and BMI in women (while the slope is high in men irrespective of diabetes status) leads to a possible proposition that pre-existing diabetes narrows down sex-specific differences in the impact of obesity on blood pressure.

Impact of hypertension on the association of BMI with risk and age at onset of type 2 diabetes mellitus: age- and gender-mediated modifications.

AIMS: Given that BMI correlates with risk of Type 2 diabetes mellitus (T2DM), and that hypertension is a common comorbid condition, we hypothesize that hypertension augments significantly the impact of obesity on T2DM onset. METHODS: We obtained data on T2DM in Kuwaiti natives from Kuwait Health Network Registry. We considered 1339 comorbid individuals with onset of hypertension preceding that of T2DM, and 3496 non-hypertensive individuals but with T2DM. Multiple linear regressions, ANOVA tests, and Cox proportional hazards models were used to quantify the impact of hypertension on correlation of BMI with age at onset and risk of T2DM. RESULTS: Impact of increasing levels of BMI on age at onset ot T2DM is seen augmented in patients diagnosed with hypertension. We find that the slope of the inverse linear relationship between BMI and onset age of T2DM is much steep in hypertensive patients (-0.69, males and -0.39, females) than in non-hypertensive patients (-0.36, males and -0.17, females). The decline in onset age for an unit increase of BMI is two-fold in males than in females. Upon considering BMI as a categorical variable, we find that while the mean onset age of T2DM in hypertensive patients decreases by as much as 5-12 years in every higher BMI categories, significant decrease in non-hypertensive patients exists only when severely obese. Hazard due to hypertension (against the baseline of non-hypertension and normal weight) increases at least two-fold in every obese category. While males have higher hazard due to hypertension in early adulthood, females have higher hazard in late adulthood. CONCLUSION: Pre-existing condition of hypertension augments the association of BMI with Type 2 diabetes onset in both males and females. The presented results provide health professionals directives on the extent of weight-loss required to delay onset of Type 2 diabetes in hypertensive versus non-hypertensive patients.

Predictive models to assess risk of type 2 diabetes, hypertension and comorbidity: machine-learning algorithms and validation using national health data from Kuwait--a cohort study.

OBJECTIVE: We build classification models and risk assessment tools for diabetes, hypertension and comorbidity using machine-learning algorithms on data from Kuwait. We model the increased proneness in diabetic patients to develop hypertension and vice versa. We ascertain the importance of ethnicity (and natives vs expatriate migrants) and of using regional data in risk assessment. DESIGN: Retrospective cohort study. Four machine-learning techniques were used: logistic regression, k-nearest neighbours (k-NN), multifactor dimensionality reduction and support vector machines. The study uses fivefold cross validation to obtain generalisation accuracies and errors. SETTING: Kuwait Health Network (KHN) that integrates data from primary health centres and hospitals in Kuwait. PARTICIPANTS: 270 172 hospital visitors (of which, 89 858 are diabetic, 58 745 hypertensive and 30 522 comorbid) comprising Kuwaiti natives, Asian and Arab expatriates. OUTCOME MEASURES: Incident type 2 diabetes, hypertension and comorbidity. RESULTS: Classification accuracies of >85% (for diabetes) and >90% (for hypertension) are achieved using only simple non-laboratory-based parameters. Risk assessment tools based on k-NN classification models are able to assign 'high' risk to 75% of diabetic patients and to 94% of hypertensive patients. Only 5% of diabetic patients are seen assigned 'low' risk. Asian-specific models and assessments perform even better. Pathological conditions of diabetes in the general population or in hypertensive population and those of hypertension are modelled. Two-stage aggregate classification models and risk assessment tools, built combining both the component models on diabetes (or on hypertension), perform better than individual models. CONCLUSIONS: Data on diabetes, hypertension and comorbidity from the cosmopolitan State of Kuwait are available for the first time. This enabled us to apply four different case-control models to assess risks. These tools aid in the preliminary non-intrusive assessment of the population. Ethnicity is seen significant to the predictive models. Risk assessments need to be developed using regional data as we demonstrate the applicability of the American Diabetes Association online calculator on data from Kuwait.