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A Case Report of Primary Neonatal Hypocholinesterase Caused by Homozygous Frameshift Mutation of the utyrylcholinesterase (BCHE) Gene and Review of Literature.
Lv, HY, Yang, LH, Bu, LN, Wang, QL, Gu, XL, Wang, ZY, Ren, PS, Li, LX
Clinical laboratory. 2019;(7)
Abstract
BACKGROUND Primary neonatal hypocholinesterase is rare; its genetic pattern and mutation still need to be further studied. METHODS The patient and his parents are studied using next-generation sequencing technology. RESULTS A boy one day after birth is admitted to the Neonatal Intensive Care Unit at our hospital after experiencing intermittent vomiting for 12 hours. The patient's serum cholinesterase level (113 - 283 U/L) is lower than normal value (4,000 - 12,600 U/L). Many factors of low serum cholinesterase are excluded. We highly suspect that it may be related to congenital factors. Molecular genetic test results show that the patient carried the BCHE gene (NM_000055.2) and has homozygous frameshift mutations at exon 2 c.401dupA (p.Asn134fs) of chromosome 3q26. It is a pathogenicity mutation. This locus mutation belongs to a novel pathogenic mutation. As a result of this mutation, the 134th amino acid Asn began to frameshift and the translation is terminated early. It can cause the Encoding of protein to truncate and lose its normal function. His parents' serum cholinesterase levels (father: 5,135 U/L; mother: 4,367 U/L) are in the normal value range, but his parents carried a heterozygous BCHE gene. CONCLUSIONS This study suggests that gene sequence detection should be carried out early in hypocholinesterase of nknown cause in neonates. This study can not only improve understanding of the etiology and pathological mechanism of hypocholinesterase, but also it can enlarge the hypocholinesterase gene mutation spectrum.
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Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI-EBI Catalog of published genome-wide association studies.
Kaur, Y, Wang, DX, Liu, HY, Meyre, D
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2019;(3):385-406
Abstract
We conducted a hypothesis-free cross-trait analysis for waist-to-hip ratio adjusted for body mass index (WHRadjBMI ) loci derived through genome-wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHRadjBMI single-nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross-trait associations between WHRadjBMI SNPs and other traits through the NHGRI-EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHRadjBMI SNPs. We found 160 WHRadjBMI SNPs and 3675 proxy SNPs. Cross-trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes-related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross-trait associations were found for triglycerides (n = 10), high-density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHRadjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHRadjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.
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Opportunities and challenges for transcriptome-wide association studies.
Wainberg, M, Sinnott-Armstrong, N, Mancuso, N, Barbeira, AN, Knowles, DA, Golan, D, Ermel, R, Ruusalepp, A, Quertermous, T, Hao, K, et al
Nature genetics. 2019;(4):592-599
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Abstract
Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn's disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). TWAS is especially prone to spurious prioritization with expression data from non-trait-related tissues or cell types, owing to substantial cross-cell-type variation in expression levels and eQTL strengths. Nonetheless, TWAS prioritizes candidate causal genes more accurately than simple baselines. We suggest best practices for causal-gene prioritization with TWAS and discuss future opportunities for improvement. Our results showcase the strengths and limitations of using eQTL datasets to determine causal genes at GWAS loci.
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Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease.
Ashton, JJ, Latham, K, Beattie, RM, Ennis, S
Alimentary pharmacology & therapeutics. 2019;(8):885-900
Abstract
BACKGROUND The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.
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Primary Aldosteronism.
Funder, JW
Hypertension (Dallas, Tex. : 1979). 2019;(3):458-466
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A decade in psychiatric GWAS research.
Horwitz, T, Lam, K, Chen, Y, Xia, Y, Liu, C
Molecular psychiatry. 2019;(3):378-389
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Abstract
After more than 10 years of accumulated efforts, genome-wide association studies (GWAS) have led to many findings, most of which have been deposited into the GWAS Catalog. Between GWAS's inception and March 2017, the GWAS Catalog has collected 2429 studies, 1818 phenotypes, and 28,462 associated SNPs. We reclassified the psychology-related phenotypes into 217 reclassified phenotypes, which accounted for 514 studies and 7052 SNPs. In total, 1223 of the SNPs reached genome-wide significance. Of these, 147 were replicated for the same psychological trait in different studies. Another 305 SNPs were replicated within one original study. The SNPs rs2075650 and rs4420638 were linked to the most replications within a single reclassified phenotype or very similar reclassified phenotypes; both were associated with Alzheimer's disease (AD). Schizophrenia was associated with 74 within-phenotype SNPs reported in independents studies. Alzheimer's disease and schizophrenia were both linked to some physical phenotypes, including cholesterol and body mass index, through common GWAS signals. Alzheimer's disease also shared risk SNPs with age-related phenotypes such as age-related macular degeneration and longevity. Smoking-related SNPs were linked to lung cancer and respiratory function. Alcohol-related SNPs were associated with cardiovascular and digestive system phenotypes and disorders. Two separate studies also identified a shared risk SNP for bipolar disorder and educational attainment. This review revealed a list of reproducible SNPs worthy of future functional investigation. Additionally, by identifying SNPs associated with multiple phenotypes, we illustrated the importance of studying the relationships among phenotypes to resolve the nature of their causal links. The insights within this review will hopefully pave the way for future evidence-based genetic studies.
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Reverse Cascade Screening for Familial Hypercholesterolemia.
Vinson, A, Guerra, L, Hamilton, L, Wilson, DP, Fnla,
Journal of pediatric nursing. 2019;:50-55
Abstract
PROBLEM Cardiovascular disease (CVD) is the leading cause of death in the U.S. and in most Western countries. Early identification and treatment of individuals with elevated levels of atherogenic cholesterol, a major contributor to CVD, have been shown to be effective and safe in reducing premature morbidity and mortality, especially in familial hypercholesterolemia (FH). Cholesterol screening of youth also provides a unique means of identifying affected family members through reverse cascade screening (RCS). ELIGIBILITY CRITERIA A PubMed review of all relevant articles from 2000 to 2016 was conducted of familial hypercholesterolemia and cholesterol screening of youth. RESULTS We provide an overview of cholesterol screening, outline the role of the pediatric nurse in the lipid clinic, and discuss effectiveness and potential barriers, including cost and confidentiality considerations of RCS. CONCLUSIONS Early identification and effective intervention of youth with FH, including adoption of a heart-healthy lifestyle, has the potential of 1) markedly reducing or eliminating atherosclerotic cardiovascular disease and related events in future generations and 2) provides a unique means of identifying affected family members. IMPLICATIONS Pediatric nurses play a vital role in the education and care coordination of children diagnosed with FH and screening of relatives. Identification of a child with FH with effective screening of relatives combines the benefits of universal and cascade screening, and has the potential of detecting all living cases of FH. While potentially providing significant benefit to those at risk for premature CVD, a RCS program needs to carefully consider ethical, psychological, and financial implications as well.
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Genetic Markers for Coronary Artery Disease.
Veljkovic, N, Zaric, B, Djuric, I, Obradovic, M, Sudar-Milovanovic, E, Radak, D, Isenovic, ER
Medicina (Kaunas, Lithuania). 2018;(3)
Abstract
Coronary artery disease (CAD) and myocardial infarction (MI) are recognized as leading causes of mortality in developed countries. Although typically associated with behavioral risk factors, such as smoking, sedentary lifestyle, and poor dietary habits, such vascular phenotypes have also long been recognized as being related to genetic background. We review the currently available data concerning genetic markers for CAD in English and non-English articles with English abstracts published between 2003 and 2018. As genetic testing is increasingly available, it may be possible to identify adequate genetic markers representing the risk profile and to use them in a clinical setting.
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Genetic studies of human neuropathic pain conditions: a review.
Zorina-Lichtenwalter, K, Parisien, M, Diatchenko, L
Pain. 2018;(3):583-594
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Abstract
Numerous studies have shown associations between genetic variants and neuropathic pain disorders. Rare monogenic disorders are caused by mutations of substantial effect size in a single gene, whereas common disorders are likely to have a contribution from multiple genetic variants of mild effect size, representing different biological pathways. In this review, we survey the reported genetic contributors to neuropathic pain and submit them for validation in a 150,000-participant sample of the U.K. Biobank cohort. Successfully replicated association with a neuropathic pain construct for 2 variants in IL10 underscores the importance of neuroimmune interactions, whereas genome-wide significant association with low back pain (P = 1.3e-8) and false discovery rate 5% significant associations with hip, knee, and neck pain for variant rs7734804 upstream of the MAT2B gene provide evidence of shared contributing mechanisms to overlapping pain conditions at the molecular genetic level.
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Association between "solute carrier family 30 member 8" (SLC30A8) gene polymorphism and susceptibility to type 2 diabetes mellitus in Chinese Han and minority populations: an updated meta-analysis.
Wang, Y, Duan, L, Yu, S, Liu, X, Han, H, Wang, J, Li, W
Asia Pacific journal of clinical nutrition. 2018;(6):1374-1390
Abstract
BACKGROUND AND OBJECTIVES In China, some studies have been reported that solute carrier family 30 member 8 (SLC30A8) gene polymorphism might increase the risk of T2DM, but some are not. The aim of this meta-analysis was to systematically investigate the association between the rs13266634 polymorphism of the SLC30A8 gene and T2DM in Chinese Han and ethnic minority populations. METHODS AND STUDY DESIGN All published electronic articles were retrieved from Pubmed, Web of Knowledge, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, VIP database and Google scholar. Pooled OR and 95% CI were calculated using random- or fixed-effects models. RESULTS Twenty-five articles involving 62,285 subjects were included in this metaanalysis. Considering the total population, significant associations between the rs13266634 polymorphism and T2DM were observed under the allele model (C vs T: OR=1.23, 95% CI=1.18-1.29), the additive models ( CC vs TT: OR=1.44, 95% CI=1.32-1.56; CC vs CT: OR=1.08, 95% CI=1.02-1.15; CT vs TT: OR=1.25, 95% CI=1.15- 1.37), the dominant model (CC vs CT+TT: OR=1.24, 95% CI=1.17-1.32) and the recessive model (CC+CT vs TT: OR=1.26, 95% CI=1.16-1.35). Based on subgroup analysis, besides the CC vs CT model, these associations were stronger in the ethnic minority groups than in the Han population. Moreover, no association was observed under the CC vs CT model (OR=1.26, 95% CI=0.95-1.66, p=0.105) in ethnic minority groups. CONCLUSIONS Chinese C allele carriers could have an increased risk of T2DM. Well-designed future studies should be conducted with a larger sample size to better understand this association in ethnic minority groups.