A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis.Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis.Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (−1920*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067–6.877), P = 0.033 and OR 1.768 (1.060–2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086–2.338), P = 0.017].Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.

Macrophage migration inhibitory factor in Nodding syndrome

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS.Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

Common Polymorphisms in the RGMa Promoter Are Associated With Cerebrovascular Atherosclerosis Burden in Chinese Han Patients With Acute Ischemic Cerebrovascular Accident

Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01–2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01–0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.

Association between common polymorphisms in IL-1 and TNFα and risk of peri-implant disease: A meta-analysis

Background Pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) play important roles in host immune response and bone metabolism during dental implant osseointegration. Whether the functional polymorphisms in IL-1α, IL-1β and TNFα were associated with peri-implant disease was unclear, and we performed the present meta-analysis for this purpose. Methods Eligible studies investigating IL-1α C-889T, IL-1β C+3954T and C-511T, TNFα G-308A, composite genotype of IL-1α C-889T and IL-1β C+3954T for association with peri-implant disease, including peri-implantitis (PI), marginal bone loss (MBL) and implant failure/loss (IF/IL), were searched on several literature databases prior to April 30, 2021. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each polymorphism in different genetic models and for composite genotype comparing carriers to non-carriers. Results Twenty-seven studies (1324 cases with peri-implant disease and 1808 controls with healthy implants) were included. There was significant correlation between IL-1α C-889T and peri-implant disease in all genetic models. IL-1β C+3954T was associated with peri-implant disease risk in allelic (OR = 1.66, 95%CI 1.17–2.35, p = 0.004) and dominant model (OR = 1.74, 95%CI 1.19–2.53, p = 0.004), and in subgroups of Asians, Caucasians, non-smokers, IF/IL and PI. TT genotype of IL-1β C-511T increased the risk of peri-implant disease (OR = 1.68, 95%CI 1.15–2.43, p = 0.007) and MBL (OR = 4.33, 95%CI 1.72–10.9, p = 0.002) compared to CC+CT genotypes. We did not observed a significant association between TNFα G-308A and peri-implant diseases in overall or subgroups analysis. Carriers of positive composite genotype of IL-1α C-889T and IL-1β C+3954T had 1.95-fold (95%CI 1.35–2.80, p<0.001) risk of peri-implant disease and 1.76-fold (95%CI 1.05–2.95, p = 0.032) risk of IF/IL than non-carriers. Conclusion Functional polymorphisms of IL-1α (C-889T), IL-1β (C+3954T, C-511T) and composite genotype of IL-1 can be used as predictive markers for peri-implant disease, whereas TNFα G-308A polymorphism was not associated with peri-implant disease.

Programmed Death-Ligand 1 (PD-L1) Gene Polymorphisms as Predictive Markers for Development of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients

Background Hepatocellular carcinoma is the sixth most common cause of cancer, and ranks fourth among the causes of cancer-related death. Major risk factors for HCC include chronic alcohol consumption, hepatitis B, hepatitis C and non-alcoholic fatty liver disease. Other, less common causes are Wilson’s disease, hereditary hemochromatosis, alpha1-antitrypsin deficiency, primary biliary cirrhosis and autoimmune hepatitis. Objective To investigate the associations of the genetic variants of PD-L1 (rs4143815 and rs2297136) with the risk of HCC in the Egyptian population. Patients and Methods This study was conducted in co-operation between Gastroenterology and Hepatology Department, Ain-Shams University and the Gastroenterology and Hepatology Department, Theodor Bilharz Research Institute “between” March 2020 to July 2020. It included total participants of 138 Divided to Group (A): 35 normal people as control. Group (B): 51 patients with HCV infection and cirrhosis Group (c): 52 patients with HCV infection and cirrhosis with HCC. The patients were recruited from the outpatient clinic of Theodor Bilharz Research Institute Hospital (after consents were obtained). Results Also, the present study demonstrated that the functional polymorphisms (rs4143815) (CG) of the PD-L1 gene were associated with HCC risk as it is expressed in (53.3%) in HCC, (25.6%) in cirrhosis and (23.1%) in control group. And, rs4143815 (CG) show significant increase in Child C patients as (75%) Child C vs. (10%) Child A and (45%) was MELD/NA (20-29) vs. (10%) &lt;9 with (61%) of patients were stage D in BCLC. There is significant increase in rs4143815 (CG) with age as 95% of gene positive patients more than 50years.With no significant in gender as 70% males and 30% females and there is no significant in smoking and DM. So, PDL-1 gene polymorphism rs4143815 (CG) could be used as a predictive marker for HCC after validation by larger studies or met analysis. Conclusion The present study demonstrated that the functional polymorphisms (rs4143815) (CG) of the PD-L1 gene were associated with HCC risk as it is expressed in (53.3%) of HCC, (25.6%) of cirrhosis and (23.1) % of control group. There is significant increase in rs4143815 (CG) with age as 95% of gene positive patients more than 50 years with no significance in gender smoking and DM. rs4143815 (CG) show significant increase in Child C patients as (75%) Child C vs. (10%) Child A and (45%) of patients was MELD/NA (20-29) vs. (10%) &lt;9 and (70%) of patients were stage D in BCLC.

Prevalence and mortality of COVID-19 are associated with the L55M functional polymorphism of Paraoxonase 1

Introduction Accumulating evidence recommends that infectious diseases including coronavirus disease 2019 (COVID-19) are often associated with oxidative stress and inflammation. Paraoxonase 1 ( PON1, OMIM: 168,820), a member of the paraoxonase gene family, has antioxidant properties. Enzyme activity of paraoxonase depends on a variety of influencing factors such as polymorphisms of PON1, ethnicity, gender, age, and a number of environmental variables. The PON1 has two common functional polymorphisms, namely, Q192R (rs662) and L55M (rs854560). The R192 and M55 alleles are associated with increase and decrease in enzyme activity, respectively. Objective The present study was conducted to investigate the possible association of rs662 and rs854560 polymorphisms with morbidity and mortality of COVID-19. Methods Data for the prevalence, mortality, and amount of accomplished diagnostic test (per 106 people) on 25 November 2020 from 48 countries were included in the present study. The Human Development Index (HDI) was used as a potential confounding variable. Results The frequency of M55 was positively correlated with the prevalence (partial r = 0.487, df = 36, p = 0.002) and mortality of COVID-19 (partial r = 0.551, df = 36, p < 0.001), after adjustments for HDI and amount of the accomplished diagnostic test as possible confounders. Conclusions This means that countries with higher M55 frequency have higher prevalence and mortality of COVID-19.

Association of a GATA Binding Protein 4 Polymorphism with the Risk of Hypospadias in the Chinese Children

<b><i>Purpose:</i></b> GATA binding protein 4 (GATA4) has been implicated in the etiology of congenital malformation of the urogenital system. The present study investigated the influence of <i>GATA4</i> polymorphisms on susceptibility to hypospadias. <b><i>Methods:</i></b> We genotyped 4 potentially functional polymorphisms (rs12458, rs12825, rs884662, and rs904018) in <i>GATA4</i> in the hospital-based case-control study including 410 child patients and 520 nonmalformed individuals by the TaqMan MGB method. Risk associations were assessed using unconditional logistic regression, adjusted for potential confounding factors. <b><i>Results:</i></b> A significant association was found between rs12458 (3′-UTR of <i>GATA4</i>) and susceptibility to hypospadias (<i>p</i> = 0.008). Compared with rs12458 AA genotype individuals, those harboring the variant allele (rs12458 AT/TT) were correlated with significantly higher risk of hypospadias (AT/TT vs. AA: OR = 1.42, 95% CI = 1.17–2.35, <i>p</i> = 0.036). Furthermore, the rs12458T allele showed significantly decreased activity in a luciferase reporter assay, indicating a possible role of rs12458 variant in regulating the combination of microRNAs with the <i>GATA4</i> mRNA. <b><i>Conclusions:</i></b> The present results indicate that the functional <i>GATA4</i> rs12458 variant confers individuals’ susceptibility to hypospadias, possibly through regulating the <i>GATA4</i> expression level.

CD33 mRNA Has Elevated Expression Levels in the Leukocytes of Peripheral Blood in Patients with Late-Onset Alzheimer’s Disease

<b><i>Background/Aims:</i></b> In despite of conflicting results among different ethnic groups, the rs3865444 of CD33 gene has previously been identified as a risk factor for late-onset Alzheimer’s disease (LOAD).This study was aimed to evaluate the association between rs3865444 SNP with LOAD occurrence, and to investigate whether CD33 mRNA expression will change in the leukocytes of peripheral blood in LOAD patients. <b><i>Methods:</i></b> The rs3865444 polymorphism was genotyped in 233 LOAD and 238 control subjects using the Tetra-ARMS-PCR method. CD33 mRNAs expression in leukocytes were assessed and analyzed using the real-time qPCR method. We used in silico approach to analyze potential effects imparted by rs3865444 polymorphism in LOAD pathogenesis. <b><i>Results:</i></b> Our results show a significant increase in CD33 mRNA expression levels in white blood cells of LOAD patients, however, the association between CD33 rs3865444 polymorphism and LOAD was found to be not significant. We also noticed that LOAD patients with the C/A genotype had higher CD33 mRNA levels in their peripheral blood than those of the control group. <b><i>Conclusions:</i></b> rs3865444, located upstream of the 5′CD33 coding region, might positively influence CD33 mRNAs expression in leukocytes of LOAD versus healthy people. This is likely to happen through interfering rs3865444 (C) with the functional activity of several other transcription factors given that rs3865444 is in linkage disequilibrium with other functional polymorphisms in this coding region according to an in silico study. We propose that CD33 mRNAs elevation in peripheral immune cells – as a potential biomarker in LOAD – is related to peripheral immune system impairment.

Endothelial nitric oxide synthase G894T, intron 4 VNTR, and T786C polymorphisms in retinopathy of prematurity

BACKGROUND: Our objective in this study was to assess the association between eNOS gene, that achieves synthesis of nitric oxide especially in the endothelial cells known to have an important role in angiogenesis and vasculogenesis, G894T, intron 4 VNTR (27-bp repeat) and T786C functional polymorphisms and retinopathy of prematurity (ROP), which is an important cause of morbidity in premature or low birth weight babies. METHODS: A total of 139 babies who were followed up in our neonatal intensive care unit because of premature birth in our hospital or admitted to our unit. 69 of them had retinopathy of prematurity and comprised the patients group. The remaining 70 babies who did not have ROP comprised the control group. An additional of 1 ml of blood samples were drawn from babies who were in the study groups during routine laboratory analysis. eNOS gene polymorphisms were determined by using polymerase chain reaction method. RESULTS: eNOS G894T, intron 4 VNTR and T786C gene polymorphisms did not differ between the patient and control groups (p > 0.05). Using logistic regression analysis; while gender did not differ between two groups; gestational age, birth weight, time on mechanical ventilation differ between two groups. After adjustment for variables other than eNOS gene polymorphisms, we found no significant difference in the genotype distribution of eNOS G894T, intron 4 VNTR and T786C polymorphisms (p > 0.05). CONCLUSION: We observed no association between ROP and eNOS gene polymorphisms but needs more investigation.

C3435T Polymorphism of the ABCB1 gene in the Yakut Population

Background: The ABCB1 gene is responsible for resistance to various cytotoxic drugs. The product of the ABCB1 gene, P-glycoprotein (P-gp), acts as a transmembrane pump and influences the action of many drugs. More than 40 SNPs of the ABCB1 gene that alter the expression of P-gp have been identified. The ABCB1 rs1045642 SNP, designated as C3435T (C-the wild-type allele, T-the variant allele), correlates with the activity of P-gp. The aim of our research was to study the distribution of alleles and genotypes of the ABCB1 C3435T polymorphism in Yakuts, in comparison with other human populations. Methods and Results: The studied cohort included 149 healthy Yakut volunteers (36 men and 113 women). The average age of participants was 30.67±0.06 years. The ABCB1 gene is a highly polymorphic gene; the allele frequency of the C3435T polymorphism differs widely among the studied populations. The frequency of the mutant T-allele among the Yakuts was 51% .In the studied group of Yakuts, we revealed the prevalence of the heterozygous CT genotype (75.8%). The Yakuts have a relatively low frequency of CC (10.7%) and TT (13.4%) genotypes. This preliminary study did not include the objective of proving the relationship between the ABCB1 C3435T polymorphism and addictive disorders in Yakuts. The further search for functional polymorphisms of the ABCB1 gene and associations with addictive behavior using a systematic approach on larger samples is of great practical importance.