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1.
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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2.
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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The genetic landscape of Alzheimer disease.
Carmona, S, Hardy, J, Guerreiro, R
Handbook of clinical neurology. 2018;:395-408
Abstract
Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first clues were provided by genetic linkage studies that led to the identification of APP, PSEN1, and PSEN2 mutations as the main causes of autosomal-dominant early-onset AD. Another important hallmark was the identification of the APOE ɛ4 allele as a risk factor for late-onset AD. Over the last 20 years the development and implementation of new genetic and genomic technologies have allowed the identification of other genetic players in this disease. Genome-wide association studies identified more than 20 loci with common variability having small contributions to the susceptibility of AD. The majority of the genes mapped in these loci are known to be involved in specific biologic pathways: cholesterol metabolism, immune response, and endocytosis. More recently, the application of next-generation sequencing (mainly whole-exome sequencing) has begun to reveal the contribution of rarer variants with medium effects on risk for AD. This area of research has come a long way with many and important results allowing a better understanding of the disease. More efforts are still needed, however, to fully understand the etiology of this disease in order to establish reliable individual predictive models and put us closer to the development of a curative, preventive, or modulator drug.
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[Search for risk genes in Alzheimer's disease].
Karaca, I, Wagner, H, Ramirez, A
Der Nervenarzt. 2017;(7):744-750
Abstract
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. The susceptibility to AD is determined by a complex interaction between genetic, epigenetic, and environmental factors. Herein, the risk that can be attributed to genetic factors is high (up to 80%). While most AD patients are sporadic, in rare families Mendelian mode of inheritance can be observed. In these rare familial cases, full penetrant mutations have been identified in APP, PSEN1, and PSEN2. Mutations in these three genes are however rarely found in sporadic AD. For over 20 years, the only known genetic risk factor in sporadic AD cases was the APOE-ε4 allele, which increases susceptibility to AD by approximately threefold. Unfortunately, none of these genes explain the frequency of AD. Identification of additional genetic factors was propelled by the advent of genomic approaches such as genome-wide association studies, which has already led to the characterization of 26 novel genetic risk factors. Interestingly, several of these genetic signals cluster in biological pathways including cholesterol, lipid metabolism, immune response, and endocytic trafficking. An additional impulse in genetic research came from the development of novel sequencing technologies. For example, the whole exome sequencing approach has identified an association between the risk of AD and rare coding variants (minor allele frequency <1%) located in genes such as TREM2, SORL1, and ABCA7. Thus, progress from genetic research has significantly increased our understanding of the disease mechanisms operating in AD. However, even though our knowledge of the genetics of sporadic forms of AD has progressed markedly over the last years, it is still far from complete. Additional research is needed to complete the genetic architecture of AD.
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5.
Genetics of celiac disease.
Ricaño-Ponce, I, Wijmenga, C, Gutierrez-Achury, J
Best practice & research. Clinical gastroenterology. 2015;(3):399-412
Abstract
New insights into the underlying molecular pathophysiology of celiac disease (CeD) over the last few years have been guided by major advances in the fields of genetics and genomics. The development and use of the Immunochip genotyping platform paved the way for the discovery of 39 non-HLA loci associated to CeD, and for follow-up functional genomics studies that pinpointed new disease genes, biological pathways and regulatory elements. By combining information from genetics with gene expression data, it has become clear that CeD is a disease with a dysregulated immune response, which can probably occur in a variety of immune cells. This type of information is crucial for our understanding of the disease and for providing leads for developing alternative therapies to the current gluten-free diet. In this review, we place these genetic findings in a wider context and suggest how they can assist the clinical care of CeD patients.
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6.
[Monogenic obesity - current status of molecular genetic research and clinical importance].
Aldhoon-Hainerová, I, Včelák, J, Zamrazilová, H
Casopis lekaru ceskych. 2014;(4):200-6
Abstract
Obesity and its comorbidities represent one of the major health problems worldwide. A positive energy balance due to inappropriate life-style changes plays a key role in the current obesity epidemic. The influence of genetic factors is also significant - several studies concluded that genes contribute to the development of obesity by 40-70%. Genetic variability predisposes an individual to tendency or resistance to increase body weight in obesogenic environment. Polygenic type of inheritance is responsible in most of obese individuals. However, an intensive research of the past 20 years has led to an identification of several genes causing monogenic forms of obesity. To date, several monogenic genes (leptin, leptin receptor, prohormon convertase 1, proopiomelanocortin, melanocortin 4 receptor, single-minded homolog 1, brain-derived neurotrophic factor, neurotrophic tyrosine kinase receptor type 2) that are either involved in the neuronal differentiation of the paraventricular nucleus or in the leptin-melanocortin pathway are known to cause obesity. Mutation carriers apart from severe early onset obesity manifest with additional phenotypic characteristics as adrenal insufficiency, impaired immunity and impaired fertility. This review provides an overview of molecular-genetic and clinical research in the field of monogenic obesities including therapeutical approaches.
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7.
Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: a systematic review and meta-analysis.
Weng, PH, Huang, YL, Page, JH, Chen, JH, Xu, J, Koutros, S, Berndt, S, Chanock, S, Yeager, M, Witte, JS, et al
PloS one. 2014;(10):e110569
Abstract
BACKGROUND Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews. METHODS We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls. RESULTS Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity. CONCLUSIONS TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
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8.
The conundrum of iron in multiple sclerosis--time for an individualised approach.
van Rensburg, SJ, Kotze, MJ, van Toorn, R
Metabolic brain disease. 2012;(3):239-53
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Abstract
Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome--some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.
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Germline melanoma susceptibility and prognostic genes: a review of the literature.
Ward, KA, Lazovich, D, Hordinsky, MK
Journal of the American Academy of Dermatology. 2012;(5):1055-67
Abstract
In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed 'candidate melanoma susceptibility or prognostic genes.' This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patient's risk of, and prognosis in, cutaneous malignant melanoma.
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Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis.
Czaja, AJ
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2008;(4):379-88
Abstract
Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67-72 in the DRbeta polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRbeta71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRbeta71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-alpha gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor-receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general.