Association between Functional CYP2D6 Polymorphisms and Susceptibility to Autoimmune Diseases: A Meta-Analysis

Objective: This study aimed to explore whether functional CYP2D6 polymorphisms are associated with susceptibility to autoimmune diseases.

Methods: A meta-analysis was conducted on associations between autoimmune diseases and functional CYP2D6*4 1934 A/G and *3 polymorphisms and CYP2D6 phenotypes.

Results: Twelve studies with 1,472 patients and 3,328 controls were included. Autoimmune disease and the CYP2D6 1934 A allele were significantly associated in the overall group, consistent with the Hardy–Weinberg equilibrium (OR = 1.227, 95% CI = 1.071–1.406, p = 0.003); stratification by ethnicity indicated that the CYP2D6 1934 A allele and autoimmune diseases were associated in Caucasians (OR = 1.225, 95% CI = 1.010–1.485, p = 0.039). The CYP2D6*3 allele was also associated with autoimmune diseases in Caucasians (OR = 1.977, 95% CI = 1.125–3.472, p = 0.018). Stratified by autoimmune disease type revealed that the CYP2D6 1934 AA genotype was associated with systemic lupus erythematosus (SLE; OR = 2.007, 95% CI = 1.170–3.442, p = 0.011) and ankylosing spondylitis (AS; OR = 2.317, 95% CI = 1.422–3.774, p = 0.001). The CYP2D6 PM+IM phenotype was significantly associated with autoimmune diseases in Caucasians (OR = 1.526, 95% CI = 1.038–2.246, p = 0.032) and with SLE (OR = 1.778, 95% CI = 1.249–2.532, p = 0.001).

Conclusions: This meta-analysis indicates that CYP2D6*4 and *3 polymorphisms and the CYP2D6 phenotype are associated with susceptibility to autoimmune diseases in Caucasians; particularly, the CYP2D6*4 polymorphism and CYP2D6 PM+IM phenotype are risk factors for SLE development.     

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using a next generation sequencing platform

Background: CYP3A5 is the predominant sub-family of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of inter-individual and inter-ethnic differences in CYP3A-mediated drug disposition and response.

Aim: This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using a next generation sequencing platform.

Methods: Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed.

Results: A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524, which is in the 3’UTR, and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3).

Conclusions: The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unravelled and the findings in this study may serve as a guide for the optimisation of pharmacotherapy for the Orang Asli community.     

Matrix Metalloproteinase-9 rs17576 Gene Polymorphism and Behçet’s Disease: Is There an Association?

Background: Clinical studies have reported a significant association between matrix metalloproteinases (MMP), particularly (MMP-9), and inflammatory diseases including Behçet’s disease (BD).

Purpose: To study the relationship between MMP-9 rs17576 gene polymorphism and the development of BD, and its relation to disease activity among Egyptian patients.

Methods: A total of 100 BD patients and 100 healthy control volunteers were genotyped for MMP-9 rs17576 polymorphism with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), followed by the confirmation of our results in random subgroups using direct DNA sequencing technique.

Results: The frequency of the GG genotype and G allele was significantly higher in BD patients as compared to the normal controls (p = 0.011, OR 8.61; p = 0.03, OR 1.65, respectively). There was no significant association between the MMP-9 rs17576 polymorphism and the clinical outcomes of BD.

Conclusion: our study suggests a significant association of the MMP-9 rs17576 A/G polymorphism with increased risk of BD development in Egyptian patients.     

Identification of IL2RG and CYBB mutations in two Chinese primary immunodeficiency patients by whole-exome sequencing

Background: Primary immunodeficiency diseases are a group of genetic disorders that lead to increased propensity to a variety of infections, sometimes with fatal outcomes.

Method: In this study, whole-exome sequencing (WES) was used to identify mutations in two patients suspected of having primary immunodeficiency. Sanger sequencing was used to confirm the results in the patients and their family.

Result: One patient was diagnosed as X-linked severe combined immunodeficiency (X-SCID) and another patient as X-linked chronic granulomatous disease (X-CGD) by WES. Sequencing analysis of IL2RG gene revealed a novel mutation (c.794T>A, p.I265N) and CYBB gene revealed a missense mutation (c.935T>A, p.M312K).

Discussion and conclusion: This study identifies one novel mutation in the IL2RG gene and another, previously described mutation in the CYBB genes. It is the first report establishing a diagnosis of X-SCID and X-CGD using WES in Chinese patients.     

Harpagoside-induced anaphylactic reaction in an IgE-independent manner both in vitro and in vivo

Background: Harpagoside (HAR) is an active component of Scrophularia ningpoensis (SN), which has anti-inflammatory and anti-immune effects. SN is used widely in China to treat various diseases. Recently, SN has been used as a traditional Chinese medicine injection and used clinically. However, allergic responses to these injections are frequently reported.

Aim: We examined whether the main component of SN, HAR, is associated with the allergic reaction to SN.

Methods: This study assessed the effects of HAR in mice and mast cell activation to characterize its anaphylactic effects and underlying mechanisms. Mice hindpaw swelling, serum allergy factor detection, enzyme-linked immunosorbent assays, and degranulation assays were performed to measure allergic mediators both in vivo and in vitro.

Results: The present study indicated that HAR induced paw swelling, interleukin-6, inositol triphosphate, tumor necrosis factor-α, and histamine increases in mice. Our in vitro data also showed that HAR induced β-hexosaminidase, inositol triphosphate, and interleukin-6 release, leading to mast cell degranulation. In contrast, neither C48/80 nor HAR induced local anaphylaxis in STOCK Kit^W-sh/HNihrJaeBsmJNju mice.

Conclusions: HAR is a potential sensitization compound in SN, and these results provide information for the safe clinical use of SN.     

Lack of Association between MYO9B Gene Polymorphisms and Susceptibility to Coeliac Disease in Caucasians: Evidence from a Meta-Analysis

Objective: Coeliac disease (CD) is a complex disorder influenced by environmental and genetic factors. Recently, a number of studies reported MYO9B gene is associated with CD, but the results are controversial. The aim of this study is to clarify this dispute by means of a meta-analysis.

Methods: The databases of PubMed, Web of Science, and Embase updated to August 2015 were retrieved. Crude odds ratio (OR) and corresponding 95% confidence interval (95%CI) as effect size were calculated by fixed or random effect model according to the heterogeneity.

Results: A total of 8 studies including 2272 cases and 5419 controls were enrolled in this meta-analysis. There was no significant association both in allele and genotype comparisons between the MYO9B (rs2305764, rs2305767, rs1457092) polymorphism and CD in Caucasian populations. No publication bias was detected in this meta-analysis.

Conclusions: This meta-analysis indicates that MYO9B gene polymorphisms might be not associated with CD susceptibility in Caucasians. Further studies are still needed for definitive conclusions.     

Distribution of xenobiotic metabolising enzyme genotypes in different Tunisian populations

Background: The N-acetyltransferase 2 (NAT2) and glutathione transferase enzymes play a crucial role in the metabolism of xenobiotics. Genetic polymorphisms affecting these enzymes can modify their activities with an effect on individual susceptibility for different pathologies. These metabolic phenotypes occur with varying prevalence in different populations.

Aim: This study sought to analyse the prevalence of important allelic variants of NAT2, GSTM1 and GSTT1 in different Tunisian populations and compare them to other previously reported data.

Subjects and methods: A total of 253 unrelated subjects from different Tunisian populations participated in this study. Subjects were examined with respect to the frequency of slow NAT2, GSTM1*0 and GSTT1*0 genotypes.

Results: The frequency of ‘slow’ NAT2, GSTM1*0 and GSTT1*0 genotypes in the Tunisian population were, respectively, estimated at 23.3%, 53.75% and 29.24%. The frequency of slow NAT2 and GSTM1*0 genotypes were significantly different between the North, Centre and South of Tunisia. However, this study doesn’t report any significant differences in the genotype distribution between Cosmopolitan, Arab and Berber populations.

Conclusions: In conclusion, these data indicate that the Tunisian population is highly heterogenic and, therefore, a strict definition of the populations involved in studies investigating the clinical effect of polymorphisms is required.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

Frequency of three prothrombotic polymorphisms among Syrian population: factor V G1691A,prothrombin G20210A and methylenetetrahydrofolate reductase C677T

Background: Thrombophilia is a multi-factorial disorder caused by inherited and acquired factors. Among the inherited factors are factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphisms (SNPs).

Aim: The main aim of this study was to assess the incidence of these three SNPs in the Syrian population.

Subjects and methods: A total of 200 unrelated healthy Syrians (100 males and 100 females) were recruited.

Results: The prevalence of factor V G1691A, prothrombin G20210A and MTHFR C677T SNPs among Syrians is 11.5%, 2.5% and 84.5%, respectively. Prevalence of factor V G1691A and prothrombin G20210A SNPs among apparently healthy Syrian individuals is very high.

Conclusion: To the best of the authors knowledge, the Syrian population harbours the highest prevalence of the MTHFR C677T polymorphism compared to all other populations reported so far.     

The timing of mandibular tooth formation in two African groups

Background: Ethnic differences in the timing of human tooth development are unclear.

Aim: To describe similarities and differences in the timing of tooth formation in two groups of Sudanese children and young adults.

Subjects and methods: The sample consisted of healthy individuals from Khartoum, Sudan, aged 2–23 years. The Northern group was of Arab origin (848 males, 802 females) and the Western group was of African origin (846 males, 402 females). Each mandibular left permanent tooth from first incisor to third molar was assessed from dental radiographs into one of 15 development stages. Mean ages at entry for 306 tooth stages were calculated using probit regression in males/females in each group and compared using a t-test.

Results: Mean ages were not significantly different in most tooth stage comparisons between ethnic groups for both males (61/75) and females (56/76), despite a tendency of earlier mean ages in the Western group. Mean ages for most tooth stage comparisons between males and females (137/155) were not significantly different within ethnic groups suggesting low sexual dimorphism.

Conclusion: The mean ages of most mandibular tooth formation stages were generally not significantly different between ethnic groups or between males and females in this study.     

Mechanical compression upregulates MMP9 through SMAD3 but not SMAD2 modulation in hypertrophic scar fibroblasts

Purpose: Activation of transforming growth factor-β (TGF-β) signaling and matrix metalloproteinases are involved in hypertrophic scar (HS) formation. Compression therapy is known to be an effective approach for the treatment of hypertrophic scarring; however, the underlying molecular mechanisms remain poorly understood. We investigated the relationship between TGF-β signaling activation and matrix metalloproteinases in HS fibroblasts during mechanical compressive stress.

Materials and methods: Two groups of skin tissue from HS and the nearby normal tissue were obtained from surgical patients and analyzed. Primary fibroblasts from the HS tissue and normal fibroblasts were isolated. Pressure therapy was recapitulated in an in vitro three-dimensional culture model, using mechanical stress produced with the Flexcell FX-4000C Compression Plus System. Quantitative real-time PCR (qPCR) was used to analyze the gene expression profiles in skin tissue and cultured primary cells exposed to compressive stress. Knockdown of SMAD2 and SMAD3 was performed using their specific siRNA in HS and normal fibroblasts subjected to compressive stress, and gene expression was examined by qPCR and Western blot.

Results: There was a significant upregulation of the mRNA expression of matrix metalloproteinase-2 (MMP2) and MMP9 in primary HS fibroblasts in response to mechanical stress. In contrast, the mRNA levels of collagen I and collagen III were downregulated in primary HS fibroblasts compared with those in the control cells. SiRNA-mediated knockdown of SMAD3 in the primary fibroblasts exposed to mechanical stress resulted in a decrease in the expression of MMP9 compared to control cells.

Conclusion: These results demonstrate that compressive stress upregulates MMP9 by SMAD3 but not by SMAD2.     

Alu insertion polymorphisms in the African Sahel and the origin of Fulani pastoralists

Background: The origin of Western African pastoralism, represented today by the Fulani nomads, has been a highly debated issue for the past decades, and has not yet been conclusively resolved.

Aim: This study focused on Alu polymorphisms in sedentary and nomadic populations across the African Sahel to investigate patterns of diversity that can complement the existing results and contribute to resolving issues concerning the origin of West African pastoralism.

Subjects and methods: A new dataset of 21 Alu biallelic markers covering a substantial part of the African Sahel has been analysed jointly with several published North African populations.

Results: Interestingly, with regard to Alu variation, the relationship of Fulani pastoralists to North Africans is not as evident as was earlier revealed by studies of uniparental loci such as mtDNA and NRY. Alu insertions point rather to an affinity of Fulani pastoralists to Eastern Africans also leading a pastoral lifestyle.

Conclusions: It is suggested that contemporary Fulani pastoralists might be descendants of an ancestral Eastern African population that, while crossing the Sahara in the Holocene, admixed slightly with a population of Eurasian (as evidenced by uniparental polymorphisms) ancestry. It seems that, in the Fulani pastoralists, Alu elements reflect more ancient genetic relationships than do uniparental genetic systems.     

Discriminating between first- and second-order cognition in first-episode paranoid schizophrenia*

Introduction: An impairment of visually perceiving backward masked stimuli is commonly observed in patients with schizophrenia, yet it is unclear whether this impairment is the result of a deficiency in first or higher order processing and for which subtypes of schizophrenia it is present.

Methods: Here, we compare identification (first order) and metacognitive (higher order) performance in a visual masking paradigm between a highly homogenous group of young first-episode patients diagnosed with paranoid schizophrenia (N?=?11) to that of carefully matched healthy controls (N?=?13).

Results: We find no difference across groups in first-order performance, but find a difference in metacognitive performance, particularly for stimuli with relatively high visibility.

Conclusions: These results indicate that the masking deficit is present in first-episode patients with paranoid schizophrenia, but that it is primarily an impairment of metacognition.     

Correlation of Proteinuria with Podocyte Foot Process Effacement in IgA Nephropathy: An Ultrastructural Study

Background: Proteinuria is an uncommon clinical manifestation of IgA nephropathy and is usually seen in cases with severe lesions like endocapillary proliferation. However, it is occasionally seen even with cases with mild glomerular manifestations and may even be of nephrotic range.

Predictor: Podocyte foot process effacement.

Outcome: Severity of proteinuria.

Measurements: Podocyte foot process effacement was measured. Morphometric analysis was performed on transmission electron microscope images using a computerized digital photomicrograph system (BioWizard 4.2 Image analysis software, New Delhi, India). Proteinuria was measured quantitatively assigned into five grades.

Results: It was found that as the extent of proteinuria increased, the effacement ratio also increased, and this was most significant between “no” proteinuria and the rest of the categories.

Conclusion: Nephrotic presentation in IgA nephropathy is a known phenomenon and in certain cases may show near normal glomerular morphology with severe foot process effacement on EM being the only significant finding to explain the proteinuria. Proteinuria in these cases shows a significant correlation with degree of foot process effacement. Renal biopsy is important in these cases because they are known to have a better prognosis and are usually steroid responsive.     

Leprosy in a Lombard-Avar cemetery in central Italy (Campochiaro,Molise, 6th–8th century AD): ancient DNA evidence and demography

Background: The study of past infectious diseases increases knowledge of the presence, impact and spread of pathogens within ancient populations.

Aim: Polymerase chain reaction (PCR) was used to examine bones for the presence of Mycobacterium leprae ancient DNA (aDNA) as, even when leprosy is present, bony changes are not always pathognomonic of the disease. This study also examined the demographic profile of this population and compared it with two other populations to investigate any changes in mortality trends between different infectious diseases and between the pre-antibiotic and antibiotic eras.

Subjects and methods: The individuals were from a site in Central Italy (6th–8th CE) and were examined for the presence of Mycobacterium leprae aDNA. In addition, an abridged life mortality table was constructed.

Results: Two individuals had typical leprosy palaeopathology, and one was positive for Mycobacterium leprae aDNA. However, the demographic profile shows a mortality curve similar to that of the standard, in contrast to a population that had been subjected to bubonic plague.

Conclusions: This study shows that, in the historical population with leprosy, the risk factors for health seem to be constant and distributed across all age classes, similar to what is found today in the antibiotic era. There were no peaks of mortality equivalent to those found in fatal diseases such as the plague, probably due to the long clinical course of leprosy.