Publications by authors named "Abderrahim Oussalah"

51 Publications

Cardiovascular manifestations of intermediate and major hyperhomocysteinemia due to vitamin B12 and folate deficiency and/or inherited disorders of one-carbon metabolism: a 3.5-year retrospective cross-sectional study of consecutive patients.

Am J Clin Nutr 2021 Mar 10. Epub 2021 Mar 10.

Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital (CHRU) of Nancy, Nancy, France.

Background: The association of moderate hyperhomocysteinemia (HHcy) (15-30 μmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy.

Objective: We sought to evaluate the association of intermediate (30-50 and 50-100 μmol/L) and severe (>100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes.

Methods: We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing.

Results: We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 μmol/L, 27% Hcy >50 μmol/L (44/165) and 3% Hcy >100 μmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6-60.4 compared with 12.1-28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up.

Conclusion: The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.
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http://dx.doi.org/10.1093/ajcn/nqaa432DOI Listing
March 2021

Elastase and exacerbation of neutrophil innate immunity are involved in multi-visceral manifestations of COVID-19.

Allergy 2021 Jan 23. Epub 2021 Jan 23.

Department Inserm UMRS_1116 DCAC, Université de Lorraine, Nancy, France.

Background: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19.

Methods: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls.

Results: Blood neutrophil elastase, histone-DNA, myeloperoxidase-DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10-fold, compared with controls. Neutrophil elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin-6 (IL-6), IL-8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL-8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity.

Conclusion: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.
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http://dx.doi.org/10.1111/all.14746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014109PMC
January 2021

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.

J Neurol 2021 Jan 8. Epub 2021 Jan 8.

Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Rue du Morvan, 54500, Vandoeuvre-lès-Nancy, France.

Background: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.

Objective: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.

Methods: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).

Results: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).

Conclusion: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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http://dx.doi.org/10.1007/s00415-020-10348-xDOI Listing
January 2021

The spectrum of biochemical alterations associated with organ dysfunction and inflammatory status and their association with disease outcomes in severe COVID-19: A longitudinal cohort and time-series design study.

EClinicalMedicine 2020 Oct 20;27:100554. Epub 2020 Sep 20.

Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, F-54000 Nancy, France.

Background: In patients with severe COVID-19, no data are available on the longitudinal evolution of biochemical abnormalities and their ability to predict disease outcomes.

Methods: Using a retrospective, longitudinal cohort study design on consecutive patients with severe COVID-19, we used an extensive biochemical dataset of serial data and time-series design to estimate the occurrence of organ dysfunction and the severity of the inflammatory reaction and their association with acute respiratory failure (ARF) and death.

Findings: On the 162 studied patients, 1151 biochemical explorations were carried out for up to 59 biochemical markers, totaling 15,260 biochemical values. The spectrum of biochemical abnormalities and their kinetics were consistent with a multi-organ involvement, including lung, kidney, heart, liver, muscle, and pancreas, along with a severe inflammatory syndrome. The proportion of patients who developed an acute kidney injury (AKI) stage 3, increased significantly during follow-up (0·9%, day 0; 21·4%, day 14; <0·001). On the 20 more representative biochemical markers (>250 iterations), only CRP >90 mg/L (odds ratio [OR] 6·87, 95% CI, 2·36-20·01) and urea nitrogen >0·36 g/L (OR 3·91, 95% CI, 1·15-13·29) were independently associated with the risk of ARF. Urea nitrogen >0·42 g/L was the only marker associated with the risk of COVID-19 related death.

Interpretation: Our results point out the lack of the association between the inflammatory markers and the risk of death but rather highlight a significant association between renal dysfunction and the risk of COVID-19 related acute respiratory failure and death.
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http://dx.doi.org/10.1016/j.eclinm.2020.100554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502281PMC
October 2020

[Phenylketonuria, from diet to gene therapy].

Med Sci (Paris) 2020 Aug-Sep;36(8-9):725-734. Epub 2020 Aug 21.

Centre de référence des maladies métaboliques, Service de pédiatrie, CHRU de Nancy, 54000 Nancy, France - Inserm UMR_S 1256 (NGERE, Nutrition Génétique et Exposition aux Risques Environnementaux), Faculté de médecine de Nancy, Université de Lorraine, 54000 Nancy, France.

The prognosis for phenylketonuria (PKU) has been improved by neonatal screening and dietary management via a low-phenylalanine diet. This treatment must be followed throughout life, which induces severe compliance problems. Drug treatment with sapropterin (or BH4) has come to help a reduced percentage of patients who respond to this drug. A subcutaneous enzyme therapy is available in the USA and has obtained European marketing authorization, but generates significant side effects, which limits its effectiveness. New therapeutic options for PKU are currently being developed, in particular gene therapy. The purpose of this article is to take stock of the pathophysiology and the various new therapeutic modalities currently in development.
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http://dx.doi.org/10.1051/medsci/2020127DOI Listing
October 2020

Coronavirus disease 2019: acute Fanconi syndrome precedes acute kidney injury.

Clin Kidney J 2020 Jun 8;13(3):362-370. Epub 2020 Jun 8.

Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University of Lorraine, CHRU-Nancy, Vandoeuvre, France.

Background: Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients.

Methods: A retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) ( = 28) or the Medical department ( = 14) and were screened at least once for four markers of proximal tubulopathy.

Results: The mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%,  = 22), hyperuricosuria (43%,  = 17) and normoglycaemic glycosuria (30%,  = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43-0.76) versus 0.77 (0.66-1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge.

Conclusion: Incomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.
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http://dx.doi.org/10.1093/ckj/sfaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314200PMC
June 2020

Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France.

Clin Infect Dis 2020 12;71(9):2447-2456

Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Nancy, France.

Background: In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes.

Methods: We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures.

Results: On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% confidence interval [CI], 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05-11.96).

Conclusions: Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.
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http://dx.doi.org/10.1093/cid/ciaa677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454376PMC
December 2020

Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1).

Calcif Tissue Int 2020 08 19;107(2):191-194. Epub 2020 May 19.

Reference Center for Inborn Errors of Metabolism, Pediatric Unit, University Hospital of Nancy, Nancy, France.

Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH) vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.
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http://dx.doi.org/10.1007/s00223-020-00704-4DOI Listing
August 2020

Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial.

Biochimie 2020 Jun 7;173:57-61. Epub 2020 May 7.

Inserm UMRS 1256 N-GERE (Nutrition-Genetics-Environmental Risks), Regional University Hospital of Nancy and University of Lorraine, BP 184, 54511, Nancy (Vandoeuvre), France. Electronic address:

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily. Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (-2.78 vs. -0.4 points) and (-1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed. This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.
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http://dx.doi.org/10.1016/j.biochi.2020.04.019DOI Listing
June 2020

Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles.

Biochimie 2020 Jun 11;173:123-128. Epub 2020 Apr 11.

INSERM UMR_S 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure and National Center of Inborn Errors of Metabolism, University of Lorraine, Nancy (Vandoeuvre-lès-Nancy), F-54000, France.

Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.
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http://dx.doi.org/10.1016/j.biochi.2020.03.015DOI Listing
June 2020

E-health education interventions on HbA in patients with type 1 diabetes on intensive insulin therapy: A systematic review and meta-analysis of randomized controlled trials.

Diabetes Metab Res Rev 2020 09 6;36(6):e3313. Epub 2020 Apr 6.

Université de Lorraine, CHRU-Nancy, Department of Endocrinology, Diabetology and Nutrition, Nancy, France.

Aims: Patient-centered education improves glycemic control in subjects with type 1 diabetes (T1D). E-health technologies are widely used to support medical decision-making, patient advising or teleconsultations; however, the active participation of a patient is missing. Challenges remain whether e-health education can be effectively incorporated into clinical pathways. The purpose of the study was to examine the effects of e-health education, compared to standard care, on HbA MATERIAL AND METHODS: We conducted a literature search (EMBASE, MEDLINE, The Cochrane Library and Web of Science) up to February 2018 for randomized controlled trials (RCTs) of Internet-/ mobile application-based educational interventions, with the active involvement of patients, provided in addition to, or substituting usual care in patients with T1D on intensive insulin therapy. The primary outcome was the standardized difference in means (SDM) of HbA change from baseline between intervention and comparator groups.

Results: Eight RCTs involving 757 subjects were included on 6335 screened citations. After excluding two trials with a high risk of bias from the meta-analysis, the HbA change from baseline did not significantly differ between intervention and comparator groups (SDM = -0.154, 95% CI: -0.335 to 0.025; P = 0.01, random-effect model). The number of studies is limited with a relatively short duration. Reporting of educational outcomes was not rigorous.

Conclusions: The effect of e-health educational interventions on HbA in patients with T1D is comparable to the standard care. This review highlights the need for further well-designed RCTs that will investigate the opportunities of incorporating e-health education into clinical pathways.
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http://dx.doi.org/10.1002/dmrr.3313DOI Listing
September 2020

Health outcomes associated with vegetarian diets: An umbrella review of systematic reviews and meta-analyses.

Clin Nutr 2020 Nov 11;39(11):3283-3307. Epub 2020 Mar 11.

University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000, Nancy, France; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, F-54000, Nancy, France; Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000, Nancy, France. Electronic address:

Background: Several meta-analyses evaluated the association between vegetarian diets and health outcomes. To integrate the large amount of the available evidence, we performed an umbrella review of published meta-analyses that investigated the association between vegetarian diets and health outcomes.

Methods: We performed an umbrella review of the evidence across meta-analyses of observational and interventional studies. PubMed, Embase, Cochrane Database of Systematic Reviews, and ISI Web of Knowledge. Additional articles were retrieved from primary search references. Meta-analyses of observational or interventional studies that assessed at least one health outcome in association with vegetarian diets. We estimated pooled effect sizes (ESs) using four different random-effect models: DerSimonian and Laird, maximum likelihood, empirical Bayes, and restricted maximum likelihood. We assessed heterogeneity using I statistics and publication bias using funnel plots, radial plots, normal Q-Q plots, and the Rosenthal's fail-safe N test.

Results: The umbrella review identified 20 meta-analyses of observational and interventional research with 34 health outcomes. The majority of the meta-analyses (80%) were classified as moderate or high-quality reviews, based on the AMSTAR2 criteria. By comparison with omnivorous diets, vegetarian diets were associated with a significantly lower concentration of blood total cholesterol (pooled ES = -0.549 mmol/L; 95% CI: -0.773 to -0.325; P < 0.001), LDL-cholesterol (pooled ES = -0.467 mmol/L; 95% CI: -0.600 to -0.335); P < 0.001), and HDL-cholesterol (pooled ES = -0.082 mmol/L; 95% CI: -0.095 to -0.069; P < 0.001). In comparison to omnivorous diets, vegetarian diets were associated with a reduced risk of negative health outcomes with a pooled ES of 0.886 (95% CI: 0.848 to 0.926; P < 0.001). In comparison to omnivores, Seventh-day Adventists (SDA) vegetarians had a significantly reduced risk of negative health outcomes with a pooled ES of 0.721 (95% CI: 0.625 to 0.832; P < 0.001). Non-SDA vegetarians had no significant reduction of negative health outcomes when compared to omnivores (pooled ES = 0.973; 95% CI: 0.873 to 1.083; P = 0.51). Vegetarian diets were associated with harmful outcomes on one-carbon metabolism markers (lower concentrations of vitamin B12 and higher concentrations of homocysteine), in comparison to omnivorous diets.

Conclusions: Vegetarian diets are associated with beneficial effects on the blood lipid profile and a reduced risk of negative health outcomes, including diabetes, ischemic heart disease, and cancer risk. Among vegetarians, SDA vegetarians could represent a subgroup with a further reduced risk of negative health outcomes. Vegetarian diets have adverse outcomes on one-carbon metabolism. The effect of vegetarian diets among pregnant and lactating women requires specific attention. Well-designed prospective studies are warranted to evaluate the consequences of the prevalence of vitamin B12 deficiency during pregnancy and infancy on later life and of trace element deficits on cancer risks.

Prospero Registration Number: CRD42018092470.
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http://dx.doi.org/10.1016/j.clnu.2020.02.037DOI Listing
November 2020

Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing.

Hum Mol Genet 2020 Jul;29(12):1969-1985

Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France.

Vitamin B12 or cobalamin (Cbl) metabolism can be affected by genetic defects leading to defective activity of either methylmalonyl-CoA mutase or methionine synthase or both enzymes. Patients usually present with a wide spectrum of pathologies suggesting that various cellular processes could be affected by modifications in gene expression. We have previously demonstrated that these genetic defects are associated with subcellular mislocalization of RNA-binding proteins (RBP) and subsequent altered nucleo-cytoplasmic shuttling of mRNAs. In order to characterize the possible changes of gene expression in these diseases, we have investigated global gene expression in fibroblasts from patients with cblC and cblG inherited disorders by RNA-seq. The most differentially expressed genes are strongly associated with developmental processes, neurological, ophthalmologic and cardiovascular diseases. These associations are consistent with the clinical presentation of cblC and cblG disorders. Multivariate analysis of transcript processing revaled splicing alterations that led to dramatic changes in cytoskeleton organization, response to stress, methylation of macromolecules and RNA binding. The RNA motifs associated with this differential splicing reflected a potential role of RBP such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed. This study reports a dramatic alteration of gene expression in fibroblasts of patients with cblC and cblG disorders, which resulted partly from disturbed function of RBP. These data suggest to evaluate the rescue of the mislocalization of RBP as a potential strategy in the treatment of severe cases who are resistant to classical treatments with co-enzyme supplements.
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http://dx.doi.org/10.1093/hmg/ddaa027DOI Listing
July 2020

Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study.

EBioMedicine 2020 Jan 7;51:102623. Epub 2020 Jan 7.

University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Nancy, France; Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy F-54000, France.

Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus.

Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH.

Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin_H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively.

Interpretation: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH.

Funding: French National Institute of Health and Medical Research (INSERM) UMR_S 1256.
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http://dx.doi.org/10.1016/j.ebiom.2019.102623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000351PMC
January 2020

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Allergy 2020 05;75(5):1069-1098

Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.
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http://dx.doi.org/10.1111/all.14174DOI Listing
May 2020

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

J Hum Genet 2020 Jan 23;65(2):91-98. Epub 2019 Oct 23.

INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
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http://dx.doi.org/10.1038/s10038-019-0689-yDOI Listing
January 2020

Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway.

Hum Genet 2019 Jul 28;138(7):703-713. Epub 2019 May 28.

INSERM U1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, 54000, Nancy, Vandoeuvre-lès-Nancy, France.

Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identification of genetic predictors by genome exome sequencing and their influence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could influence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most significant associations in 81 other cases. The analysis of exome sequencing identified one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identified five gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMT and GLI3 with NTD risk in the 81 cases. We found a significant hemimethylation of CFAP46 that may influence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identified new candidate genes and rare variants that highlight an interacting influence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.
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http://dx.doi.org/10.1007/s00439-019-02015-7DOI Listing
July 2019

Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis.

J Clin Med 2019 Apr 23;8(4). Epub 2019 Apr 23.

University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France.

The risk of adverse effects of nitrous oxide (NO) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with NO exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2-78.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0-88.0%), unsteady gait (58%; 48.2-67.8%), and weakness (43%; 33.1-52.9%). At least one hematological abnormality was retrieved in 71.7% (59.9-83.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 <150 pmol/L (70.7%; 60.7-80.8%), homocysteine >15 µmol/L (90.3%; 79.3-100%), and methylmalonic acid >0.4 µmol/L (93.8%; 80.4-100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. NO can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The NO-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent NO-related toxicity, particularly in countries with a high prevalence of B12 deficiency.
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http://dx.doi.org/10.3390/jcm8040551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518054PMC
April 2019

COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas.

Virchows Arch 2019 Jun 13;474(6):721-734. Epub 2019 Mar 13.

Department of Pathology, CHRU de Nancy, Université de Lorraine, F-54000, Nancy, France.

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P < 0.0001) and shorter PFS (P = 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (P = 0.004 and P < 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (P = 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (P < 0.0001) and shorter PFS (P < 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (P < 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.
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http://dx.doi.org/10.1007/s00428-019-02553-5DOI Listing
June 2019

Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma.

EBioMedicine 2018 Apr 28;30:138-147. Epub 2018 Mar 28.

Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, F-54000, France; INSERM, U1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; Department of Hepatology and Gastroenterology, University Hospital of Nancy, Nancy F-54000, France. Electronic address:

Background: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients.

Methods: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test.

Findings: We included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900-0.970, p<0.0001) in the initial study (replication: 0.930 [0.862-0.971, p<0.0001]; meta-analysis: AUROC=0.940 [0.910-0.970, p<0.0001], no heterogeneity: I=0%, p=0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR=6.30, for each mSEPT9 positive triplicate [2.92-13.61, p<0.0001]; replication: OR=6.07 [3.25-11.35, p<0.0001]; meta-analysis: OR=6.15 [2.93-9.38, p<0.0001], no heterogeneity: I=0%, p=0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930-0.989) and 0.942 (0.878-0.978), respectively, with a pooled AUROC of 0.962 ([0.937-0.987, p<0.0001], no heterogeneity: I=0%, p=0.36; and no publication bias).

Interpretation: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC.
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http://dx.doi.org/10.1016/j.ebiom.2018.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952996PMC
April 2018

Publisher Correction: A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.

Nat Commun 2018 02 2;9(1):554. Epub 2018 Feb 2.

Department of Human Genetics, McGill University and Research Institute McGill University Health Centre, H4A 3J1, Montreal, Quebec, Canada.

The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'.
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http://dx.doi.org/10.1038/s41467-018-03054-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797229PMC
February 2018

APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.

Nat Commun 2018 01 4;9(1):67. Epub 2018 Jan 4.

Department of Human Genetics, McGill University and Research Institute McGill University Health Centre, Montreal, H4A 3J1, Quebec, Canada.

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.
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http://dx.doi.org/10.1038/s41467-017-02306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754367PMC
January 2018

Association of rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies.

Am J Clin Nutr 2017 Oct 16;106(4):1142-1156. Epub 2017 Aug 16.

Department of Molecular Medicine and Personalized Therapeutics,

Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions. We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease. We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition. Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, -0.217; < 0.001); = 48.16% (95% CI: 0.00%, 78.10%; = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; = 0.01); = 0.00% (95% CI: 0.00%, 49.59%; = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease. Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504.
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http://dx.doi.org/10.3945/ajcn.117.156349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611783PMC
October 2017

Genetic Predictors of Drug Hypersensitivity.

Curr Pharm Des 2016 ;22(45):6725-6733

Faculte de Medecine, Batiment C 2eme etage, 9 avenue de la Foret de Haye - B.P. 184, 54505 Vandoeuvre- les-Nancy CEDEX, France.

Our knowledge of genetic predisposing factors of drug hypersensitivity reactions (DHRs) is still scarce. The analysis of the genetic basis of these reactions may contribute to dissect the underlying mechanisms. We will outline current knowledge of the genetic predictors of most common DHRs, including reactions to betalactam antibiotics (BLs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents. The predictors of DHRs to BLs are mostly linked to IgE-class switching, IgE pathway and atopy (IL4R, NOD2, LGALS3) in replicated candidate gene studies, and to antigen presentation (HLA-DRA) in the single replicated GWAS performed so far. The HLA-DRA variants are predictors of allergy to penicillins, but not to cephalosporins and they influence also the sensitization against prevalent allergens. The predictors of DHRs against NSAIDs are mostly linked to metabolism of eicosanoids (ALOX5, ALOX5AP, TBXAS1, PTGDR, CYSLTR1). Single nucleotide polymorphisms (SNPs) in genes involved in histamine biosynthesis and antigen presentation, HLA, could also have a role in DHRs against NSAIDs. The intriguing association of DHRs to NSAIDs with atopy should deserve further attention. Predictors of DHRs against asparaginase and other biological agents relate to antigen presentation (HLA-DRB1 and HLA-A alleles, respectively). The potential relationship of genetic predictors of DHRs with pathomechanisms also involved in environmental exposure and atopy highlights the need to perform GWAS in contrasted populations, taking into account world-wide variations of allele frequencies and contrasted situations of environmental exposure.
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http://dx.doi.org/10.2174/1381612822666160927114941DOI Listing
December 2017

Cystathionine β-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations.

J Med Genet 2016 12 17;53(12):828-834. Epub 2016 Aug 17.

Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.

Background: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways.

Objective: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism.

Methods: We performed a case-control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls).

Results: In the discovery study on 'mothers', the CBS locus reached array-wide significance (p=9.13×10; Bonferroni p=4.77×10; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10; Bonferroni p=2.00×10; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10; Bonferroni p=7.80×10; OR 0.40 (0.25 to 0.63)). In the 'children' group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele).

Conclusions: The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies.
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http://dx.doi.org/10.1136/jmedgenet-2016-104111DOI Listing
December 2016

coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease.

Oncotarget 2017 Sep 17;8(38):62842-62857. Epub 2016 Aug 17.

INSERM, U954, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France.

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the locus reached array-wide significance (Chi-squared SV-Perm, =5.00×10) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The '' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)-=1.31×10]. In the Derivation#2 study, results were confirmed for the '' haplotype [OR, 0.53 (0.36-0.79); FDR-=3.90×10]. In both Validation#1 and #2 studies, '' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR-=7.30×10; and OR, 6.45 (4.17-9.99); FDR-=2.33×10, respectively]. Association between the locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.
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http://dx.doi.org/10.18632/oncotarget.11327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609885PMC
September 2017

Predictors of High Motivation Score for Performing Research Initiation Fellowship, Master 1, Research Master 2, and PhD Curricula During Medical Studies: A Strobe-Compliant Article.

Medicine (Baltimore) 2016 Feb;95(5):e2633

From the University of Poitiers, UFR Médecine Pharmacie (EF, SH, RM, PR); Department of Endocrinology, University Hospital of Poitiers, Poitiers, (EF, SH, RM); Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France (AO, J-LG); INSERM, U954, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France (AO, J-LG); Medical Simulation Centre, Faculty of Medicine of Nice, University of Nice-Sophia-Antipolis, Nice (J-PF); Direction du Numérique, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy (AA); Department of Internal Medicine and Infectious Diseases, University Hospital of Poitiers, University of Poitiers, Poitiers (PR); Department of Neuroradiology, University Hospital of Nancy, Nancy, France (MB); and Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France ; University Centre for Education by Medical Simulation (CUESIM) - The Virtual Hospital of Lorraine of the Faculty of Medicine of Nancy; INSERM U947, IADI - Diagnostic and Interventional Adaptive Imaging, Vandoeuvre-lès-Nancy, France (MB).

Translational research plays a crucial role in bridging the gap between fundamental and clinical research. The importance of integrating research training into medical education has been emphasized. Predictive factors that help to identify the most motivated medical students to perform academic research are unknown. In a cross-sectional study on a representative sample of 315 medical students, residents and attending physicians, using a comprehensive structured questionnaire we assessed motivations and obstacles to perform academic research curricula (ie, research initiation fellowship, Master 1, Research Master 2, and PhD). Independent predictive factors associated with high "motivation score" (top quartile on motivation score ranging from 0 to 10) to enroll in academic research curricula were derived using multivariate logistic regression analysis. Independent predictors of high motivation score for performing Master 1 curriculum were: "considering that the integration of translational research in medical curriculum is essential" (OR, 3.79; 95% CI, 1.49-9.59; P = 0.005) and "knowledge of at least 2 research units within the university" (OR, 3.60; 95% CI, 2.01-6.47; P < 0.0001). Independent predictors of high motivation score for performing Research Master 2 curriculum were: "attending physician" (OR, 4.60; 95% CI, 1.86-11.37; P = 0.001); "considering that the integration of translational research in medical curriculum is essential" (OR, 4.12; 95% CI, 1.51-11.23; P = 0.006); "knowledge of at least 2 research units within the university" (OR, 3.51; 95% CI, 1.91-6.46; P = 0.0001); and "male gender" (OR, 1.82; 95% CI, 1.02-3.25; P = 0.04). Independent predictors of high motivation score for performing PhD curriculum were: "considering that the integration of translational research in medical curriculum is essential" (OR, 5.94; 95% CI, 2.33-15.19; P = 0.0002) and "knowledge of at least 2 research units within the university" (OR, 2.63; 95% CI, 1.46-4.77; P = 0.001). This is the first study that has identified factors determining motivations and barriers to carry out academic research curricula among undergraduate and postgraduate medical students. Improving these 2 areas will certainly have an impact on a better involvement of the next generation of physicians in translational medicine.
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http://dx.doi.org/10.1097/MD.0000000000002633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748895PMC
February 2016

Diagnostic Accuracy of Procalcitonin for Predicting Blood Culture Results in Patients With Suspected Bloodstream Infection: An Observational Study of 35,343 Consecutive Patients (A STROBE-Compliant Article).

Medicine (Baltimore) 2015 Nov;94(44):e1774

From the Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy (AO, PF-T, IA-G, FN, MG, J-LG); INSERM, U954, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine (AO, IA-G, FN, J-LG); Department of Bacteriology, University Hospital of Nancy (JF, NA, AL), and EA7300, Stress Immunity Pathogens Laboratory, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France (JF, NA, AL).

Previous studies have suggested that procalcitonin is a reliable marker for predicting bacteremia. However, these studies have had relatively small sample sizes or focused on a single clinical entity. The primary endpoint of this study was to investigate the diagnostic accuracy of procalcitonin for predicting or excluding clinically relevant pathogen categories in patients with suspected bloodstream infections. The secondary endpoint was to look for organisms significantly associated with internationally validated procalcitonin intervals. We performed a cross-sectional study that included 35,343 consecutive patients who underwent concomitant procalcitonin assays and blood cultures for suspected bloodstream infections. Biochemical and microbiological data were systematically collected in an electronic database and extracted for purposes of this study. Depending on blood culture results, patients were classified into 1 of the 5 following groups: negative blood culture, Gram-positive bacteremia, Gram-negative bacteremia, fungi, and potential contaminants found in blood cultures (PCBCs). The highest procalcitonin concentration was observed in patients with blood cultures growing Gram-negative bacteria (median 2.2 ng/mL [IQR 0.6-12.2]), and the lowest procalcitonin concentration was observed in patients with negative blood cultures (median 0.3 ng/mL [IQR 0.1-1.1]). With optimal thresholds ranging from ≤0.4 to ≤0.75 ng/mL, procalcitonin had a high diagnostic accuracy for excluding all pathogen categories with the following negative predictive values: Gram-negative bacteria (98.9%) (including enterobacteria [99.2%], nonfermenting Gram-negative bacilli [99.7%], and anaerobic bacteria [99.9%]), Gram-positive bacteria (98.4%), and fungi (99.6%). A procalcitonin concentration ≥10 ng/mL was associated with a high risk of Gram-negative (odds ratio 5.98; 95% CI, 5.20-6.88) or Gram-positive (odds ratio 3.64; 95% CI, 3.11-4.26) bacteremia but dramatically reduced the risk of PCBCs or fungemia. In this large real-life setting experience with more than 35,000 patients, procalcitonin was highly effective at excluding bloodstream infections regardless of pathogen categories. The results from our study are limited by its cross-sectional design and deserve to be validated in prospective longitudinal studies.
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http://dx.doi.org/10.1097/MD.0000000000001774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915876PMC
November 2015

Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects: A Strobe Compliant Article.

Medicine (Baltimore) 2015 Jun;94(22):e925

From the Inserm, NGERE - Nutrition, Genetics, and Environmental Risk Exposure (AO, R-MG-R, CC, PR, J-PB, J-LG); Faculty of Medicine of Nancy, University of Lorraine (AO, R-MG-R, CC, J-PB, J-LG); University Hospital of Nancy, Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism (AO, R-MG-R, CC, TJ, J-LG); Reference Centre for Inherited Metabolic Diseases (ORPHA67872), Vandoeuvre-lès-Nancy, France (AO, R-MG-R, CC, TJ, J-LG); IRCCS, Oasi Maria SS-Institute for Research on Mental Retardation, Troina (PB, GA, RS, AR, ME); Department of Internal Medicine and Geriatrics, UCSC, CI Columbus, Roma, Italy (AR); and Department of Gastroenterology and Hepatology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France (J-PB).

Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 × 10(-34), P = 7.02 × 10(-34), and P = 8.27 × 10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10(-26); rs2070959, p.Thr181Ala, P = 2.87 × 10(-27); and rs1105879, p.Arg184Ser, P = 3.27 × 10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P = 3.21 × 10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.
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http://dx.doi.org/10.1097/MD.0000000000000925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616369PMC
June 2015