Deficient Genotypes Research Articles

Alpha-1-Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Meta-analysis and Clinical Practice Guideline.

Alpha-1-Antitrypsin (A1AT) deficiency is a common hereditary disorder associated with increased risk of developing chronic obstructive pulmonary disease (COPD). Many individuals with severe A1AT deficiency go undiagnosed, or are diagnosed late, and fail to benefit from disease-specific counseling and modifying care. Since the 2012 Canadian Thoracic Society (CTS) A1AT deficiency clinical practice guideline, new approaches to optimal diagnosis using modern genetic testing and studies of A1AT augmentation therapy have been published. We performed a systematic review and meta-analysis, which along with expert clinical input, informed recommendations. We conditionally recommend testing for A1AT deficiency in all individuals with COPD at the time of diagnosis, individuals with adult-onset asthma with persistent airway obstruction, and individuals with unexplained bronchiectasis. We suggest genetic testing with DNA sequencing of SERPINA1 gene as the initial test for individuals with high clinical suspicion for A1AT deficiency, and initial measurement of serum A1AT levels in individuals with moderate clinical suspicion of A1AT deficiency, followed by genetic testing with DNA sequencing of SERPINA1 gene if A1AT level is <23 μmol/L (<1.2 g/L). Following identification of an abnormal gene for A1AT in individuals, whether heterozygote or homozygote, we suggest first-degree relatives be provided genetic counseling and offered testing for A1AT deficiency. The panel conditionally recommends A1AT augmentation therapy to non-smoking or ex-smoking patients with COPD (FEV1 < 80% predicted; associated with emphysema), with documented deficiency genotypes and severely reduced A1AT level (< 11 μmol/L or < 0.57 g/L) in addition to receiving optimal pharmacological and nonpharmacological therapies for COPD.

Alpha-1-Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Meta-analysis and Clinical Practice Guideline

ABSTRACT Alpha-1-Antitrypsin (A1AT) deficiency is a common hereditary disorder associated with increased risk of developing chronic obstructive pulmonary disease (COPD). Many individuals with severe A1AT deficiency go undiagnosed, or are diagnosed late, and fail to benefit from disease-specific counseling and modifying care. Since the 2012 Canadian Thoracic Society (CTS) A1AT deficiency clinical practice guideline, new approaches to optimal diagnosis using modern genetic testing and studies of A1AT augmentation therapy have been published. We performed a systematic review and meta-analysis, which along with expert clinical input, informed recommendations. We conditionally recommend testing for A1AT deficiency in all individuals with COPD at the time of diagnosis, individuals with adult-onset asthma with persistent airway obstruction, and individuals with unexplained bronchiectasis. We suggest genetic testing with DNA sequencing of SERPINA1 gene as the initial test for individuals with high clinical suspicion for A1AT deficiency, and initial measurement of serum A1AT levels in individuals with moderate clinical suspicion of A1AT deficiency, followed by genetic testing with DNA sequencing of SERPINA1 gene if A1AT level is <23 μmol/L (<1.2 g/L). Following identification of an abnormal gene for A1AT in individuals, whether heterozygote or homozygote, we suggest first-degree relatives be provided genetic counseling and offered testing for A1AT deficiency. The panel conditionally recommends A1AT augmentation therapy to non-smoking or ex-smoking patients with COPD (FEV1 < 80% predicted; associated with emphysema), with documented deficiency genotypes and severely reduced A1AT level (< 11 μmol/L or < 0.57 g/L) in addition to receiving optimal pharmacological and nonpharmacological therapies for COPD.

Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature

Recurrent rhabdomyolysis, marked by skeletal muscle breakdown, can stem from various causes, including genetic disorders. We detail a patient of a 22-year-old male with carnitine palmitoyltransferase II (CPT-2) deficiency manifesting recurrent rhabdomyolysis despite normal acylcarnitine profiles. Whole-genome sequencing identified two CPT2 gene variants: c.338C > T and c.482G > A, confirming the diagnosis. We conducted a case report and a comprehensive literature review encompassing 262 articles related to CPT-2 deficiency available on PubMed. The review detailed 245 cases across various forms, including lethal neonatal, severe infantile hepatocardiomuscular, and myopathic forms. The study highlighted the variability and complexity of CPT-2 deficiency phenotypes, emphasizing correlations between variants and phenotypes as well as gender distribution. Although the CPT-2 deficiency genotype does not entirely predict phenotype severity, it remains informative for most patients, assisting in assessing the severity linked to each genetic variant. The results of our study offer crucial insights into evaluating the severity associated with individual genetic variants. Notably, our patient displayed normal acylcarnitine profiles between illness episodes, indicating possible profile abnormalities only during active disease states.We propose the collection of additional blood samples for acylcarnitine analysis during episodes of rhabdomyolysis without delay in all patients presenting with rhabdomyolysis of unknown cause as a crucial diagnostic strategy. This approach may unveil unexpected underlying diseases, enabling early and accurate diagnoses.

The impact of alpha-1 antitrypsin deficiency alleles on lung cancer survival.

Different studies have shown that carrying an alpha-1 antitrypsin (AAT) deficiency allele is an independent risk factor for developing lung cancer (LC). However, to date, little is known regarding whether carrying a deficiency allele may be a prognostic factor in the evolution of LC. A prospective observational study was carried out which consecutively included patients diagnosed with LC in University Hospital "Nuestra Señora de Candelaria" between December 2017 and August 2020. A blood sample was taken from each of the patients in order to determine both AAT serum concentration and genotype. Based on AAT genotype, patients were divided into the deficiency (Pi*≠MM) or non-deficiency (Pi*=MM) group. One hundred and sixty-four patients were included. The average length of follow-up was 13±10 months. Patients were classified as stage I (4.2%), stage II (8.3%), stage III (31.2%) and stage IV (56.3%), according to tumour, node and metastasis (TNM) staging. Twenty-eight patients (17%) were carriers of a deficiency allele (6 Pi*MS, 1 Pi*MZ, 1 Pi*MMheerlen). No significant differences were found with respect to baseline characteristics between Pi*≠MM and Pi*=MM. Patients in the Pi*≠MM group had a higher risk of death in the first 6 months after the LC diagnosis compared to Pi*=MM subjects (HR =2.04; 95% CI: 1.04-4.0; P=0.038). The presence of an AAT deficiency genotype could be a potential prognostic marker in LC. However, larger studies that justify these findings are needed.

MIR27A rs895819 TC genotype increases risk of fluoropyrimidine-induced severe toxicity independently of DPYD variations.

Aim: MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of MIR27A rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. Materials & methods: MIR27A rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients. Results: In overdominance (TC vs TT+CC), TC genotype was associated with grade 3-4 toxicity (p=0.002), any grade toxicity (p=0.052), and delayed drug administration or therapy discontinuation (p=0.038). Odds of grade 3-4 toxicity were increased by both DPYD deficiency (OR: 8.923; p=0.006) and MIR27A rs895819 TC genotype (OR: 3.865; p=0.002). Conclusion: MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine-associated toxicity in the Greek population. Thus, MIR27A rs895819TC patients can be closely monitored for fluoropyrimidine-induced severe toxicity.

85 Predicting Conversion to Mild Cognitive Impairment in Parkinson’s Disease: a Random Forest Machine Learning Model Based on Parkinson’s Progression Markers Initiative Dataset.

Objective:Mild cognitive impairment (MCI) is common in Parkinson’s disease (PD). Recent scientific advances show that MCI in PD could also be impacted by neuropsychiatric symptoms (such as apathy, anxiety, depression), dopaminergic deficiency (more striatal denervation associated with MCI) and certain genotypes such as in APOE E4, MAPT H1 or SNCA C/C carriers. We used a python-based random forest machine-learning algorithm (scikit-learn) in order to evaluate the factors that are mostly involved in the MCI conversion over a 5-year follow-up period.Participants and Methods:Baseline data of healthy individuals and participants with Parkinson’s disease were extracted from the PPMI dataset. All participants also had the evaluations of their cognitive status, neuropsychiatric symptoms (hallucinations, anxiety, apathy, depression, sleepiness, impulse control disorders and rapid eye movement behaviors), dopaminergic uptake (DaT-Scan) and genetic status (APOE, MAPT and SNCA) at baseline and after 5 years. Baseline demographic (age, sex, education years) and clinical values (duration of disease, age of onset) were also included in the model. The algorithm defined (1) the most important variables in predicting MCI, (2) the threshold values to distinguish “converting” vs. “non-converting” subgroups.Results:The algorithm showed that (1) age onset of disease, (2) dopaminergic uptake, (3) age, (4) anxiety, and (5) years of education were the most important factors in predicting MCI over 5 years. Among the factors involved in predicting conversion to MCI, a lower number of years of education associated with lower dopaminergic uptake in the right putamen increased the risk of conversion. Individuals with more years of education are at higher risk of conversion if they have symptoms of depression, anxiety, and lower right striatal dopamine uptake. Other factors that were involved in increasing the risk, were the presence of sleepiness and the presence of rapid eye movement disorders. Interestingly, the genetic factors were of negligible importance and were not considered by the algorithm. Finally, the model showed an accuracy of classification of participants (converters vs. non-converters) of 92.53%.Conclusions:Random forest algorithm shows that (1) depression and anxiety are probably important factors for MCI conversion; (2) years of education influences the conversion; (3) presence of sleepiness and rapid eye movement increases the risk of conversion to MCI. Since the algorithm considers the disease’s age onset, but not the diagnosis of individuals, it would be necessary to generate a model for each group (Healthy on the one hand, Parkinson’s on the other).

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions.

Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665-0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599-0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

Lactase deficiency in Russia: multiethnic genetic study.

Lactase persistence-the ability to digest lactose through adulthood-is closely related to evolutionary adaptations and has affected many populations since the beginning of cattle breeding. Nevertheless, the contrast initial phenotype, lactase non-persistence or adult lactase deficiency, is still observed in large numbers of people worldwide. We performed a multiethnic genetic study of lactase deficiency on 24,439 people, the largest in Russia to date. The percent of each population group was estimated according to the local ancestry inference results. Additionally, we calculated frequencies of rs4988235 GG genotype in Russian regions using the information of current location and birthplace data from the client's questionnaire. The attained results show that among all studied population groups, the frequency of GG genotype in rs4988235 is higher than the average in the European populations. In particular, the prevalence of lactase deficiency genotype in the East Slavs group was 42.8% (95% CI: 42.1-43.4%). We also investigated the regional prevalence of lactase deficiency based on the current place of residence. Our study emphasizes the significance of genetic testing for diagnostics, i.e., specifically for lactose intolerance parameter, as well as the scale of the problem of lactase deficiency in Russia which needs to be addressed by the healthcare and food sectors.

THU-277 - Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with the PiZZ alpha-1 antitrypsin deficiency genotype

THU-277 - Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with the PiZZ alpha-1 antitrypsin deficiency genotype

Physiological traits and expression profile of genes associated with nitrogen and phosphorous use efficiency in wheat

Nitrogen (N) and phosphorous (P) play a very important role in the growth and development of wheat as well as major constituents of biological membranes. To meet the plant's nutritional demand these nutrients are applied in the form of fertilizers. But the plant can utilize only half of the applied fertilizer whereas the rest is lost through surface runoff, leaching and volatilization. Thus, to overcome the N/P loss we need to elucidate the molecular mechanism behind the N/P uptake. In our study, we used DBW16 (low NUE), and WH147 (high NUE) wheat genotypes under different doses of N, whereas HD2967 (low PUE) and WH1100 (high PUE) genotypes were studied under different doses of P. To check the effect of different doses of N/P, the physiological parameters like total chlorophyll content, net photosynthetic rate, N/P content, and N/PUE of these genotypes were calculated. In addition, gene expression of various genes involved in N uptake, utilization, and acquisition such as Nitrite reductase (NiR), Nitrate transporter 1/Peptide transporter family (NPF2.4/2.5), Nitrate transporter (NRT1) and NIN Like Protein (NLP) and induced phosphate starvation (IPS), Phosphate Transporter (PHT1.7) and Phosphate 2 (PHO2) acquisition was studied by quantitative real-time PCR. Statistical analysis revealed a lower percent reduction in TCC, NPR, and N/P content in N/P efficient wheat genotypes (WH147 & WH1100). A significant increase in relative fold expression of genes under low N/P concentration was observed in N/P efficient genotypes as compared to N/P deficient genotypes. Significant differences in physiological data and gene expression among N/ P efficient and deficient wheat genotypes could be useful for future improvement of N/P use efficiency.

Systemic inflammatory prognostic scores in advanced pancreatic adenocarcinoma.

Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC). Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed. We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes. Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.

Machine learning classification of plant genotypes grown under different light conditions through the integration of multi-scale time-series data

In order to mitigate the effects of a changing climate, agriculture requires more effective evaluation, selection, and production of crop cultivars in order to accelerate genotype-to-phenotype connections and the selection of beneficial traits. Critically, plant growth and development are highly dependent on sunlight, with light energy providing plants with the energy required to photosynthesize as well as a means to directly intersect with the environment in order to develop. In plant analyses, machine learning and deep learning techniques have a proven ability to learn plant growth patterns, including detection of disease, plant stress, and growth using a variety of image data. To date, however, studies have not assessed machine learning and deep learning algorithms for their ability to differentiate a large cohort of genotypes grown under several growth conditions using time-series data automatically acquired across multiple scales (daily and developmentally). Here, we extensively evaluate a wide range of machine learning and deep learning algorithms for their ability to differentiate 17 well-characterized photoreceptor deficient genotypes differing in their light detection capabilities grown under several different light conditions. Using algorithm performance measurements of precision, recall, F1-Score, and accuracy, we find that Suport Vector Machine (SVM) maintains the greatest classification accuracy, while a combined ConvLSTM2D deep learning model produces the best genotype classification results across the different growth conditions. Our successful integration of time-series growth data across multiple scales, genotypes and growth conditions sets a new foundational baseline from which more complex plant science traits can be assessed for genotype-to-phenotype connections.

Quantitative G6PD Deficiency Screening in Routine Malaria Diagnostic Units in the Brazilian Amazon (SAFEPRIM): An Operational Mixed-Methods Study.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not routinely performed before primaquine treatment in most Plasmodium vivax endemic areas, despite the risk of primaquine-associated hemolysis. This is due to the operational challenges associated with pragmatic G6PD testing and as such needs to be addressed. This mixed-methods operational study was aimed at implementing the quantitative point-of-care StandardTM G6PD (SD Biosensor, Korea) screening test in malaria treatment units (MTUs) in the municipalities of Rio Preto da Eva and Mâncio Lima, in the Brazilian Amazon, between mid-January 2020 and December 2020. In total, 1286 P. vivax cases were treated based on the Standard G6PD test: 1230 had activity equal to or greater than 4.0 U/g Hb, and 56 less than 4.0 U/g Hb. No G6PD deficient (G6PDd) genotypes were found in 96 samples from the 1230, and only 21 of the 56 G6PDd cases had confirmed G6PDd genotypes. Evaluations were conducted on the proficiency of health care professionals (HCPs) training to perform the test, the reliability of testing performed in the field, and the perceptions of HCPs and patients about the implementation. Post-training proficiency was 73.4% after a 4-hour training session. This study revealed that locations with lower malaria caseloads will need regular refresher training. The test was well accepted by both HCPs and patients. Signs and symptoms of hemolysis were not always associated with malaria treatment drugs by HCPs and patients. Point-of-care quantitative G6PD testing can be performed at MTUs in the Brazilian Amazon to inform treatment decisions with primaquine. Limitations related to technical and cultural aspects need to be addressed further when expanding screening to larger areas.

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency.

Respiratory disease is the major cause of morbidity and mortality in patients with alpha-1 antitrypsin deficiency, mainly in homozygous PI*ZZ individuals. However, this association is uncertain in subjects with other deficiency genotypes. The objective of this study was to assess, in the context of alpha-1 antitrypsin deficiency, the existence of further risk factors that have been associated with respiratory diseases. Lung function was assessed by spirometry in a sample of 1334 patients with a known genotype for the SERPINA1 gene whose serum alpha-1 antitrypsin levels had been previously determined. Patients with a normal genotype (PI*MM) were compared to 389 patients carrying a deficiency allele. Statistically significant associations were detected between (i) PI*ZZ genotype and abnormal FEV1 values (χ2 = 26.45; P <.0002), FEV1/FVC (χ2 = 14.8; P < .02) or forced mid-expiratory flow 25%-75% (χ2 =22.66; P < .0009); (ii) chronic obstructive pulmonary disease and PI*ZZ odds ratio: 26.5; 95% CI: (2.6-265.9); P <.005 and or PI*SS genotype odds ratio: 9; 95% CI: (2-40.1); P < .004; (iii) prevalence of COPD in PI*MZ subjects and smoking habit (P < .01), low body weight (P < .01) or older age (P < .0001). The PI*ZZ and PI*SS genotypes seem to be associated with the prevalence of chronic obstructive pulmonary disease. Tobacco use, low body weight, and older age are risk factors that increase the probability of prevalence of chronic obstructive pulmonary disease by up to 70% in PI*MZ individuals.

Demographic and clinical characteristics of patients with α1-antitrypsin deficiency genotypes PI*ZZ and PI*SZ in the Spanish registry of EARCO.

BackgroundThe Spanish registry of α1-antitrypsin deficiency (AATD) integrated in the European Alpha-1 Research Collaboration (EARCO) provides information about the characteristics of patients, in particular those with the PI*SZ genotype, which is frequent in Spain.MethodIndividuals with severe AATD defined as proteinase inhibitor (PI) genotypes PI*ZZ, PI*SZ and other rare deficient variants were included from February 1, 2020, to February 1, 2022. The analysis focused on a comparison of the characteristics of PI*ZZ and PI*SZ patients.Results409 patients were included (53.8% men) with a mean±sd age of 53.5±15.9 years. Genotypes were PI*ZZ in 181 (44.7%), PI*SZ in 163 (40.2%), PI*SS in 29 (7.2%) and other in 32 (7.9%). 271 (67.4%) had lung disease: 175 chronic obstructive pulmonary disease (43.5%), 163 emphysema (40.5%) and 83 bronchiectasis (20.6%). Patients with the PI*SZ genotype were younger, more frequently non-index cases and had a lower frequency of respiratory diseases except asthma compared with PI*ZZ patients. Among patients with respiratory diseases, PI*SZ individuals were significantly older both at onset of symptoms and at diagnosis; only asthma was more frequent in PI*SZ than in PI*ZZ individuals. Twelve PI*SZ patients (15.4%) received augmentation therapy compared with 94 PI*ZZ patients (66.2%; p<0.001).ConclusionsThere is a high prevalence of PI*SZ in Spain. Patients with the PI*SZ genotype were older at symptom onset and diagnosis and had less severe lung disease compared with PI*ZZ patients. The prevalence of asthma was higher in PI*SZ, and up to 15% of PI*SZ patients received augmentation therapy.

The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.

Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: Revelations about underdiagnosis

Background and objectiveAlpha-1 antitrypsin deficiency (AATD) is an underdiagnosed hereditary condition that promotes the development of lung and liver diseases, and the most common potentially life-threatening genetic condition in Caucasian adults. In this study, the clinical and genetic profile of pulmonary patients from a single center in La Palma Island (Canary Islands, Spain) was assessed to predict how to increase AATD diagnosis. MethodsAATD was tested in 1,493 pulmonary outpatients without regard to respiratory symptoms and 465 newborns. Variants of the SERPINA1 gene were characterised by real-time PCR, DNA sequencing, molecular haplotyping and phenotyping (AAT isoelectric focusing). Different respiratory pathologies were diagnosed in patients and their levels of serum AAT were measured by nephelometry. ResultsThe prevalence of pneumological patients with AATD alleles was 30.5%, including PI*S, PI*Z and 6 rare genetic variants. Certain deficiency genotypes were unevenly distributed among patients diagnosed with respiratory diseases: PI*ZZ (71.4%) and PI*SS (34.8%) genotypes were more represented in patients with chronic obstructive pulmonary disease (COPD), whereas PI*MZ (27.7%) and PI*SZ (34.5%) genotypes were more abundant in patients with bronchial asthma. The estimated frequency of PI*S and PI*Z alleles in the general population was 8.2% and 2.1%, respectively. A very significant enrichment (p< 0.01) of PI*S allele, independent of the PI*Z allele, was detected in the clinical population. ConclusionsAATD diagnosis would improve if both the COPD and the asthmatic patients were included to screening programs. The prevalence of PI*ZZ genotype in La Palma (1/2,162) was relatively high within Spain (average 1/3,344).

Alpha-1 antitrypsin deficiency and risk of lung cancer in never-smokers: a multicentre case\u2013control study

BackgroundLung cancer (LC) is the most commonly diagnosed cancer and the leading cause of cancer-related death in both sexes worldwide. Although the principal risk factor in the western world is tobacco smoking, genetic factors, including alpha-1 antitrypsin deficiency (AATD), have been associated with increased risk. This study is the continuation of an earlier one published by the same group in 2015, aimed at analysing risk of LC in never-smokers, associated with carriers of the AATD genotype.MethodsA multicentre case–control study was conducted in Spain across the period January 2011 to August 2019. Cases were non-smokers diagnosed with LC, and controls were composed of never-smoking individuals undergoing major non-cancer-related surgery. Data were collected on epidemiological characteristics, exposure to environmental tobacco smoke (ETS), residential radon levels, and alpha-1 antitrypsin (AAT) genotype.ResultsThe study included 457 cases (42%) and 631 controls (58%), with a predominance of women (72,8%). The most frequent histological type was adenocarcinoma (77.5%), followed by squamous cell carcinoma (7.7%). No association of risk of LC was found with the status of AATD genotype carrier, both overall and broken down by age, sex, or exposure to ETS.ConclusionsNo risk association was found between being a carrier of an AAT deficiency genotype and LC among never-smokers. In order to establish the existence of an association, we consider it important to expand the studies in never smokers in different geographical areas as well as to include patients with previous chronic lung diseases to assess if it influences the risk.

Genotypic glucose-6-phosphate dehydrogenase (G6PD) deficiency protects against Plasmodium falciparum infection in individuals living in Ghana.

The global effort to eradicate malaria requires a drastic measure to terminate relapse from hypnozoites as well as transmission via gametocytes in malaria-endemic areas. Primaquine has been recommended for the treatment of P. falciparum gametocytes and P. vivax hypnozoites, however, its implementation is challenged by the high prevalence of G6PD deficient (G6PDd) genotypes in malaria endemic countries. The objective of this study was to profile G6PDd genotypic variants and correlate them with malaria prevalence in Ghana. A cross-sectional survey of G6PDd genotypic variants was conducted amongst suspected malaria patients attending health care facilities across the entire country. Malaria was diagnosed using microscopy whilst G6PD deficiency was determined using restriction fragment length polymorphisms at position 376 and 202 of the G6PD gene. The results were analysed using GraphPad prism. A total of 6108 subjects were enrolled in the study with females representing 65.59% of the population. The overall prevalence of malaria was 36.31%, with malaria prevalence among G6PDd genotypic variants were 0.07% for A-A- homozygous deficient females, 1.31% and 3.03% for AA- and BA- heterozygous deficient females respectively and 2.03% for A- hemizygous deficient males. The odd ratio (OR) for detecting P. falciparum malaria infection in the A-A- genotypic variant was 0.0784 (95% CI: 0.0265-0.2319, p<0.0001). Also, P. malariae and P. ovale parasites frequently were observed in G6PD B variants relative to G6PD A- variants. G6PDd genotypic variants, A-A-, AA- and A- protect against P. falciparum, P. ovale and P. malariae infection in Ghana.

P-198 Prevalence of deleterious DPYD variants in patients with gastrointestinal malignancies: Real-world data from a single institution in Italy

Fluoropyrimidine (FP) represents a cornerstone in the treatment of gastrointestinal (GI) malignancies. Severe adverse drug reaction (ADR) may occur in 10% to 30% of patients treated with FP. Dihydropyrimidine dehydrogenase (DPYD) is a polymorphic gene encoding for DPD, involved in FP catabolism. The identification of variants associated with deleterious enzyme activity and increased risk of toxicity is recommended before treatment initiation [c.1905+1G>A(*2A); c.1679T>G(*13); c.1129-5923C>G, c.1236G>A(HapB3); c.2846A>T) or during treatment in case of ADR [c.2194G>A (*6)]. The estimated prevalence of DPYD deficient genotypes in the European population is < 8%. We aimed at determining the prevalence of DPYD deficient gene variants in a cohort of patients with GI malignancies treated at our department. A consecutive series of patients diagnosed with GI malignancies at our department from 15th June 2020 to 15th March 2021 and candidate to a FP-based therapy was assessed for germline DPYD testing before treatment initiation. The following variants were examined: c.1905+1G>A(*2A); c.1679T>G(*13); c.1129-5923C>G, c.1236G>A(HapB3); c.2846A>T; c.2194G>A(*6). The analysis included 310 patients, of which 226 with colorectal [CRC], 37 gastro-esophageal [GEC], 36 biliopancreatic [BPC], 7 other GI cancer (i.e. anal, NET), and 2 with double-tumor diagnosis (CRC/GEC, GEC/BPC). Overall, 261 patients (84%) were DPYD wild-type (WT) and 49 (16%) were carriers of a deleterious DPYD variant. Among positive cases, 39 (80%) had CRC, 5 BPC (10%), 3 GEC (6%), 1 other GI tumor-type (2%) and 1 had a second GI cancer (CRC/GEC) (2%). No association was observed between DPYD status and tumor-type (p=0.48). Out of 310 patients, 50 deleterious variants were observed in 49 patients: c.2194G>A(*6) in 37 cases (12%), of which one homozygous; c.1905+1G>A(*2A) in 6 (2%); c.1129-5923C>G in 4 (1%); c.2846A>T in 2 ( G(*13) in 1 ( In patients carrier of a deleterious variant, in 35 cases (11%) the recommended total dose (TD) of FP was 85%, in 10 (3%) was 50%, in 4 ranged from 50% to 75% (1%), whereas no variation in the TD was recommended (TD 100%) in WT cases (N=261, 84%). Of interest, of 54 patients enrolled in interventional phase II or III clinical trials including FP treatment, 6 patients (12%) displayed a gene variant requiring a FP-dose reduction. In our cohort, the prevalence of DPYD deleterious variants was more frequent than in reported data. DPYD*6 c.2194G>A was the most frequent genotype requiring a dose adjustment. No correlation between DPYD variants and tumor type was observed. According to our data, the assessment of deleterious DPYD variants and consequent FP-dose adjustment should be included in clinical trials protocols including FP treatment in order to prevent ADR and to adequately report toxicity profile and changes in patients' quality of life.