Association of the CYP39A1 G204E genetic variant with increased risk of glaucoma and blindness in patients with exfoliation syndrome

The purpose of the Utah Project on Exfoliation Syndrome (UPEXS) is to identify associations between exfoliation syndrome (XFS) and other diseases that share the commonality of abnormalities in elastin and Lysyl Oxidase-Like 1 gene regulation. The UPEXS is unique because it uses the Utah Population Database, which is linked to the Utah genealogy, that contains a compilation of large pedigrees of most families in the state of Utah that go back multiple generations (3 to ≥11). The health and medical records of these family members are linked to vital records and can be used effectively in studies focused on genetic disorders like XFS, where familial clustering of a disorder is a trend. There is increasing evidence that patients with XFS have a higher risk of certain systemic disorders that reflect the systemic tissue abnormalities of XFS. Epidemiological studies focused on patients with XFS have shown that there is an increased risk of these individuals developing other pathologies that have abnormalities in extracellular matrix metabolism and repair. UPEXS has focused on suspected comorbidities that involve abnormalities in elastin maintenance, a protein that plays a role in the makeup of the extracellular matrix. In this paper, the results from the analysis of chronic obstructive pulmonary disease, inguinal hernias, pelvic organ prolapse, obstructive sleep apnoea and atrial fibrillation are summarised along with the utility of using such a large dataset.

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WNT3A rs752107(C > T) Polymorphism Is Associated With an Increased Risk of Essential Hypertension and Related Cardiovascular Diseases

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.675222 ◽

2021 ◽

Vol 8 ◽

Author(s):

Huan Ren ◽

Jian-Quan Luo ◽

Fan Ouyang ◽

Li Cheng ◽

Xiao-Ping Chen ◽

...

Keyword(s):

Heart Failure ◽

Essential Hypertension ◽

Signaling Pathway ◽

Genetic Variant ◽

Eqtl Analysis ◽

Cardiovascular Development ◽

Genomic Variants ◽

Increased Risk ◽

First Time

Essential Hypertension (EH) results in the burden of cardiovascular disease (CVD) such as Heart Failure (HF) and Ischemic Stroke (IS). A rapidly emerging field involving the role of Wnt/β-catenin signaling pathway in cardiovascular development and dysfunction has recently drawn extensive attention. In the present study, we conducted a genetic association between genomic variants in Wnt/β-catenin signaling pathway and EH, HF, IS. A total of 95 SNPs in 12 Wnt signaling genes (WNT3A, WNT3, WNT4, DKK1, DKK2, LRP5, LRP6, CTNNB1, APC, FZD1, FRZB, SFRP1) were genotyped in 1,860 participants (440 patients with EH, 535 patients with HF, 421 patients with IS and 464 normal control subjects) using Sequenom MassArray technology. WNT3A rs752107(C > T) was strongly associated with an increased risk of EH, HF and IS. Compared with WNT3A rs752107 CC genotype, the CT genotype carriers had a 48% increased risk of EH (OR = 1.48, 95% CI = 1.12–1.96, P = 0.006), the TT genotype conferred a 139% increased risk of EH (OR = 2.39, 95% CI = 1.32–4.34, P = 0.003). Regarding HF and IS, the risk of HF in the T allele carriers (CT + TT) was nearly increased by 58% (OR = 1.58, 95% CI = 1.22–2.04, P = 4.40 × 10−4) and the risk of IS was increased by 37% (OR = 1.37, 95% CI = 1.04–1.79, P = 0.025). Expression quantitative trait loci (eQTL) analysis indicated that rs752107 C allele corresponded to a significant reduction of WNT3A expression. We described a genetic variant of WNT3A rs752107 in Wnt/β-catenin signaling strongly associated with the risk of EH, HF and IS for the first time.

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O5-04-01: A RARE GENETIC VARIANT IN THE PLCG2 GENE IS ASSOCIATED WITH A REDUCED RISK OF ALL MAJOR TYPES OF DEMENTIA AND AN INCREASED RISK TO REACH AN EXTREMELY OLD AGE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.3013 ◽

2006 ◽

Vol 14 (7S_Part_31) ◽

pp. P1648-P1649

Author(s):

Sven J. Van der Lee ◽

Iris E. Jansen ◽

Olga Pletnikova ◽

Cornelis Blauwendraat ◽

Marc Hulsman ◽

...

Keyword(s):

Old Age ◽

Genetic Variant ◽

Rare Genetic Variant ◽

Increased Risk ◽

Reduced Risk

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A15374 Genetic Variant of Human Cholesterol Ester Transfer Protein (CETP) Raises HDL levels and Is Associated with Increased Risk for Large Vessel and Small Vessel Stroke in Chinese Patients

Journal of Hypertension ◽

10.1097/01.hjh.0000548327.56066.a6 ◽

2018 ◽

Vol 36 ◽

pp. e83

Author(s):

Xingyu Wang ◽

Xin Liu ◽

Wei Zhang ◽

Hongye Zhang ◽

Guillaume Pare ◽

...

Keyword(s):

Cholesterol Ester ◽

Genetic Variant ◽

Cholesterol Ester Transfer Protein ◽

Large Vessel ◽

Small Vessel ◽

Chinese Patients ◽

Transfer Protein ◽

Increased Risk

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3421 Evaluation of novel biomarkers of hepatocellular carcinoma development and recurrence in liver transplant patients

Journal of Clinical and Translational Science ◽

10.1017/cts.2019.326 ◽

2019 ◽

Vol 3 (s1) ◽

pp. 143-144

Author(s):

Jenna Mancinelli ◽

David Walls ◽

Baoli Chang ◽

Brendan Keating ◽

Maarouf Hoitet ◽

...

Keyword(s):

Liver Transplant ◽

Clinical Utility ◽

Genetic Variant ◽

Prediction Models ◽

Disease Recurrence ◽

Visceral Adiposity ◽

Transplant Patients ◽

Increased Risk ◽

Novel Biomarkers ◽

Level Of Risk

OBJECTIVES/SPECIFIC AIMS: Given the poor prognosis of HCC and its increasing incidence worldwide, identifying biomarkers of HCC has been an active area of research. While biomarkers are being identified at a rapid pace, many are still in early phases of clinical study and very few have proven clinical utility. The objective of this study is to identify novel biomarkers of HCC and evaluate their clinical utility as predictors of disease development and prognosis with specific emphasis on disease recurrence after liver transplantation. Biomarkers will be identified through GWAS, as well as through analysis of qualitative and quantitative liver traits by magnetic resonance imaging (MRI). These novel biomarkers will then by implemented into risk prediction models aimed to assess an individual’s risk for development of HCC and stratify their level of risk according to predicted disease prognosis. METHODS/STUDY POPULATION: This will be a case-control study, analyzing data from previously created biorepositories from four cohorts of recipients across multiple centers which have undergone liver transplant. First, a GWAS will be performed to identify genetic variant(s). Second, pre-transplant MRI’s will be evaluated using CAVASS software to assess liver quantitative and qualitative traits, including visceral adiposity. Lastly, these findings will be implemented into risk stratification models to assess each individual’s level of risk for development of HCC and for recurrence of HCC after transplant. RESULTS/ANTICIPATED RESULTS: We hypothesize that genetic variant(s) are associated with positive HCV status and the development of HCC. Additionally, we hypothesize that increased visceral adiposity measured by MRI will have an association with recurrence of HCC after transplant. Lastly, we hypothesize that possession of these aforementioned features will be associated with an increased risk of HCC development and recurrence after transplant. DISCUSSION/SIGNIFICANCE OF IMPACT: As more is learned about the nature and reliability of these biomarkers, their potential clinical applications will be revealed. Ideally these proposed risk score models will ultimately be used by clinicians to provide personalized disease management while optimizing the allocation of health care resources. For instance, this may lead to changes in the MRI screening frequency of patients considered to be at high risk for HCC. The ability to diagnose patients early and provide personalized therapies may ultimately result in fewer disease related mortalities in the future.

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A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Is Associated with Increased Risk for Selective Mutism and Social Anxiety-Related Traits

Biological Psychiatry ◽

10.1016/j.biopsych.2010.11.008 ◽

2011 ◽

Vol 69 (9) ◽

pp. 825-831 ◽

Cited By ~ 46

Author(s):

Murray B. Stein ◽

Bao-Zhu Yang ◽

Denise A. Chavira ◽

Carla A. Hitchcock ◽

Sharon C. Sung ◽

...

Keyword(s):

Social Anxiety ◽

Genetic Variant ◽

Selective Mutism ◽

Common Genetic Variant ◽

Increased Risk

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A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder

Journal of Affective Disorders ◽

10.1016/j.jad.2016.10.008 ◽

2017 ◽

Vol 208 ◽

pp. 218-222 ◽

Cited By ~ 12

Author(s):

Tahereh Dadkhah ◽

Simin Rahimi-Aliabadi ◽

Javad Jamshidi ◽

Hamid Ghaedi ◽

Shaghyegh Taghavi ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Binding Site ◽

Glutamate Receptor ◽

Genetic Variant ◽

Mirna Binding Site ◽

Major Depressive ◽

Increased Risk

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Association of FTO gene variant (rs8050136) with type 2 diabetes and markers of obesity, glycaemic control and inflammation

Journal of Medical Biochemistry ◽

10.2478/jomb-2018-0023 ◽

2019 ◽

Vol 38 (2) ◽

pp. 153-163 ◽

Cited By ~ 8

Author(s):

Tamer Bego ◽

Adlija Čaušević ◽

Tanja Dujić ◽

Maja Malenica ◽

Zelija Velija-Asimi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Genetic Variant ◽

Health Centre ◽

University Hospital ◽

Healthy Population ◽

Allelic Discrimination ◽

Genotype Frequencies ◽

Increased Risk ◽

Clinical Centre

Summary Background FTO, a gene recently discovered in genomewide associated studies for type 2 diabetes mellitus (T2D), play an important role in the management of energy homeostasis, nucleic acid demethylation and regulation of body fat mass by lipolysis. The aim of this study was to analyze the association of FTO rs8050136 A>C genetic variant with clinical and biochemical parameters of T2D in the population of West Balkan region (Bosnians and Herzegovinians and Kosovars). Methods The study included 638 patients with T2D and prediabetes and 360 healthy controls of both genders, aged from 40 to 65 years. Patients were recruited at the Clinical Centre University of Sarajevo, University Hospital of Clinical Centre in Banja Luka, General Hospital in Tešanj and Health Centre in Prizren. Genotyping of analyzed FTO polymorphism rs8050136 A>C was performed by qPCR allelic discrimination. Results Genotype frequencies of the analyzed polymorphism were comparable between patients with T2D, prediabetic patients, and healthy population. Logistic regression analyses didn’t show significant association of FTO rs8050136 A allele with increased risk of T2D. However, risk A allele was significantly associated with higher levels of HbA1c, insulin, HOMA-IR index, diastolic blood pressure, and inflammatory markers (fibrinogen and leukocytes) as well as showed tendency of association with increased values of obesity markers (BMI, waist and hip circumference). Conclusions Results of our study showed a significant association of FTO genetic variant rs8050136 A>C with the major markers of insulin resistance, obesity and inflammation, opening new avenues for solving many unclear questions in the pathogenesis of T2D.

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Itraconazol Inhibits the P-Glycoprotein Pump and Increases Vincristine Induced Toxicity in Patients with Acute Lymphoblastic Leukemia Carrying a Genetic Variant of the MDR1 Gene

Blood ◽

10.1182/blood.v118.21.231.231 ◽

2011 ◽

Vol 118 (21) ◽

pp. 231-231

Author(s):

D. Maroeska W.M. te Loo ◽

Melanie Hagleitner ◽

Peter M. Hoogerbrugge ◽

Rosalinde Masareeuw ◽

Marieke Coenen

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Genetic Variant ◽

Efflux Pump ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Mdr1 Gene ◽

Peripheral Neurotoxicity ◽

P Glycoprotein ◽

Increased Risk

Abstract Abstract 231 One of the most well known drug interactions in pediatric oncology concerns the interaction of vincristine, one of the cornerstones in treatment of acute lymphoblastic leukemia( ALL), and the antifungal agent itraconazole. Several studies have shown that the co-administration of itraconazole with vincristine can induce increased neurotoxicity. It is believed that this increased neurotoxicity is mainly caused by the inhibitory effect of itraconazole on the CYP3A subfamily enzymes system (e.g. CYP3A4/5) and that, depending on the genetic variation, some patients are more prone to exhibit this neurotoxicity. However, itraconazole can also inhibit the efflux pump P-glycoprotein (Pg) but so far, data on the role of the Pg pump on vincristine toxicity are lacking. We therefore performed a pharmacogenetic analysis in 103 Caucasian pediatric patients with ALL analyzing both the MDR1 gene and the CYP3A5 gene in the germ-line. CYP3A5 was not associated with vincristine-related toxicity in our cohort. However, one SNP in MDR1 (3435C>T) was significantly associated with developing peripheral neuropathy (Odds Ratio [OR] = 3.8, 95% confidence interval [CI] 1.2 – 11.9, p=0.026). It is known that this genetic variant of the MDR gene (3435T/2677T), leads to a reduced expression of the Pg-pump. Peripheral neurotoxicity in patients carrying this SNP was present even without the co-administration of itraconazole. A subgroup of these patients did receive itraconazole, and the patients with the genetic variant 3435T/2677T of MDR1 showed not only increased peripheral neurotoxicity, but also developed central nervous toxicity (OR=6.4, 95% CI 1.1 – 37.4 p=0.038) upon combined VCR-itraconazole therapy. To gain more insight in the mechanisms of increased vincristine induced toxicity during azole treatment, in vitro experiments using the LLC-PK1-MDR cell line that over-expresses the MDR1 gene and has no expression of the CYP3A4, were performed. The LLC-PK1-MDR cells were resistant to vincristine exposure in vitro, but became sensitive for VCR after inhibition of the Pg-pump bij PSC833. In contrast, LLC-PK1-MDR1 cells exposed to vincristine in the presence of itraconazole (0.5 and 5 microgram/ml) showed significantly decreased survival in a dose dependent way (LD50 at a dose of 10 −4M and 10−7 M vincristine at dose respectively of 0.5 and 5.0 microgram/ml itraconazole), in contrast to a cell survival of 100% with the same dose of vincristine itraconazole (p< 0.001). These results indicate that itraconazol indeed inhibits the efflux Pg-pump which may explain the CNS toxicity that occurred in our patient group during the period in which itraconazole was co-administerd during vincristine treatment. Based on these data, we conclude that the Pg- pump plays a dominant role in increased vincristine toxicity during azole treatment. Furthermore, those patients carrying the genetic variant 3435T/2677T of the MDR gene are at increased risk for this toxicity due to reduced expression of the efflux pump Pg. Disclosures: No relevant conflicts of interest to declare.

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