Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

Background: Type 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies. Methods: This cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina’s Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control. Findings: The analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4). Interpretation: We have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina’s Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies

An insight into the paradigms of osteoporosis: From genetics to biomechanics

© 2019 The Authors Considered as one of the major epidemics of the 21st century, osteoporosis affects approximately 200 million people globally, with significant worldwide impact on rates of morbidity and mortality and massive socioeconomic burdens. Mainly characterized by decreased bone mineral density (BMD) and increased risk of bone fragility/deterioration, this devastating silent epidemic typically has no symptoms until a fracture occurs. The multifactorial disease, osteoporosis is instigated by complex interactions between genetic, metabolic and environmental factors, with severe impact on the biomechanics of the musculoskeletal system. This article provides a review of the epidemiology, genetic and biomechanical aspects of primary osteoporosis. The review begins with a summary of the epidemiology and global prevalence of osteoporosis. Sections 1 and 2 discuss the genetic associations and molecular signaling pathways involved in normal and pathological osteogenesis while Section 3 explores the biomechanics of osteoporosis and its quantitative damaging effects on critical bone mechanical properties, and associated bone remodeling. Overall, this review summarizes the recent findings about osteoporosis and emphasizes the importance of an integrative holistic approach in investigating osteoporosis towards providing better informed, more effective preventive and treatment modalities. Importantly, this work also explores the limited available literature on the various aspects of osteoporosis in the United Arab Emirates (UAE), Gulf Cooperation Council (GCC), and Middle East despite its alarming prevalence in the region, and highlights the need for further research and studies taking into consideration the importance of the vitamin D receptor (VDR) gene influencing the development of osteoporosis

HLA pharmacogenetic markers of drug hypersensitivity from the perspective of the populations of the Greater Middle East

Specific HLA associations with drug hypersensitivity may vary between geographic regions and ethnic groups. There are little to no data related to HLA-drug hypersensitivity on populations who reside in the Greater Middle East (GME), a vast region spanning from Morocco in the west to Pakistan in the east. In this review, the authors intended to summarize the significant HLA alleles associated with hypersensitive drug reactions induced by different drugs, as have been found in different populations, and to summarize the prevalence of these alleles in the specific and diverse populations of the GME. For example, HLA-B * 57:01 allele prevalence, associated with abacavir-induced hypersensitivity, ranges from 1 % to 3 %, and HLA-DPB1 * 03:01 prevalence, associated with aspirin-induced asthma, ranges from 10 % to 14 % in the GME population. Studying pharmacogenomic associations in the ethnic groups of the GME may allow the discovery of new associations, confirm ones found with a low evidence rate and enable cost-effectiveness analysis of allele screening before drug use

COVID-19 disease severity and death in relation to vitamin D status among SARS-CoV-2-positive UAE residents

Insufficient blood levels of the neurohormone vitamin D are associated with increased risk of COVID-19 severity and mortality. Despite the global rollout of vaccinations and promising preliminary results, the focus remains on additional preventive measures to manage COVID-19. Results conflict on vitamin D’s plausible role in preventing and treating COVID-19. We examined the relation between vitamin D status and COVID-19 severity and mortality among the multiethnic population of the United Arab Emirates. Our observational study used data for 522 participants who tested positive for SARS-CoV-2 at one of the main hospitals in Abu Dhabi and Dubai. Only 464 of those patients were included for data analysis. Demographic and clinical data were retrospectively analyzed. Serum samples immediately drawn at the first hospital visit were used to measure serum 25-hydroxyvitamin D [25(OH)D] concentrations through automated electrochemiluminescence. Levels \u3c 12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and of death. Age was the only other independent risk factor, whereas comorbidities and smoking did not contribute to the outcomes upon adjustment. Sex of patients was not an important predictor for severity or death. Our study is the first conducted in the UAE to measure 25(OH)D levels in SARS-CoV-2-positive patients and confirm the association of levels \u3c 12 ng/mL with COVID-19 severity and mortality

Altered Composition of the Oral Microbiota in Depression Among Cigarette Smokers: A Pilot Study

Alterations in the oral microbiota composition may influence mental health. However, linkages between compositional changes in the oral microbiota and their role in mental health among cigarette smokers remain largely unknown. In this study, we used shotgun metagenomics data for the oral microbiome of 105 participants. The data showed Bacteroidota, Fusobacteriota, Firmicutes, Proteobacteria, and Actinobacteria to be the most abundant phyla; Streptococcus, Haemophilus D, and Veillonella are the most abundant genera. Then, we clustered our subjects into avoidance and activation groups based on the behavioral activation for depression scale (BADS). Interestingly, the avoidance group exhibited a higher oral microbiome richness and diversity (alpha diversity). Differential abundance testing between BADS avoidance and activation groups showed the phyla Bacteroidota (effect size 0.5047, q = 0.0037), Campylobacterota (effect size 0.4012, q = 0.0276), Firmicutes A (effect size 0.3646, q = 0.0128), Firmicutes I (effect size 0.3581, q = 0.0268), and Fusobacteriota (effect size 0.6055, q = 0.0018) to be significantly increased in the avoidance group, but Verrucomicrobiota (effect size−0.6544, q = 0.0401), was found to be significantly decreased in the avoidance risk group. Network analysis of the 50 genera displaying the highest variation between both groups identified Campylobacter B, Centipeda, and Veillonella as hub nodes in the avoidance group. In contrast, Haemophilus and Streptococcus were identified as hub nodes in the activation group. Next, we investigated functional profiles of the oral microbiota based on BADS avoidance and activation groups and found Lysine degradations pathway was significantly enriched between both groups (ANCOM-BC, q = 0.0692). Altogether, we provide evidence for the presence of depression-related changes in the oral microbiota of smokers and possible functional contribution. The identified differences provide new information to enrich our understanding of oral microbiota-brain axis interplay and their potential impact on mental health

Genetic studies of metabolic syndrome in Arab populations: A systematic review and meta-analysis

Background: The metabolic syndrome (MetS) is prevalent in Arabian populations. Several small-scale studies have been performed to investigate the genetic basis of MetS. This systematic review and meta-analysis aimed to examine whether candidate gene polymorphisms are associated with MetS susceptibility among ethnic groups of the Arabian world and to suggest possible directions for future research regarding genetic markers and MetS. Methods: A search was conducted for peer-reviewed articles that examined the genetic association of MetS in Arabian populations in the following databases: Medline, Embase, Scopus, Direct Science, Web of Science, ProQuest, and Google Scholar until March 31, 2021. Articles were eligible if they were case-control studies, which investigated MetS as a dichotomous outcome (MetS vs no MetS). To assess the quality of the studies, the Q-Genie tool (Quality of Genetic Association Studies) was used. A non-central chi2 (random-effect) distribution was used to determine the heterogeneity (H) of Q and I (Galassi et al., The American journal of medicine, 2006, 119, 812–819) statistics. Results: Our search strategy identified 36 studies that met our inclusion criteria. In most cases, studies were excluded due to a lack of statistical information such as odds ratios, confidence intervals, and p-values. According to the Q-Genie tool, 12 studies scored poorly (a score of ≤ 35), 13 studies scored moderately ( \u3e 35 and ≤ 45), and 12 studies had good quality ( \u3e 45 or higher). The most frequently studied genes were FTO and VDR (both included in four studies). Three SNPs indicated increased risk for MetS after calculating the pooled odds ratios: FTO-rs9939609 (odds ratio 1.49, 95% CI: 0.96–2.32); LEP-rs7799039 (odds ratio 1.85, 95% CI: 1.37–2.5); and SERPINA12-rs2236242 (odds ratio 1.65, 95% CI: 1.21–2.24). Meta-analysis studies showed no significant heterogeneity. Conclusion: There were many sources of heterogeneity in the study settings. Most of the studies had low to moderate quality because of sample size and power issues, not considering all potential sources of bias, and not providing details about genotyping methods and results. As most studies were small-scale, aimed to replicate findings from other populations, we did not find any unique genetic association between MetS and Arabian populations

Introducing the first whole genomes of nationals from the United Arab Emirates

Whole Genome Sequencing (WGS) provides an in depth description of genome variation. In the era of large-scale population genome projects, the assembly of ethnic-specific genomes combined with mapping human reference genomes of underrepresented populations has improved the understanding of human diversity and disease associations. In this study, for the first time, whole genome sequences of two nationals of the United Arab Emirates (UAE) at \u3e27X coverage are reported. The two Emirati individuals were predominantly of Central/South Asian ancestry. An in-house customized pipeline using BWA, Picard followed by the GATK tools to map the raw data from whole genome sequences of both individuals was used. A total of 3,994,521 variants (3,350,574 Single Nucleotide Polymorphisms (SNPs) and 643,947 indels) were identified for the first individual, the UAE S001 sample. A similar number of variants, 4,031,580 (3,373,501 SNPs and 658,079 indels), were identified for UAE S002. Variants that are associated with diabetes, hypertension, increased cholesterol levels, and obesity were also identified in these individuals. These Whole Genome Sequences has provided a starting point for constructing a UAE reference panel which will lead to improvements in the delivery of precision medicine, quality of life for affected individuals and a reduction in healthcare costs. The information compiled will likely lead to the identification of target genes that could potentially lead to the development of novel therapeutic modalities

Clinical and genetic associations of renal function and diabetic kidney disease in the United Arab Emirates: A cross-sectional study

OBJECTIVES: Within the Emirati population, risk factors and genetic predisposition to diabetic kidney disease (DKD) have not yet been investigated. The aim of this research was to determine potential clinical, laboratory and reported genetic loci as risk factors for DKD. RESEARCH DESIGN AND METHODS: Four hundred and ninety unrelated Emirati nationals with type 2 diabetes mellitus (T2DM) were recruited with and without DKD, and clinical and laboratory data were obtained. Following adjustments for possible confounders, a logistic regression model was developed to test the associations of 63 single nucleotide polymorphisms (SNPs) in 43 genetic loci with DKD (145 patients with DKD and 265 without DKD). Linear regression models, adjusted for age and gender, were then used to study the genetic associations of five renal function traits, including 83 SNPs with albumin-to-creatinine ratio, 92 SNPs with vitamin D (25-OH cholecalciferol), 288 SNPs with estimated glomerular filtration rate (eGFR), 363 SNPs with serum creatinine and 73 SNPs with blood urea. RESULTS: Patients with DKD, as compared with those without the disease, were mostly men (52%vs38% for controls), older (67vs59 years) and had significant rates of hypertension and dyslipidaemia. Furthermore, patients with DKD had T2DM for a longer duration of time (16vs10 years), which in an additive manner was the single factor that significantly contributed to the development of DKD (p=0.02, OR=3.12, 95% CI 1.21 to 8.02). Among the replicated associations of the genetic loci with different renal function traits, the most notable included CONCLUSIONS: Associations were found between several genetic loci and risk markers for DKD, which may influence kidney function traits and DKD in a population of Arab ancestry