Increased release and activity of matrix metalloproteinase-9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome

Mandibuloacral dysplasia type A (MADA; OMIM 248370), a rare disorder caused by mutation in the LMNA gene, is characterized by post-natal growth retardation, craniofacial and skeletal anomalies (mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, low bone mass and joint contractures), cutaneous changes and partial lipodystrophy. Little is known about the molecular mechanisms by which LMNA mutations produce bone alterations. An altered bone extracellular matrix (ECM) remodelling could play a pivotal role in this disorder and influence part of the typical bone phenotype observed in patients. Therefore, we have focused our investigation on matrix metalloproteinases (MMPs), which are degradative enzymes involved in ECM degradation and ECM remodelling, thus likely contributing to the altered bone mineral density and bone metabolism values seen in five MADA patients. We evaluated the serum levels of several MMPs involved in bone development, remodelling and homeostasis, such as MMP-9, -2, -3, -8 and -13, and found that only the 82 kDa active enzyme forms of MMP-9 are significantly higher in MADA sera compared with healthy controls (n = 16). The serum level of MMP-3 was instead lower in all patients. No significant differences were observed between controls and MADA patients for the serum levels of MMP-2, -8 and -13 and of tissue inhibitor of metalloproteinase 2, a natural inhibitor of MMP-9. Similarly, normal serum levels of tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta were detected. These data suggest a possible involvement of MMP-9 in MADA disease, underlying the potential use in diagnosis and therapy

Phosphotyrosine-protein-phosphatases and human reproduction: an association between low molecular weight acid phosphatase (ACP1) and spontaneous abortion.

ACP1 (low molecular weight acid phosphatase) genetic polymorphism has been studied in 173 women with a history of two or more consecutive spontaneous abortions and in 1508 control subjects, including 482 normal pregnant women. The proportion of carriers of ACP1 *C allele (* A/ *C, *B/*C) in women with a history of repeated spontaneous abortion is lower than in normal pregnant women and other control groups, Women with repeated spontaneous abortion show a specific decrease of ACPI S isoform concentration as compared to normal pregnant women, The other component of ACP I activity, the F isoform, does not show a significant difference between the two groups. The data suggest that women with ACP1 genotypes showing a high concentration of S isoform are relatively 'protected' against spontaneous abortion, Preliminary analysis of a sample of 352 normal puerperae along with their newborn babies supports this hypothesis

COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity

TRAF3IP2 gene is associated with cutaneous extraintestinal manifestations in Inflammatory bowel disease

Background and aims: Genome-wide association (GWA) studies recently identified a novel gene, TRAF3IP2, involved in the susceptibility to psoriasis. Common immune-mediated mechanisms involving the skin or the gut have been suggested. We therefore aimed to assess the role of TRAF3IP2 gene in IBD, with particular regard to the development of cutaneous extraintestinal manifestations (pyoderma gangrenosum, erythema nodosum). The association with psoriasis was also assessed in a secondary analysis. Methods: The analysis included 267 Crohn's disease (CD), 200 ulcerative colitis (UC) patients and 278 healthy controls. Three TRAF3IP2 SNPs were genotyped by allelic discrimination assays. A case/control association study and a genotype/phenotype correlation analysis have been performed. Results: All three SNPs conferred a high risk to develop cutaneous manifestations in IBD. A higher risk of pyoderma gangrenosum and erythema nodosum was observed in CD patients carrying the Rs33980500 variant (OR 3.03; P=0.026)In UC, a significantly increased risk was observed for both the Rs13190932 and the Rs13196377 SNPs (OR 5.05; P=0.02 and OR 4.1; P=0.049). Moreover, association of TRAF3IP2 variants with ileal (OR = 1.92), fibrostricturing (OR = 1.91) and perianal CD (OR = 2.03) was observed. Conclusions: This is the first preliminary report indicating that TRAF3IP2 variants increase the risk of cutaneous extraintestinal manifestations in IBD suggesting that the analysis of the TRAF3IP2 variants may be useful for identifying IBD patients at risk to develop these manifestations. © 2012 European Crohn's and Colitis Organisation

Enzyme variability and neonatal jaundice. The role of adenosine deaminase and acid phosphatase

Peer Reviewe

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population

The initial GWAS was funded by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a non-profit organization dedicated to identifying and validating DNA variants useful in predicting the risk of drug-related serious adverse events. The Consortium brings together the pharmaceutical industry, regulatory authorities and academic centres to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC’s current funding members include: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda and the Wellcome Trust. Mas Chaponda was funded by a 3 year Wellcome Trust training fellowship WT078857MA administered through the University of Liverpool. Malawi-Liverpool-Wellcome Trust Clinical Research Programme is funded through a Core Programme Grant award from the Wellcome Trust. Munir Pirmohamed is a National Institute for Health Research Senior Investigator, and also wishes to thank the MRC Centre for Drug Safety Science for support. The DART study was supported by the UK Medical Research Council (grant number G0600344), the UK Department for International Development and the Rockefeller Foundation. Andrew P. Morris is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Louise Y. Takeshita is funded by a PhD fellowship from CNPq (National Council for Scientific and Technological Development, Brazil). Panos Deloukas’ work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research

Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

<p>Abstract</p> <p>Background</p> <p><it>CYP2C9 </it>and <it>VKORC1 </it>are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients.</p> <p>Methods</p> <p>Direct sequencing method was used to identify SNPs in <it>CYP2C9, VKORC1, CYP4F2, EPHX1, PROC </it>and <it>GGCX </it>genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing.</p> <p>Results</p> <p>From the 40 SNPs analyzed, <it>CYP2C9 </it>rs17847036 and <it>VKORC1 </it>rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between <it>CYP2C9*3, CYP2C9C</it>-65 (rs9332127), <it>CYP4F2 </it>rs2108622, <it>GGCX </it>rs12714145, <it>EPHX1 </it>rs4653436 and <it>PROC </it>rs1799809 with warfarin sensitivity.</p> <p>Conclusions</p> <p><it>VKORC1 </it>rs9923231 AA and <it>CYP2C9 </it>rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). <it>CYP2C9 </it>and <it>VKORC1 </it>genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.</p

A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant interpopulation pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/ or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective

Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration : significant association of twelve variants

Age-related Macular Degeneration (AMD) represents one of the most sightthreatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/ protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants (CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life