Vitamin D deficiency (VDD) is widespread in the Arab world despite ample sunshine throughout the year. In our previous study, lifestyle and socio-demographic factors could explain only 45% of variability in vitamin D levels in Kuwaiti adolescents, suggesting that genetics might contribute to VDD in this region. Single nucleotide polymorphisms (SNP) in the 25-hydroxylase (CYP2R1) and the GC globulin (GC) genes have been reported to affect vitamin D levels in various ethnic groups in adults. In this study, we investigated the association of two SNPs from GC (rs4588 and rs7041) and three SNPs from CYP2R1 (rs10741657, rs11023374 and rs12794714) with vitamin D levels and VDD in a nationally representative sample of adolescents of Arab ethnicity from Kuwait. Multivariable linear regression, corrected for age, sex, parental education, governorate, body mass index, and exposure to sun, demonstrated that each of the 5 study variants showed significant associations with plasma 25(OH)D levels in one or more of the additive, recessive, and dominant genetic models - the rs10741657 under all the three models, rs12794714 under both the additive and recessive models, rs7041 under the recessive model; and rs4588 and rs11023374 under the dominant model. Minor alleles at rs4588 (T), rs7041 (A), rs11023374 (C), and rs12794714 (A) led to a decrease in plasma 25(OH)D levels - rs4588:[β (95%CI) = -4.522 (-8.66,-0.38); p=0.033]; rs7041:[β (95%CI) = -6.139 (-11.12,-1.15); p=0.016]; rs11023374:[β (95%CI) = -4.296 (-8.18,-0.40); p=0.031]; and rs12794714:[β (95%CI) = -3.498 (-6.27,-0.72); p=0.014]. Minor allele A at rs10741657 was associated with higher levels of plasma 25(OH)D levels [β (95%CI) = 4.844 (1.62,8.06); p=0.003)] and lower odds of vitamin D deficiency (OR 0.40; p=0.002). These results suggest that the CYP2R1 and GC SNP variants are partly responsible for the high prevalence of VDD in Kuwait. Genotyping these variants may be considered for the prognosis of VDD in Kuwait.

Angiopoietin-like proteins (ANGPTLs) mediate many metabolic functions. We had recently reported increased plasma levels of ANGPTL8 in obese adults of Arab ethnicity. However, data on ANGPTL8 levels in adolescent obesity is lacking. Arab population is characterized by a rapid transition, due to sudden wealth seen in the post-oil era, in lifestyle, food habits and extent of physical activity. We adopted a cross-sectional study on Arab adolescents from Kuwait to examine the role of ANGPTL8 in adolescent obesity. The study cohort included 452 adolescents, aged 11-14 years, recruited from Middle Schools across Kuwait. BMI-for-age growth charts were used to categorize adolescents as normal-weight, overweight, and obese. ELISA and bead-based multiplexing assays were used to measure plasma levels of ANGPTL8 and other inflammation and obesity-related biomarkers. Data analysis showed significant differences in the plasma levels of ANGPTL8 among the three subgroups, with a significant increase in overweight and obese children compared to normal-weight children. This observation persisted even when the analysis was stratified by sex. Multinomial logistic regression analysis illustrated that adolescents with higher levels of ANGPTL8 were 7 times more likely to become obese and twice as likely to be overweight. ANGPTL8 levels were correlated with those of hsCRP, leptin and chemerin. ANGPTL8 level had a reasonable prognostic power for obesity with an AUC of 0.703 (95%-CI=0.648-0.759). These observations relating to increased ANGPTL8 levels corresponding to increased BMI-for-age z-scores indicate that ANGPTL8, along with hsCRP, leptin and chemerin, could play a role in the early stages of obesity development in children. ANGPTL8 is a potential early marker for adolescent obesity and is associated with well-known obesity and inflammatory markers.

Leucine-rich α-2 glycoprotein1 (LRG1) has been shown to be associated with several health conditions; however, its association with iron deficiency anemia, especially in children, has not been previously explored. In this study, we investigated the association between LRG1 and several iron deficiency anemia markers, including hemoglobin (Hb), albumin, red cell distribution width (RDW), iron, ferritin, and Hb transferrin saturation. A total of 431 participants were included in this analysis aged between 11 and 14 years. Higher LRG1 levels were observed in children diagnosed with anemia [31.1 (24.6, 43.2) µg/mL] compared to non-anemic children [29.2 (22.7–35.95) µg/mL]. Statistically significant differences of LRG1 level across the three groups (tertiles) of Hb, iron, transferrin saturation, albumin, RDW, ferritin, and WBC were observed. Strong negative correlations were observed between LRG1 and Hb (Spearman’s rho = −0.11, p = 0.021), albumin (Spearman’s rho = −0.24, p < 0.001), iron (Spearman’s rho = −0.25, p < 0.001), and Hb transferrin saturation (Spearman’s rho = −0.24, p < 0.001), whereas circulating LRG1 levels were positively associated with RDW (Spearman’s rho = 0.21, p < 0.001). In conclusion, our findings demonstrate for the first time the strong association between iron deficiency anemia markers and LRG1 in otherwise healthy school-aged children. However, further studies are needed to corroborate those results and to look for similar associations in other population subgroups.

Efficient signal transduction is important in maintaining the function of the nervous system across tissues. An intact neurotransmission process can regulate energy balance through proper communication between neurons and peripheral organs. This ensures that the right neural circuits are activated in the brain to modulate cellular energy homeostasis and systemic metabolic function. Alterations in neurotransmitters secretion can lead to imbalances in appetite, glucose metabolism, sleep, and thermogenesis. Dysregulation in dietary intake is also associated with disruption in neurotransmission and can trigger the onset of type 2 diabetes (T2D) and obesity. In this review, we highlight the various roles of neurotransmitters in regulating energy balance at the systemic level and in the central nervous system. We also address the link between neurotransmission imbalance and the development of T2D as well as perspectives across the fields of neuroscience and metabolism research.

The Wolfram syndrome 1 gene (WFS1) is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 WFS1 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on WFS1 play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3’ UTR variant from WFS1, namely rs1046322, influenced the affinity of miR-668 to WFS1 mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the WFS1 rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m2], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for WFS1 in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.

AIMS:Melanocortin 4 receptor (MC4R) has a well-established role in regulating appetite, food intake and energy homeostasis. Setmelanotide is an MC4R agonist currently approved for weight loss in obese adults and children with mutations in components of the leptin-melanocortin pathway. This study aims to compare structural and functional aspects of the physiological MC4R agonist α-melanocyte-stimulating hormone (α-MSH) with setmelanotide. We also aim to show the binding affinity of setmelanotide to known MC4R human missense mutations associated with obesity.MAIN METHODS:AutoDock Vina was used in the structural analysis to calculate induced fit docking scores of ligand binding to MC4R wild type or the selected variants. HEK293-MC4R were utilized in the functional analysis of MC4R-actiavted pathways upon stimulating with α-MSH or setmelanotide.KEY FINDINGS:Our data shows that setmelanotide has a higher potency for cAMP formation and a weaker effect on ERK1/2 phosphorylation when compared to α-MSH indicating functional selectivity otherwise known as biased agonism. We also present structural data showing that setmelanotide has a higher binding affinity to MC4R compared to α-MSH. Lastly, we show that two loss-of-function and two gain-of-function MC4R variants change the conformation not only of the ligand binding pocket of the receptor but also of the peptide when bound to the receptor because the interaction network and the residues involved in the binding are altered.SIGNIFICANCE:Taken together, our study provides important insights into the diversity of MC4R signaling pathways which will facilitate the development of personalized anti-obesity drugs via refining MC4R agonists.

Diabetic nephropathy (DN) is a serious complication of diabetes affecting about half the people with diabetes and the leading cause of end stage renal disease (ESRD). Albuminuria and creatinine levels are currently the classic markers for the diagnosis of DN. However, many shortcomings are arising from the use of these markers mainly because they are not specific to DN and their levels are altered by multiple non-pathological factors. Therefore, the aim of this study is to identify better markers for the accurate and early diagnosis of DN. The study was performed on 159 subjects including 42 control subjects, 50 T2D without DN and 67 T2D subjects with DN. Our data show that circulating N-cadherin levels are significantly higher in the diabetic patients who are diagnosed with DN (842.6 ± 98.6 mg/l) compared to the diabetic patients who do not have DN (470.8 ± 111.5 mg/l) and the non-diabetic control group (412.6 ± 41.8 mg/l). We also report that this increase occurs early during the developmental stages of the disease since N-cadherin levels are significantly elevated in the microalbuminuric patients when compared to the healthy control group. In addition, we show a significant correlation between N-cadherin levels and renal markers including creatinine (in serum and urine), urea and eGFR in all the diabetic patients. In conclusion, our study presents N-cadherin as a novel marker for diabetic nephropathy that can be used as a valuable prognostic and diagnostic tool to slow down or even inhibit ESRD.

Obstructive sleep apnea (OSA) is prevalent in the bariatric population. OSA should be recognized in patients undergoing bariatric surgery preoperatively to prevent peri- and post-operative complications. Lipid metabolism-related biomarkers are associated with OSA. Triglyceride metabolism is, among others, regulated by angiopoietin-like protein five (ANGPTL5). We aimed to evaluate the level of ANGPTL5 in patients with OSA of different severity levels before and after bariatric surgery. We performed a single-center prospective cohort study including a consecutive series of patients who underwent bariatric surgery. We collected the clinical data, polysomnography (PSG) or polygraphy (PG) parameters, and plasma derived via venipuncture before and 6 to 12 months after surgery. Lipid profile, glucose levels, and ANGPTL5 levels were assessed. ANGPTL5 levels were measured using an enzyme-linked immunosorbent assay (ELISA). The study included 88 patients for analysis. The patients were divided into two subgroups: no or mild OSA (apnea–hypopnea index (AHI) < 15 events/hour, n = 57) and moderate-to-severe OSA (AHI ≥ 15 events/hour, n = 31). The ANGPTL5 level was higher in the moderate-to-severe OSA group (20.5 [15.6, 26.5] ng/mL) compared to the no or mild OSA group (16.3 [12.5, 19.4] ng/mL) (p = 0.008). A significant positive correlation was observed between ANGPTL5 and AHI (ρ = 0.256, p = 0.017), apnea index (AI) (ρ = 0.318, p = 0.003), and triglyceride levels (ρ = 0.240, p = 0.025). ANGPTL5 levels were reduced significantly after bariatric surgery in both moderate-to-severe OSA (15.6 [10.3, 18.7] ng/mL) and no or mild OSA (13.4 [9.2, 15.8] ng/mL) groups, though to a lower level in the group without or mild OSA. Post-surgery, the significant positive correlation between ANGPTL5 and AHI (ρ = 0.210, p = 0.047), AI (ρ = 0.230, p = 0.034), and triglyceride (ρ = 0.397, p < 0.001) remained. The data showed increased levels of ANGPTL5 in patients with moderate-to-severe OSA. Both AHI and ANGPTL5 levels decreased significantly after bariatric surgery. We also report an association between ANGPTL5 levels and OSA severity.

The corticotropin-releasing hormone (CRH) and urocortins (UCNs) have been implicated in energy homeostasis and the cellular stress response. However, the expression of these neuropeptides in children remains unclear. Therefore, we determined the impact of obesity on their expression in 40 children who were normal weight, overweight, and had obesity. Peripheral blood mononuclear cells (PBMCs) and plasma were used to assess the expression of neuropeptides. THP1 cells were treated with 25 mM glucose and 200 µM palmitate, and gene expression was measured by real-time polymerase chain reaction (RT-PCR). Transcript levels of neuropeptides were decreased in PBMCs from children with increased body mass index as indicated by a significant decrease in UCN1, UCN3, and CRH mRNA in overweight and obese children. UCN3 mRNA expression was strongly correlated with UCN1, UCN2, and CRH. Exposure of THP1 cells to palmitate or a combination of high glucose and palmitate for 24 h increased CRH, UCN2, and UCN3 mRNA expression with concomitant increased levels of inflammatory and endoplasmic reticulum stress markers, suggesting a crosstalk between these neuropeptides and the cellular stress response. The differential impairment of the transcript levels of CRH and UCNs in PBMCs from overweight and obese children highlights their involvement in obesity-related metabolic and cellular stress.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that is implicated in multiple diseases, including cancer, aging, and heart failure, as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β-oxidation. In this study, we investigated the association of LRG1 with obesity markers, including leptin and other adipokines in adolescents (11–14 years; n = 425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA, while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese (30 (25, 38) µg/mL) and overweight (30 (24, 39) µg/mL) adolescents, compared to normal-weight participants (27 (22, 35) µg/mL). The highest tertile of LRG1 had an OR [95% CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of high sensitivity c-reactive protein (HsCRP) (ρ = 0.2), leptin (ρ = 0.2), and chemerin (ρ = 0.24) with p < 0.001. Additionally, it was positively associated with plasma level of IL6 (ρ = 0.17) and IL10 (ρ = 0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese adolescents and are associated with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It is a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Our aim was to quantify levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP7 in fasting plasma samples of 69 Kuwaiti participants and explore its correlation with indices of OSA. The quantification was performed using multiplexing assay. The study involved 28 controls and 41 patients with OSA. Levels of circulating IGFBP4 were significantly higher in people with OSA (289.74 ± 23.30 ng/ml) compared to the control group (217.60 ± 21.74 ng/ml, p = 0.028). The increase in IGFBP4 correlated significantly and positively with AHI (r = .574, p = .01) and AI (r = .794, p = .001) in people with moderate and severe OSA. There was a significant decline in circulating IGFBP4 after 3 months of surgery (225.89 ± 18.16 ng/ml, p = 0.012). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001). In this study, our data showed a significant increase in circulating IGFBP4 in people with OSA. We also report a significant positive correlation between IGFBP4 and indices of OSA at baseline, which suggests IGFBP4 as a potential diagnostic biomarker for OSA. There was a significant improvement in OSA after 3 months of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, the detected change suggests a potential link between IGFBP4 and OSA or an OSA-related factor, whereby OSA might play a role in triggering the induction of IGFBP4 expression.

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of metabolism. In adults, IGFBPs are associated with obesity and insulin resistance. However, the association of IGFBPs with metabolic homeostasis in children and adolescents is not yet fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight, central adiposity and cardiovascular disease markers HsCRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. Results showed that levels of IGFBP-1 were significantly lower in obese and overweight children when compared to normal weight children. Correlation analysis showed negative association between the level of IGFBP- 1 and waist circumference to height (WC/Ht) ratio. IGFBP-1 level was also negatively associated with Hs-CRP. It was also observed that the levels of IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. Our data demonstrate a strong negative association of IGFBP-1 with overweight/obesity, and the inflammatory marker Hs-CRP. This was not seen with the levels of IGFBP-3 and 7. The association of IGFBP-1 with central adiposity (WC/Ht ratio) was stronger than its association with BMI-for-age zscore. Therefore we suggest that IGFBP-1 could potentially be used as a sensitive biomarker for obesity and its subsequent effects in screening and monitoring of obesityrelated metabolic complications in adolescents.

The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people (81 diabetic and 181 non-diabetic persons) that took two doses of BNT162b2 (Pfizer–BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. The mean ( ± 1 standard deviation) levels were 154 ± 49.1 vs. 138 ± 59.4 BAU/ml for IgG and 87.1 ± 11.6 vs. 79.7 ± 19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection, and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95% CI: 27.08 to 0.64 BAU/ml, p=0.041) less IgG antibodies and 4.42% (95% CI: 8.53 to 0.32%, p=0.036) fewer neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine; nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity. Nonetheless, it is important that people get their COVID-19 vaccination especially people with diabetes.

COVID-19 is challenging healthcare preparedness, world economies, and livelihoods. The infection and death rates associated with this pandemic are strikingly variable in different countries. To elucidate this discrepancy, we analyzed 2431 early spread SARS-CoV-2 sequences from GISAID. We estimated continental-wise admixture proportions, assessed haplotype block estimation, and tested for the presence or absence of strains’ recombination. Herein, we identified 1010 unique missense mutations and seven different SARS-CoV-2 clusters. In samples from Asia, a small haplotype block was identified, whereas samples from Europe and North America harbored large and different haplotype blocks with nonsynonymous variants. Variant frequency and linkage disequilibrium varied among continents, especially in North America. Recombination between different strains was only observed in North American and European sequences. In addition, we structurally modelled the two most common mutations, Spike_D614G and Nsp12_P314L, which suggested that these linked mutations may enhance viral entry and replication, respectively. Overall, we propose that genomic recombination between different strains may contribute to SARS-CoV-2 virulence and COVID-19 severity and may present additional challenges for current treatment regimens and countermeasures. Furthermore, our study provides a possible explanation for the substantial second wave of COVID-19 presented with higher infection and death rates in many countries.

Background: The emergence of new COVID-19 variants of concern coupled with a global inequity in vaccine access and distribution has prompted many public health authorities to circumvent the vaccine shortages by altering vaccination protocols and prioritizing persons at high risk. Individuals with previous COVID-19 infection may not have been prioritized due to existing humoral immunity. Objective: We aimed to study the association between previous COVID-19 infection and antibody levels after COVID-19 vaccination. Methods: A serological analysis to measure SARS-CoV-2 immunoglobulin (Ig)G, IgA, and neutralizing antibodies was performed on individuals who received one or two doses of either BNT162b2 or ChAdOx1 vaccines in Kuwait. A Student t-test was performed and followed by generalized linear regression models adjusted for individual characteristics and comorbidities were fitted to compare the average levels of IgG and neutralizing antibodies between vaccinated individuals with and without previous COVID-19 infection. Results: A total of 1,025 individuals were recruited. The mean levels of IgG, IgA, and neutralizing antibodies were higher in vaccinated subjects with previous COVID-19 infections than in those without previous infection. Regression analysis showed a steeper slope of decline for IgG and neutralizing antibodies in vaccinated individuals without previous COVID-19 infection compared to those with previous COVID-19 infection. Conclusion: Previous COVID-19 infection appeared to elicit robust and sustained levels of SARS-CoV-2 antibodies in vaccinated individuals. Given the inconsistent supply of COVID-19 vaccines in many countries due to inequities in global distribution, our results suggest that even greater efforts should be made to vaccinate more people, especially individuals without previous COVID-19 infection.

Angiopoietin-like proteins (ANGPTL) is a family of eight members known to play an important role in metabolic diseases. Of these, ANGPTL5 is suggested to regulate triglyceride metabolism and is increased in obesity and diabetes. However, its role in metabolic diseases in adolescents is not well-studied. In this study, we tested the hypothesis of a positive association between plasma ANGPTL5, and obesity, high sensitivity C-reactive protein (HsCRP) and oxidized low-density lipoprotein (Ox-LDL) in adolescents. Adolescents (N = 431; age 11–14 years) were randomly selected from middle schools in Kuwait. Obesity was classified by the BMI-for-age based on the WHO growth charts. Plasma ANGPTL5, HsCRP, and Ox-LDL were measured using ELISA. The prevalence of overweight and obesity was 20.65% and 33.18%, respectively. Mean (SD) plasma ANGPTL5 levels were significantly higher in obese, compared with overweight and normal-weight adolescents (23.05 (8.79) vs 18.39 (7.08) ng/mL, and 18.26 (6.95) ng/ml, respectively). ANGPTL5 was positively associated with both HsCRP (ρ=0.27, p < 0.001) and Ox-LDL (ρ = 0.24, p < 0.001). In Conclusion, ANGPTL5 levels are elevated in obese adolescents and are associated with cardiovascular disease risk factors, HsCRP and Ox-LDL. The use of ANGPTL5 as a powerful diagnostic and prognostic tool in obesity and metabolic diseases needs to be further evaluated.

Melanocortin 4 receptor (MC4R), a notable component of the melanocortin system, regulates appetite, body weight, and energy homeostasis. Genome-wide association studies have identified several MC4R variants associated with adiposity; of these, rs17782313, which is associated with increased body mass index (BMI) and overeating behavior, is of particular interest. Another gene associated with increased adiposity in global genome-wide association studies is DNAJC27, a heat shock protein known to be elevated in obesity. The detailed mechanisms underlying the role of MC4R variants in the biological pathways underlying metabolic disorders are not well-understood. To address this, we assessed variations of rs17782313 in a cohort of 282 Arab individuals from Kuwait, who are deeply phenotyped for anthropometric and metabolic traits and various biomarkers, including DNAJC27. Association tests showed that the rs17782313_C allele was associated with BMI and DNAJC27 levels. Increased levels of DNAJC27 reduced the MC4R-mediated formation of cAMP in MC4R ACTOne stable cells. In conclusion, this study demonstrated an association between the rs17782313 variant near MC4R and increased BMI and DNAJC27 levels and established a link between increased DNAJC27 levels and lower cAMP levels. We propose that regulation of MC4R activity by DNAJC27 enhances appetite through its effect on cAMP, thereby regulating obesity.

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.

Myeloperoxidase (MPO) is positively associated with obesity and diet-induced insulin resistance. Angiopoietin-like protein 6 (ANGPTL6) regulates metabolic processes and counteract obesity through increased energy expenditure. This study aims to evaluate the plasma MPO and ANGPTL6 levels in obese and diabetic individuals as well as MPO association with biochemical markers of obesity. A total of 238 participants were enrolled, including 137 control and 101 type 2 diabetes (T2D) patients. ANGPTL6 and MPO levels and other biomarkers were measured via ELISA. ANGPTL6 levels were significantly higher in the diabetic population and obese individuals. When the group was stratified based on T2D, ANGPTL6 levels were significantly higher in obese-diabetic participants compared with non-obese-diabetics, but obese-non-diabetic individuals had similar ANGPTL6 levels to their controls. MPO levels were higher in obese compared with non-obese participants but did not differ between T2D and control participants. MPO levels were upregulated in obese compared with non-obese in both diabetics and non-diabetics. MPO was positively associated with ANGPTL6, triglyceride, BMI, TNF-alpha, high-sensitivity C-reactive protein, interleukin-6, and plasminogen activator inhibitor-1. Taken together, our findings suggest that both MPO and ANGPTL6 may regulate obesity, although MPO exerts this effect independent of diabetes while ANGPTL6 may have a modulatory role in diabetes.

Background: IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It’s a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive Sleep Apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Methods: We quantified levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4 and IGFBP7 in fasting plasma samples of 67 Kuwaiti participant using Multiplexing assay. The study involved 28 controls, and 39 patients with OSA.Results: Levels of circulating IGFBP4 were significantly higher in people with OSA (253.65 ±20.46 ng/ml) compared to the control group (173.35 ±20.86 ng/ml, p = 0.008). There was an increase in levels of IGFBP3 and IGFBP7, however it was not significant. People with OSA had a significantly high AHI score (22.99 ±3.39 events/h) in comparison to the control (2.12 ±0.2 events/h). The increase in IGFBP4 correlated positively to IGFBP7 (r = 0.422, P = 0.01). There was a significant decline in circulating IGFBP4 after 3-months of surgery (225.89 ±18.16 ng/ml, p = 0.012). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001). Conclusion: In this study our data showed a significant increase in circulating IGFBP4 in people with OSA. we also report a significant positive correlation between IGFBP4 and IGFBP7 at baseline, which suggests a potential synergy in the actions of IGFBP4 and IGFBP7 at conditions of OSA-induced hypoxia. OSA significantly improved after 3-month of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, this suggests a potential role for IGFBP4 in OSA-induced hypoxia.