Virome-wide serological profiling reveals association of herpesviruses with obesity.

The relationship between viral infection and obesity has been known for several decades but epidemiological data is limited to only a few viral pathogens. The association between obesity and a wide range of viruses was assessed using VirScan, a pan-viral serological profiling tool. Serum specimens from 457 Qatari adults (lean = 184; obese = 273) and 231 Qatari children (lean = 111; obese = 120) were analyzed by VirScan. Associations with obesity were determined by odds ratio (OR) and Fisher's test (p values), and by multivariate regression analysis to adjust for age and gender. Although there was no association of viral infections with obesity in the pediatric population, a nominal association of obesity with seropositivity to members of the Herpesviridae family is observed for the adult population (OR = 1.5-3.3; p < 0.05). After adjusting p values for multiple comparisons (Bonferroni correction) the odds of being obese is significantly higher in herpes simplex virus 1 (HSV-1) seropositive Qatari adults (OR = 3.3; 95% CI 2.15-4.99; p = 2.787E - 08). By VirScan, the sero-prevalence of HSV1 is 81.3% and 57.1% among Qatari obese and lean adult populations, respectively. Higher prevalence of antibodies against several peptide epitopes of HSV-1/2 is positively associated with obesity (OR = 2.35-3.82; p ≤ 3.981E - 05). By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. Our results suggest that obesity among Qataris may be associated with a higher prevalence of herpesvirus infections, in particular HSV-1. Furthermore, the high prevalence of antibodies against peptide antigens specific to HSV-1 and -2 in the obese population suggests that these viral peptides may play a role in adipogenesis. Further studies with these candidate peptides in cell culture or animal models may confirm their adipogenic roles.

Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population.

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified 'novel' risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders.

Presenting symptoms and time to diagnosis for Pediatric Central Nervous System Tumors in Qatar: a report from Pediatric Neuro-Oncology Service in Qatar.

INTRODUCTION: There are no previous published reports on primary pediatric tumors of the central nervous system (CNS) in Qatar. We undertook this retrospective cohort study to review the diagnosis of CNS tumors in children in Qatar to analyze the presentation characteristics including symptoms, referral pathways, and time to diagnosis. METHODS: All children registered with Pediatric Neuro-Oncology service (PNOS) were included in the study. Data from the time of diagnosis (October 2007 to February 2020) were reviewed retrospectively. Presenting symptoms were recorded and pre-diagnosis symptom interval (PSI) was calculated from the onset of the first symptom to the date of diagnostic imaging. RESULTS: Of the 61 children registered with PNOS during the study period, 51 were included in the final analysis. Ten children were excluded because they were either diagnosed outside Qatar (n = 7) or were asymptomatic at the time of diagnosis (n = 3). The median age was 45 (range 1-171) months. Common tumor types included low-grade glioma (LGG) (47.1%) and medulloblastoma/primitive neuro-ectodermal tumors (PNET) (23.5%). Nine children had an underlying neurocutaneous syndrome. Thirty-eight patients (74.5%) had at least one previous contact with healthcare (HC) professional, but 27 (52%) were still diagnosed through the emergency department (ED). Presenting symptoms included headache, vomiting (36.2%), oculo-visual symptoms (20.6%), motor weakness (18.9%), seizures, ataxia (17.2% each), irritability, cranial nerve palsies (12% each), and endocrine symptoms (10.3%). Median PSI was 28 days (range 1-845 days) for all CNS tumors. Longest PSI was seen with germ cell tumors (median 146 days), supratentorial location (39 days), and age above 3 years (30 days). Tumor characteristics of biological behavior (high-grade tumor) and location (infratentorial) were significantly associated with shorter PSI, as were presenting symptoms of ataxia, head tilt, and altered consciousness. CONCLUSIONS: Although overall diagnostic times were acceptable, some tumor types were diagnosed after a significant delay. The awareness campaign, such as the "HeadSmart" campaign in the United Kingdom (UK), can improve diagnostic times in Qatar. Further research is required to better understand the reasons for the delay.

Convalescent plasma for the treatment of patients with severe coronavirus disease 2019: A preliminary report.

BACKGROUND: The role of convalescent plasma therapy for patients with coronavirus disease 2019 (COVID-19) is unclear. METHODS: We retrospectively compared outcomes in a cohort of critical COVID-19 patients who received standard care (SC Group) and those who, in addition, received convalescent plasma (CP Group). RESULTS: In total, 40 patients were included in each group. The median patient age was 53.5 years (interquartile range [IQR] 42-60.5), and the majority of patients required invasive ventilation (69, 86.2%). Plasma was harvested from donors after a median of 37 days (IQR 31-46) from the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) result and 26 days (IQR 21-32) after documented viral clearance; it was administered after a median of 10 days (IQR 9-10) from the onset of symptoms and 2.5 days (IQR 2-4) from admission to intensive care unit. The primary endpoint of improvement in respiratory support status within 28 days was achieved in 26 patients (65%) in the SC Group and 31 patients (77.5%) in the CP Group (p = .32). The 28-day all-cause mortality (12.5% vs. 2.5%; p = .22) and viral clearance (65% vs. 55%; p = .49) were not significantly different between the two groups. Convalescent plasma was not significantly associated with the primary endpoint (adjusted hazard ratio 0.87; 95% confidence interval 0.51-1.49; p = .62). Adverse events were balanced between the two study groups. CONCLUSION: In severe COVID-19, convalescent plasma therapy was not associated with clinical benefits. Randomized trials are required to confirm our findings.

Adult Diabetes and Prediabetes Prevalence in Kuwait: Data from the Cross-Sectional Kuwait Diabetes Epidemiology Program.

BACKGROUND: This study aimed to estimate the prevalence of diabetes and prediabetes in adults in Kuwait. METHODS: The Kuwait Diabetes Epidemiology Program was a nationally representative, cross-sectional study of diabetes and obesity in Kuwait conducted between 2011 and 2014. The survey sampled 4937 adults in Kuwait aged 20 years or more and recorded participants' demographics, behaviours, medical history, physical measurements and blood biochemical measurements. Prediabetes was defined as fasting plasma glucose between 6.1 and 6.9 mmol/L or HbA1c between 6 and 6.4% (42-47 mmol/mol). Diabetes was defined as self-reported history with prescribed glucose-lowering medication or FPG ≥7mmol/L or HbA1c level ≥6.5% (≥48 mmol/mol). RESULTS: The overall adjusted prevalence of diabetes was 19.1%. The overall adjusted prevalence of prediabetes was 13.5%. Diabetes prevalence was 5.4%, 14.2%, 38.7% and 64.8% in adults aged 20-29, 30-44, 45-59 and 60 years or more, respectively. Diabetes prevalence was 22.4% in men and 14.4% in women. Prediabetes prevalence was 14.8% in men and 11.5% in women. In Kuwaitis, diabetes and prediabetes prevalence was 21.8% and 11.1%, respectively, while prevalence in non-Kuwaitis was 18.2% for diabetes and 14.3% for prediabetes. CONCLUSION: These findings illustrate the severe public health challenge posed by diabetes in Kuwait.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

BACKGROUND: Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. METHODS: We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aß-40), amyloid-beta-42 (Aß-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD. RESULTS: Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated. CONCLUSIONS: The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.

Genome-wide association study identifies novel risk variants from RPS6KA1, CADPS, VARS, and DHX58 for fasting plasma glucose in Arab population.

Consanguineous populations of the Arabian Peninsula, which has seen an uncontrolled rise in type 2 diabetes incidence, are underrepresented in global studies on diabetes genetics. We performed a genome-wide association study on the quantitative trait of fasting plasma glucose (FPG) in unrelated Arab individuals from Kuwait (discovery-cohort:n = 1,353; replication-cohort:n = 1,196). Genome-wide genotyping in discovery phase was performed for 632,375 markers from Illumina HumanOmniExpress Beadchip; and top-associating markers were replicated using candidate genotyping. Genetic models based on additive and recessive transmission modes were used in statistical tests for associations in discovery phase, replication phase, and meta-analysis that combines data from both the phases. A genome-wide significant association with high FPG was found at rs1002487 (RPS6KA1) (p-discovery = 1.64E-08, p-replication = 3.71E-04, p-combined = 5.72E-11; ß-discovery = 8.315; ß-replication = 3.442; ß-combined = 6.551). Further, three suggestive associations (p-values < 8.2E-06) with high FPG were observed at rs487321 (CADPS), rs707927 (VARS and 2Kb upstream of VWA7), and rs12600570 (DHX58); the first two markers reached genome-wide significance in the combined analysis (p-combined = 1.83E-12 and 3.07E-09, respectively). Significant interactions of diabetes traits (serum triglycerides, FPG, and glycated hemoglobin) with homeostatic model assessment of insulin resistance were identified for genotypes heterozygous or homozygous for the risk allele. Literature reports support the involvement of these gene loci in type 2 diabetes etiology.

PR3 levels are impaired in plasma and PBMCs from Arabs with cardiovascular diseases.

Cardiovascular disease (CVD) risks persist in patients despite treatment. CVD susceptibility also varies with sex and ethnicity and is not entirely explained by conventional CVD risk factors. The aim of the present study was to identify novel CVD candidate markers in circulating Peripheral blood mononuclear cells (PBMCs) and plasma from Arab obese subjects with and without CVD using proteomic approaches. Human adults with confirmed CVD (n = 208) and matched non-CVD controls (n = 152) living in Kuwait were examined in the present cross-sectional study. Anthropometric and classical biochemical parameters were determined. We employed a shotgun proteomic profiling approach on PBMCs isolated from a subset of the groups (n = 4, each), and differentially expressed proteins selected between the two groups were validated at the mRNA level using RT-PCR (n = 6, each). Plasma levels of selected proteins from the proteomics profiling: Proteinase-3 (PR3), Annexin-A3 (ANX3), Defensin (DEFA1), and Matrix Metalloproteinase-9 (MMP9), were measured in the entire cohort using human enzyme-linked immunosorbent assay kits and were subsequently correlated with various clinical parameters. Out of the 1407 we identified and quantified from the proteomics profiling, 47 proteins were dysregulated with at least twofold change between the two subject groups. Among the differentially expressed proteins, 11 were confirmed at the mRNA levels. CVD influenced the levels of the shortlisted proteins (MMP9, PR3, ANX3, and DEFA1) in the PBMCs and plasma differentially. Despite the decreased levels of both protein and mRNA in PBMCs, PR3 circulating levels increased significantly in patients with CVD and were influenced by neither diabetes nor statin treatment. No significant changes were; however, observed in the DEFA1, MMP9, and ANX3 levels in plasma. Multivariate logistic regression analysis revealed that only PR3 was independently associated with CVD. Our results suggest that the dysregulation of PR3 levels in plasma and PBMCs reflects underlying residual CVD risks even in the treated population. More prospective and larger studies are required to establish the role of PR3 in CVD progression.

A Teaching Intervention Increases the Performance of Handheld Ultrasound Devices for Assessment of Left Ventricular Ejection Fraction.

BACKGROUND: Few studies have demonstrated the utility of a teaching program for evaluation of left ventricular ejection fraction (LVEF) of echocardiographic images acquired with high-end machines. No study to date explored the value of similar programs when a handheld ultrasound device is used. The aim of this study was to determine whether a teaching intervention could improve the accuracy and the reliability of LVEF visual assessment of echocardiographic images acquired with HUD. MATERIALS AND METHODS: Twenty echocardiograms acquired with a hand-held ultrasound device with a spectrum of LVEF were presented to 26 participants with varying experience in echocardiography (range 2-12 years) for single-point LVEF visual estimates. After this baseline assessment, participants underwent three training sessions which included analysis of the individual baseline results and review and interpretation of additional 60 cases from the same platform. After 2 months, 20 new echocardiograms were presented to the same 26 participants for visual LVEF assessment. For each participant, the visual LVEF for each case was compared with the reference LVEF (quantitative measurements by experts), and a difference of > ±5% was considered a misclassification. RESULTS: The misclassification rate was 61% preintervention and decreased to 41% after intervention (P < 0.0001). The mean absolute differences in LVEF between visual estimates and reference before and after intervention for all readers were -7.9 ± 9.6 and -1.2 ± 7.8, respectively (P < 0.0001). Inter-rater repeatability analysis was performed using the intraclass correlation coefficient. The intraclass correlation coefficient for inter-rater reliability was fair preintervention (0.65, 95% confidence interval [CI] 0.59 0.71) and good after intervention (0.80, 95% CI 0.73 0.87), and there were no differences when categorized according to the level of experience. CONCLUSIONS: A teaching intervention can improve the accuracy and the reliability in the visual LVEF assessment of images acquired with handheld ultrasound device.

A Systematic Review of Childhood Diabetes Research in the Middle East Region.

Background: Diabetes mellitus (DM) is a common chronic disorder in children and is caused by absolute or relative insulin deficiency, with or without insulin resistance. There are several different forms of childhood DM. Children can suffer from neonatal diabetes mellitus (NDM), type 1 diabetes (T1DM), type 2 diabetes (T2DM), Maturity Onset Diabetes of the Young (MODY), autoimmune monogenic, mitochondrial, syndromic and as yet unclassified forms of DM. The Middle East has one of the highest incidences of several types of DM in children; however, it is unclear whether pediatric diabetes is an active area of research in the Middle East and if ongoing, which research areas are of priority for DM in children. Objectives: To review the literature on childhood DM related to research in the Middle East, summarize results, identify opportunities for research and make observations and recommendations for collaborative studies in pediatric DM. Methods: We conducted a thorough and systematic literature review by adhering to a list recommended by PRISMA. We retrieved original papers written in English that focus on childhood DM research, using electronic bibliographic databases containing publications from the year 2000 until October 2018. For our final assessment, we retrieved 429 full-text articles and selected 95 articles, based on our inclusion and exclusion criteria. Results: Our literature review suggests that childhood DM research undertaken in the Middle East has focused mainly on reporting retrospective review of case notes, a few prospective case studies, systemic reviews, questionnaire-based studies, and case reports. These reported studies have focused mostly on the incidence/prevalence of different types of DM in childhood. No studies report on the establishment of National Childhood Diabetes Registries. There is a lack of consolidated studies focusing on national epidemiology data of different types of childhood DM (such as NDM, T1DM, T2DM, MODY, and syndromic forms) and no studies reporting on clinical trials in children with DM. Conclusions: Investing in and funding basic and translational childhood diabetes research and encouraging collaborative studies, will bring enormous benefits financially, economically, and socially for the whole of the Middle East region.

The Effect of High-Dose Postpartum Maternal Vitamin D Supplementation Alone Compared with Maternal Plus Infant Vitamin D Supplementation in Breastfeeding Infants in a High-Risk Population. A Randomized Controlled Trial.

In view of continuing reports of high prevalence of severe vitamin D deficiency and low rate of infant vitamin D supplementation, an alternative strategy for prevention of vitamin D deficiency in infants warrants further study. The aim of this randomized controlled trial among 95 exclusively breastfeeding mother-infant pairs with high prevalence of vitamin D deficiency was to compare the effect of six-month post-partum vitamin D3 maternal supplementation of 6000 IU/day alone with maternal supplementation of 600 IU/day plus infant supplementation of 400 IU/day on the vitamin D status of breastfeeding infants in Doha, Qatar. Serum calcium, parathyroid hormone, maternal urine calcium/creatinine ratio and breast milk vitamin D content were measured. At baseline, the mean serum 25-hydroxyvitamin D (25(OH)D) of mothers on 6000 IU and 600 IU (35.1 vs. 35.7 nmol/L) and in their infants (31.9 vs. 29.6) respectively were low but similar. At the end of the six month supplementation, mothers on 6000 IU achieved higher serum 25(OH)D mean ± SD of 98 ± 35 nmol/L than 52 ± 20 nmol/L in mothers on 600 IU (p < 0.0001). Of mothers on 6000 IU, 96% achieved adequate serum 25(OH)D (≥50 nmol/L) compared with 52%in mothers on 600 IU (p < 0.0001). Infants of mothers on 600 IU and also supplemented with 400 IU vitamin D3 had slightly higher serum 25(OH)D than infants of mothers on 6000 IU alone (109 vs. 92 nmol/L, p = 0.03); however, similar percentage of infants in both groups achieved adequate serum 25(OH)D ≥50 nmol/L (91% vs. 89%, p = 0.75). Mothers on 6000 IU vitamin D3/day also had higher human milk vitamin D content. Safety measurements, including serum calcium and urine calcium/creatinine ratios in the mother and serum calcium levels in the infants were similar in both groups. Maternal 6000 IU/day vitamin D3 supplementation alone safely optimizes maternal vitamin D status, improves milk vitamin D to maintain adequate infant serum 25(OH)D. It thus provides an alternative option to prevent the burden of vitamin D deficiency in exclusively breastfeeding infants in high-risk populations and warrants further study of the effective dose.

The Complex Etiology of Childhood Obesity in Arabs Is Highlighted by a Combination of Biological and Socio-Economic Factors.

Objectives: To identify predictors of childhood and adolescent obesity in Kuwaitis with Arab ethnicity. Methods: A cross-sectional sample of 6-18 year-old schoolchildren was randomly selected from 244 public schools across all six governorates in the State of Kuwait. Anthropometric data were measured from 6,574 Arab Kuwaiti schoolchildren, and a structured questionnaire was used to collect information on possible risk factors associated with obesity. Overweight and obesity were defined in accordance with the Center for Disease Control and Prevention criteria. Results: The prevalence of overweight and obesity in children (aged 6-18 years) were 17.7% and 33.7%, respectively. The likelihood of childhood obesity increased with birth weights >4.0 Kg [odds ratio (OR) = 2.3; p < 0.0001], maternal employment (OR = 1.26, p = 0.0006), maternal age at pregnancy >30 years (OR = 1.24; p = 0.0016) and family size of <6 members (OR = 1.16, p = 0.0106). Conclusions: Public health professionals should be aware that advanced maternal age, maternal employment, smaller family size, and high birthweight may predict the risk of obesity in Kuwaiti Arab children and adolescents.

Genome-wide association study identifies novel recessive genetic variants for high TGs in an Arab population.

Abnormal blood lipid levels are influenced by genetic and lifestyle/dietary factors. Although many genetic variants associated with blood lipid traits have been identified in Europeans, similar data in Middle Eastern populations are limited. We performed a genome-wide association study with Arab individuals (discovery cohort: 1,353; replication cohort: 1,176) from Kuwait to identify possible associations of genetic variants with high lipid levels. We used Illumina HumanOmniExpress BeadChip and candidate SNP genotyping in the discovery and replication phases, respectively. For association tests, we used genetic models that were based on additive and recessive modes of inheritance. High triglycerides (TGs) were recessively associated with six risk variants (rs1002487/RPS6KA1, rs11805972/LAD1) rs7761746/Or5v1, rs39745/CTTNBP2-LSM8, rs2934952/PGAP3, and rs9626773/RP11-191L9.4-CERK) at genome-wide significance (P  6.12E-09), and another six variants (rs10873925/ST6GALNAC5, rs4663379/SPP2-ARL4C, rs10033119/NPY1R, rs17709449/LINC00911-FLRT2, rs11654954/CDK12-NEUROD2, and rs9972882/STARD3) were associated at borderline significance (P  5.0E-08). High TG was also additively associated with rs11654954. All of the 12 identified markers are novel and are harbored in runs of homozygosity. Literature evidence supports the involvement of these gene loci in lipid-related processes. This study in an Arab population augments international efforts to identify genetic regulation of lipid traits.

Investigation of genetic variation and lifestyle determinants in vitamin D levels in Arab individuals.

BACKGROUND: Differences in the concentrations of circulating 25-hydroxyvitamin D [25(OH)D] are associated with a wide range of health outcomes; however, most studies on genetic variants that impact 25(OH)D levels have been conducted in European populations. Here we aimed to identify common genetic variants that affect vitamin D concentrations in individuals of self-reported Arab ethnicity. METHODS: The study included 1151 Arab subjects living in Kuwait. Common variants of single-nucleotide polymorphisms and genes previously associated with vitamin D levels, such as GC, PDE3B, CYP2R1, and NADSYN1, were genotyped. Raw vitamin D level data were corrected for age, body mass index, and sex and then normalized. Regression tree analyses were performed to identify the impact of genetic variants on vitamin D levels. RESULTS: Compared with other gene variants, the GC gene variants exhibited the greatest impact on vitamin D levels in our study population, of which rs2298850 had the lowest p value (0.003). Individuals homozygous for the derived allele C had lower vitamin D levels. Analyses of the interaction between the number of years for which the subjects had lived in Kuwait and genetic variation in the GC gene showed that those with the CC genotype of rs2298850 who had lived in Kuwait for < 51 years had a mean 25(OH)D level of 10 ng/ml, whereas those who were homozygous for the ancestral allele had a mean 25(OH)D level of 17 ng/ml. Furthermore, subjects who had lived in Kuwait for > 51 years had higher vitamin D levels (mean 28 ng/ml) regardless of the genotype of their GC gene. CONCLUSIONS: The GC gene may play a major role in determining vitamin D levels in Arab populations.

DUSP1 Is a Potential Marker of Chronic Inflammation in Arabs with Cardiovascular Diseases.

BACKGROUND: Cardiovascular disease (CVD) risks persist in patients despite the use of conventional treatments. This might be due to chronic inflammation as reflected in epidemiological studies associating circulating low-grade inflammatory markers with CVD recurrent events. Here, we explored this potential link by assessing plasma dual-specificity phosphatase 1 (DUSP1) levels and comparing them to high-sensitivity CRP (hsCRP) and oxidized low-density lipoprotein (oxLDL) levels and their associations to conventional CVD risk factors in confirmed CVD patients. METHODS: Human adults with reported CVD (n = 207) and controls (n = 70) living in Kuwait were used in this study. Anthropometric and classical biochemical parameters were determined. Plasma levels of DUSP1, oxLDL, and hsCRP were measured using human enzyme-linked immunosorbent assay kits. RESULTS: DUSP1 and hsCRP plasma levels and their least square means were higher in CVD cases, while oxLDL plasma levels were lower (p < 0.05). Multivariate logistic regression analysis showed that DUSP1 and hsCRP are independently associated with CVD in the studied population, as reflected by 2-fold and 1.5-fold increased risks with increased levels of DUSP1 and hsCRP, respectively. In our study, DUSP1 levels were found to be associated with CVD despite statin treatment and diabetes status (p < 0.05), whereas hsCRP mainly correlated with obesity markers. CONCLUSIONS: Circulating DUSP1 might be a predictor of chronic subclinical inflammation and residual risk in CVD patients, whereas our data suggest that the association between hsCRP and CVD is largely accounted for adiposity risk factors.

The TCN2 variant of rs9606756 [Ile23Val] acts as risk loci for obesity-related traits and mediates by interacting with Apo-A1.

OBJECTIVE: Despite alarming obesity levels in the Arabian Peninsula, its population lacks convincingly identified genetic determinants of obesity. A genome-wide association study was performed for obesity-related anthropometric traits in Arabs and to decipher mechanisms by which the variants mediate traits. METHODS: The Illumina HumanOmniExpress BeadChip was used to genotype 1,353 Arab individuals (largely with Class I obesity) from Kuwait. Genome-wide association tests for obesity-related anthropometric traits were performed. Top associations were tested for replication in an independent cohort (1,176 unrelated Arabs). Resultant variants were investigated for interactions with obesity-related plasma biomarkers. Pathway analysis was performed on genes harboring markers in linkage disequilibrium (LD) with identified variants. RESULTS: The rs9606756[c.67A>G,p.Ile23Val] variant from TCN2 was associated with waist circumference (WC) at nearly genome-wide significance (P = 8.92E-08). WC was inversely related with Apo-A1 or high-density lipoprotein levels; individuals with the AG genotype exhibited stronger relationship than those with the reference AA genotype. Interaction involving the AG genotype (effect allele = G) significantly contributed to an increase in anthropometric traits (particularly WC). Genes harboring single-nucleotide polymorphisms in LD with rs9606756 mapped onto an interaction network (with TP53 as central element) of established obesity/diabetes-related protein components. CONCLUSIONS: The TCN2 variant acts as a risk factor for WC in the Arab population. The variant mediates obesity-related anthropometric traits via interactions with Apo-A1/high-density lipoprotein or TP53.

Ethnic differences in association of high body mass index with early onset of Type 1 diabetes - Arab ethnicity as case study.

OBJECTIVE: The "accelerator hypothesis" predicts early onset of Type 1 diabetes (T1D) in heavier children. Studies testing direction of correlation between body mass index (BMI) and age at onset of T1D in different continental populations have reported differing results-inverse, direct, and neutral. Evaluating the correlation in diverse ethnic populations is required to generalize the accelerator hypothesis. METHODS: The study cohort comprised 474 Kuwaiti children of Arab ethnicity diagnosed with T1D at age 6 to 18 years during 2011-2013. Age- and sex-adjusted BMI z-scores were calculated by comparing the BMI measured at diagnosis with Kuwaiti pediatric population reference data recorded during comparable time-period. Multiple linear regression and Pearson correlation analyses were performed. RESULTS: BMI z-score was seen inversely associated with onset age (r,-0.28; p-value<0.001). Children with BMI z-score>0 (i.e. BMI >national average) showed a stronger correlation (r,-0.38; p-value<0.001) than those with BMI z-score<0 (r,-0.19; p-value<0.001); the former group showed significantly lower mean onset age than the latter group (9.6±2.4 versus 10.5±2.7; p-value<0.001). Observed inverse correlation was consistent with that seen in Anglo-saxon, central european, caucasian, and white children while inconsistent with that seen in Indian, New Zealander, and Australian children. CONCLUSIONS: The accelerator hypothesis generalizes in Arab pediatric population from Kuwait.

Genetic risk variants for metabolic traits in Arab populations.

Despite a high prevalence of metabolic trait related diseases in Arabian Peninsula, there is a lack of convincingly identified genetic determinants for metabolic traits in this population. Arab populations are underrepresented in global genome-wide association studies. We genotyped 1965 unrelated Arab individuals from Kuwait using Cardio-MetaboChip, and tested SNP associations with 13 metabolic traits. Models based on recessive mode of inheritance identified Chr15:40531386-rs12440118/ZNF106/W->R as a risk variant associated with glycated-hemoglobin at close to 'genome-wide significant' p-value and five other risk variants 'nominally' associated (p-value ≤ 5.45E-07) with fasting plasma glucose (rs7144734/[OTX2-AS1,RPL3P3]) and triglyceride (rs17501809/PLGRKT; rs11143005/LOC105376072; rs900543/[THSD4,NR2E3]; and Chr12:101494770/IGF1). Furthermore, we identified 33 associations (30 SNPs with 12 traits) with 'suggestive' evidence of association (p-value < 1.0E-05); 20 of these operate under recessive mode of inheritance. Two of these 'suggestive' associations (rs1800775-CETP/HDL; and rs9326246-BUD13/TGL) showed evidence at genome-wide significance in previous studies on Euro-centric populations. Involvement of many of the identified loci in mediating metabolic traits was supported by literature evidences. The identified loci participate in critical metabolic pathways (such as Ceramide signaling, and Mitogen-Activated Protein Kinase/Extracellular Signal Regulated Kinase signaling). Data from Genotype-Tissue Expression database affirmed that 7 of the identified variants differentially regulate the up/downstream genes that mediate metabolic traits.

Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone.

BACKGROUND AND OBJECTIVES: Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. METHODS: Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. RESULTS: Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). CONCLUSION: Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

ANGPTL8/Betatrophin R59W variant is associated with higher glucose level in non-diabetic Arabs living in Kuwaits.

BACKGROUND: ANGPTL8 (betatrophin) has been recently identified as a regulator of lipid metabolism through its interaction with ANGPTL3. A sequence variant in ANGPTL8 has been shown to associate with lower level of Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL). The objective of this study is to identify sequence variants in ANGPTL8 gene in Arabs and investigate their association with ANGPTL8 plasma level and clinical parameters. METHODS: A cross sectional study was designed to examine the level of ANGPTL8 in 283 non-diabetic Arabs, and to identify its sequence variants using Sanger sequencing and their association with various clinical parameters. RESULTS: Using Sanger sequencing, we sequenced the full ANGPTL8 gene in 283 Arabs identifying two single nucleotide polymorphisms (SNPs) Rs.892066 and Rs.2278426 in the coding region. Our data shows for the first time that Arabs with the heterozygote form of (c.194C > T Rs.2278426) had higher level of Fasting Blood Glucose (FBG) compared to the CC homozygotes. LDL and HDL level in these subjects did not show significant difference between the two subgroups. Circulation level of ANGPTL8 did not vary between the two forms. No significant changes were observed between the various forms of Rs.892066 variant and FBG, LDL or HDL. CONCLUSION: Our data shows for the first time that heterozygote form of ANGPTL8 Rs.2278426 variant was associated with higher FBG level in Arabs highlighting the importance of these variants in controlling the function of betatrophin.