Knowledge Of Genetic Risk Factors Research Articles

Comprehensive Management of Thrombosed Lower Extremity Venous Aneurysms: A Single-Center Retrospective Analysis and Insights Into Clinical Strategies.

Venous aneurysms are rare vascular abnormalities associated with venous thromboembolism. In this study, we presented our experience in managing thrombosed lower extremity venous aneurysms and evaluate the impact of vitamin D deficiency and genetic thrombophilic risk factors on patient management and outcomes. A single-center retrospective observational analysis was conducted on ten patients with thrombosed lower limb venous aneurysms who underwent surgical procedures at our hospital from July 2014 to February 2023. Collected data included venous duplex ultrasonographic imaging and laboratory tests including genetic thrombophilic risk factors and assessments of vitamin D levels. There were 5 males and 5 females. The mean age was 46.6 ± 12.1years. The aneurysms were located in the popliteal vein in three patients, the great saphenous vein in six, and the small saphenous vein in one. Venous duplex imaging revealed saccular aneurysms in eight patients and fusiform aneurysms in two, with a mean diameter of 37.2 ± 10.6mm, ranging from 23 to 52mm. Laboratory tests indicated vitamin D deficiency in all of the patients, and genetic thrombophilic risk factors were identified in two cases. Surgical interventions consisted of tangential excision with lateral venorrhaphy in three patients and total excision and ligation in seven patients. The postoperative period was favorable for all patients. Surgical treatment of thrombosed venous aneurysms in the lower extremities is essential to prevent complications such as thromboembolism. A comprehensive approach, including knowledge of genetic risk factors and vitamin D levels, may improve patient outcomes.

ECCO Global Grant Genetic risk factors for IBD in its emergent phase in sub-Saharan Africa

Abstract Background and Aims Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is an idiopathic, chronic, and frequently disabling inflammatory disorder of the intestines characterized by a dysregulated mucosal immune response. The pathophysiology of the disease remains incompletely understood. Genetic factors affecting disease are under investigation, however, genetic studies in non-European populations are scarce and it is an urgent scientific, social, and ethical requirement that research in under-studied populations is prioritized. The objective of this study is to understand the genetics of IBD in sub-Saharan African ancestry populations and to identify genetic factors that affect pathogenesis of IBD in this region. Methodology A case-control study will be conducted from January 2024 to December 2025. Consecutive eligible subjects with IBD and controls will be invited to take part in the study. Data will be collected through chart review, structured interviews, and collection of saliva samples for genotyping using the H3Africa chip in the first instance. Genome-wide imputation and replication analysis will be done. Single-marker association analyses will be performed using the Cochran Armitage trend and logistic regression test after correction for population structure. We will look at known European ancestry and African American (AA) IBD-associated variants as well as variants that are unique to our populations (we will be able to look at local admixture in the AA population to see if these variants are replicated). Anticipated Impact This study will contribute significantly to knowledge of genetic risk factors for IBD in sub-Saharan Africa. It may also help to identify potential complications of treatments such as thiopurines which have been commonly used in European populations but where experience of use in sub-Saharan Africa is lacking.

Genetics of drug-induced liver injury: Current knowledge and future prospects.

Idiosyncratic drug-induced liver injury (DILI) remains an important clinical problem, both during drug development and the prescription of a range of licensed drugs. Although rare, the consequences are serious. Ongoing studies on genetic risk factors for DILI, especially genomewide association studies, have resulted in the identification of a number of genetic risk factors, including particular HLA alleles and a few non-HLA genes, both immune-related and metabolic. Some non-HLA associations, such as N-acetyltransferase 2 in isoniazid DILI and interferon regulatory factor 6 in interferon-beta DILI are likely to be drug-specific due to the role of the associated gene, but there is also evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs. Increased knowledge of genetic risk factors should assist in better understanding underlying DILI mechanisms and help improve methods for identifying hepatotoxic drugs early in development. HLA allele-specific T cell proliferation together with in silico prediction of drug binding to specific HLA proteins have confirmed genetic findings for certain common causes of DILI. However, studies in hepatocytes exposed to high drug concentrations suggest toxicity that is not dependent on genotype also occurs. It seems likely that susceptibility to DILI involves several genetic risk factors combining with other factors that affect drug levels. Despite recent progress in detecting genetic risk factors for DILI, low positive predictive values mean that general implementation of genotyping prior to prescription of potentially hepatotoxic drugs is not useful currently.

Optimization of chronic lymphocytic leukemia treatment using game theory

The current strategy of chronic lymphocytic leukemia (CLL) treatment is based on genetic risk factors such as del(17p), TP53 mutations and/or unmutated variant of IGHV genes. Guidelines recommend the usage of targeted drugs, e.g. ibrutinib, in the first line for patients with unfavorable risk factors due to dismal results of other treatment options. Unfortunately, in real-life treatment decisions are often made without full knowledge of genetic risk factors in the treated patient. Our aim was to find the optimal therapeutic strategy for such patients, that is, those providing the best 5-year progression-free survival (PFS). Using a relatively simple game theory-based approach we here show, that currently, the used strategy is more advantageous (success rate 71%) compared to administration of immunochemotherapy to all patients (success rate with fludarabine + cyclophosphamide + rituximab — 45%, bendamustine + rituximab — 32%). However, the optimal strategy for CLL treatment in the conditions of unknown genetic risks is the administration of ibrutinib to all patients (success rate 73%). Our simple method can be used for optimization of treatment strategy of any oncologic disease and can be integrated into relevant clinical decision support systems.

Biomarkers of adverse drug reactions.

Adverse drug reactions can be caused by a wide range of therapeutics. Adverse drug reactions affect many bodily organ systems and vary widely in severity. Milder adverse drug reactions often resolve quickly following withdrawal of the casual drug or sometimes after dose reduction. Some adverse drug reactions are severe and lead to significant organ/tissue injury which can be fatal. Adverse drug reactions also represent a financial burden to both healthcare providers and the pharmaceutical industry. Thus, a number of stakeholders would benefit from development of new, robust biomarkers for the prediction, diagnosis, and prognostication of adverse drug reactions. There has been significant recent progress in identifying predictive genomic biomarkers with the potential to be used in clinical settings to reduce the burden of adverse drug reactions. These have included biomarkers that can be used to alter drug dose (for example, Thiopurine methyltransferase (TPMT) and azathioprine dose) and drug choice. The latter have in particular included human leukocyte antigen (HLA) biomarkers which identify susceptibility to immune-mediated injuries to major organs such as skin, liver, and bone marrow from a variety of drugs. This review covers both the current state of the art with regard to genomic adverse drug reaction biomarkers. We also review circulating biomarkers that have the potential to be used for both diagnosis and prognosis, and have the added advantage of providing mechanistic information. In the future, we will not be relying on single biomarkers (genomic/non-genomic), but on multiple biomarker panels, integrated through the application of different omics technologies, which will provide information on predisposition, early diagnosis, prognosis, and mechanisms. Impact statement • Genetic and circulating biomarkers present significant opportunities to personalize patient therapy to minimize the risk of adverse drug reactions. ADRs are a significant heath issue and represent a significant burden to patients, healthcare providers, and the pharmaceutical industry. • This review details the current state of the art in biomarkers of ADRs (both genetic and circulating). There is still significant variability in patient response which cannot be explained by current knowledge of genetic risk factors for ADRs; however, we discussed how specific advances in genomics have the potential to yield better and more predictive models. • Many current clinically utilized circulating biomarkers of tissue injury are valid biomarkers for a number of ADRs. However, they often give little insight into the specific cell or tissue subtype which may be affected. Emerging circulating biomarkers with potential to provide greater information on the etiology/pathophysiology of ADRs are described.

Genetics of HIV-associated sensory neuropathy and related pain in Africans.

Despite the use of safer antiretroviral medications, the rate of HIV-associated sensory neuropathy (HIV-SN), the most common neurological complication of HIV, remains high. This condition is often painful and has a negative effect on quality of life. Up to 90% of those with HIV-SN experience pain for which there is no effective analgesic treatment. Genetic factors are implicated, but there is a lack of a comprehensive body of research for African populations. This knowledge gap is even more pertinent as Africans are most affected by HIV. However, recent studies performed in Southern African populations have identified genes displaying potential as genetic markers for HIV-SN and HIV-SN-associated pain in Africans. Here, we review the published studies to describe current knowledge of genetic risk factors for this disease in Africa.

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies.

Chromosomal microarray (CMA) testing, used to identify DNA copy number variations (CNVs), has helped advance knowledge about genetics of human neurodevelopmental disease and congenital anomalies. It has aided in discovering new CNV syndromes and uncovering disease genes. It has discovered CNVs that are not fully penetrant and/or cause a spectrum of phenotypes, including intellectual disability, autism, schizophrenia, and dysmorphisms. Such CNVs can pose challenges to genetic counseling. They also have helped increase knowledge of genetic risk factors for neurodevelopmental disease and raised awareness of possible shared etiologies among these variable phenotypes. Advances in CMA technology allow CNV identification at increasingly finer scales, improving detection of pathogenic changes, although these sometimes are difficult to distinguish from normal population variation. This paper confronts some of the challenges uncovered by CMA testing while reviewing advances in genetics and the clinical use of this test that has replaced standard karyotyping in most genetic evaluations.

Genetic, psychosocial, and demographic factors associated with social disinhibition in Mexican-origin youth.

IntroductionThe genetic heritability for sensation-seeking tendencies ranges from 40 to 60%. Sensation-seeking behaviors typically manifest during adolescence and are associated with alcohol and cigarette experimentation in adolescents. Social disinhibition is an aspect of sensation-seeking that is closely tied to cigarette and alcohol experimentation.MethodsWe examined the contribution of candidate genes to social disinhibition among 1132 Mexican origin youth in Houston, Texas, adjusting for established demographic and psychosocial risk factors. Saliva samples were obtained at baseline in 2005–06, and social disinhibition and other psychosocial data were obtained in 2008–09. Participants were genotyped for 672 functional and tagging SNPs potentially related to sensation-seeking, risk-taking, smoking, and alcohol use.ResultsSix SNPs were significantly associated with social disinhibition scores, after controlling for false discovery and adjusting for population stratification and relevant demographic/psychosocial characteristics. Minor alleles for three of the SNPs (rs1998220 on OPRM1; rs9534511 on HTR2A; and rs4938056 on HTR3B) were associated with increased risk of social disinhibition, while minor alleles for the other three SNPs (rs1003921 on KCNC1; rs16116 downstream of NPY; and rs16870286 on LINC00518) exhibited a protective effect. Age, linguistic acculturation, thrill and adventure-seeking, and drug and alcohol-seeking were all significantly positively associated with increased risk of social disinhibition in a multivariable model (P < 0.001).ConclusionsThese results add to our knowledge of genetic risk factors for social disinhibition. Additional research is needed to verify whether these SNPs are associated with social disinhibition among youth of different ethnicities and nationalities, and to elucidate whether and how these SNPs functionally contribute to social disinhibition.

Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies

To review the progress that has been made in understanding the genetics of the idiopathic inflammatory myopathies (IIMs) in the past 2 years, with particular focus on polymyositis, dermatomyositis and inclusion body myositis. Candidate gene studies in the Japanese population have implicated signal transducer and activator of transcription 4 as a risk locus for IIM, and HLA-DRB1 as a risk locus for anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Evidence for gene-environment interactions has been found between HLA-DRB1*03 and smoking as a risk factor for the development of anti-histidyl tRNA synthetase antibodies, and HLA-DRB1*11:01 and statins for the development of anti-hydroxymethyl glutaryl-coenzyme A reductase-positive statin-induced myopathy. The HLA-DRB1*03:01/*01:01 genotype confers the highest disease risk in inclusion body myositis. A recent genome-wide association study has been performed in dermatomyositis. The most significant signals were in the major histocompatibility complex region, with other loci suggesting evidence of genetic overlap with different autoimmune diseases. Recent association and gene-environment interaction studies have increased our knowledge of genetic risk factors for the IIMs. Ongoing international collaborations will facilitate larger and more meaningful genetic studies revealing much about the genetic architecture of these complex diseases.

Genetic susceptibility to psoriasis: an emerging picture

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease.

Genetic Polymorphisms Associated With Inflammatory Bowel Disease Do Not Confer Risk for Primary Sclerosing Cholangitis

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have concurrent inflammatory bowel disease (IBD). The majority have ulcerative colitis, but there is also an association with Crohn's colitis. The pathogenetic link between PSC and IBD is unknown. We aimed to assess whether genetic risk factors in PSC can be identified on the basis of known IBD susceptibility genes and the shared PSC-IBD phenotype. IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes were genotyped in a large cohort of 365 Scandinavian PSC patients and 368 healthy controls using TaqMan technology. No significant association between any of the investigated genetic IBD risk variants and overall susceptibility to PSC was observed. Apart from a tendency toward an increased carrier frequency of the mutant CARD15 alleles in PSC patients with concurrent Crohn's disease as compared with healthy controls (15.6%vs 9.0%, P = 0.22), no association with any of the polymorphisms investigated was evident even when considering only PSC patients with concurrent IBD. It seems unlikely that IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes confer susceptibility to PSC. The current knowledge of genetic risk factors in IBD may not contribute to our understanding of molecular mechanisms involved in the pathogenesis of PSC or the IBD phenotype in PSC.

Genetic predisposition – understanding underlying mechanisms of onychomycosis

There are numerous factors that predispose to onychomycosis including genetic predisposition, diabetes mellitus, immunosuppression, vascular disease and psoriasis. The aims of this workshop were to discuss current knowledge of genetic risk factors and the approaches that should be used to investigate underlying mechanisms. The high prevalence of onychomycosis within certain families was initially attributed to intrafamilial transmission. However, the low prevalence of infection in people marrying into infected families together with the high prevalence among their offspring suggested a genetic basis. The state-of-the-art pedigree study by Zaias et al. suggested that Trichophyton rubrum infection shows an autosomal dominant pattern of inheritance. A consensus was reached that epidemiological and genetic studies are required to investigate this issue further. For epidemiological studies, families in which two or three generations are infected with T. rubrum should be selected. Patients with T. rubrum on different body sites should be included, and the presence of associated diseases or other common features in these individuals should be investigated to identify trigger factors. Genetic studies should explore the mode of inheritance of onychomycosis and look for the disease gene(s). Serum samples from patients and age-sex matched controls must be analysed centrally. The results of these studies will make it possible to develop therapeutic, preventive and prophylatic measures and to provide patients and their families with information.

Pharmacogenomics and Acquired Long QT Syndrome

During the past decade pharmaceutical companies have been faced with the withdrawal of some of their marketed drugs because of rare, yet lethal, postmarketing reports associated with ventricular arrhythmias. The implicated drugs include antiarrhythmics, but also non-cardiac drugs, such as histamine blockers, antipsychotics, and antibiotics. These undesired effects involve prolongation of the QT interval, which may lead to characteristic ventricular tachyarrhythmias, known as torsades de pointes. These clinical symptoms of the acquired long QT syndrome (LQTS) are also found in an inherited form of the disease, called congenital LQTS. Nowadays, a number of environmental (non-genetic) and genetic risk factors for acquired LQTS have been described. Non-genetic factors include female gender, hypokalemia, and other heart diseases. The knowledge of genetic risk factors is emerging rapidly. During the last decade, mutations in several genes encoding ion channels have been shown to cause congenital LQTS. In acquired LQTS, a number of 'silent' mutation carriers in these LQTS genes have been identified, and functional polymorphisms in the same genes have been found that are associated with an increased vulnerability for the disease. Furthermore, there is also evidence that interindividual differences in drug metabolism, caused by functional polymorphisms in drug-metabolizing enzyme genes, may be a risk factor for acquired LQTS, especially if multiple drugs are involved. This review evaluates the current knowledge on these risk factors for acquired LQTS, with an emphasis on the genetic risk factors. It also assesses the potential to develop pharmacogenetic tests that will enable clinicians and pharmaceutical companies to identify at an early stage patients or individuals in the general population who are at risk of acquired LQTS.

Implications of genetic epidemiology for the prevention of tobacco use.

Genetic epidemiology is the study of the pattern of common disease incidence in families and populations in order to infer the genetic basis of the disease. Genetic epidemiological studies are usually undertaken in advance of DNA-based studies aimed at genetic dissection. Truly transdisciplinary work on the prevention of tobacco use involving genetic epidemiology has not been conducted to date. As we prepare to move to the next generation of research on nicotine dependence, we have the advantage of being able to employ newly developed biobehavioral measures and to learn from previously encountered difficulties in the field of psychiatric genetics. Recent theoretical developments in the area of adolescent substance use clearly identify a role for both direct and indirect susceptibility to regular tobacco use that is in part determined by genetic factors. A logical next step for transdisciplinary work in this area is to design and implement a developmental study of substance use in children and their family members. A key step in the design and implementation of this longitudinal approach will be the utilization of measurement methods that determine with as much precision as possible the social, cultural, behavioral, and genetic factors that place adolescents at risk for tobacco dependence. The extent to which environmental risk factors interact with genetic risk factors to increase susceptibility to nicotine addiction is unknown. It is unlikely that knowledge of genetic risk factors alone will lead to effective prevention strategies. A longitudinal family study designed around the framework of a transdisciplinary theory of adolescent substance use offers the potential to be highly informative in the next generation of research on tobacco prevention.

Genetic and heritable risk factors in periodontal disease.

The purpose of this paper is to review current knowledge of genetic risk factors for the periodontal diseases and to present updated and additional data from the Minnesota Twin Periodontal Study. Family studies suggest that susceptibility to the early onset forms of disease, particularly prepubertal and juvenile periodontitis, is, at least in part, influenced by host genotype. Inherited phagocytic cell deficiencies appear to confer risk for prepubertal periodontitis. The prevalence and distribution of juvenile periodontitis in affected families are most consistent with an autosomal recessive mode of inheritance. However, considerable etiologic as well as genetic heterogeneity within these clinically-defined diseases is evident. Whether or not genetic factors influence the more common adult chronic periodontitis is less clear. Although results from family studies suggest that environmental factors appear to be the major determinants of variance in adult periodontitis, data from our twin studies indicate that both genetic and environmental factors influence disease. Furthermore, comparisons between reared-together and reared-apart adult monozygous twins indicate that early family environment has no appreciable influence on probing depth and attachment loss measures in adults.