A Genetic Marker Associated with De Quervain’s Tenosynovitis

2017 ◽  
Vol 38 (12) ◽  
pp. 942-948
Author(s):  
Stuart Kim ◽  
Marwa Ahmed ◽  
Andy Avins ◽  
John Ioannidis
Keyword(s):  
Genetic Marker ◽  
Chromosome 8 ◽  
De Quervain’S Tenosynovitis ◽  
Environment And Health ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
First Extensor Compartment ◽  
Repetitive Strain ◽  
Extensor Compartment

AbstractDe Quervain’s tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain’s tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain’s tenosynovitis at genome-wide significance (p=1.9×10−8; OR=1.46; 95% CI=1.38–1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

A Genetic Marker Associated with Shoulder Dislocation

2017 ◽  
Vol 38 (07) ◽  
pp. 508-514 ◽  
Author(s):  
Stuart Kim ◽  
John Kleimeyer ◽  
Marwa Ahmed ◽  
Andy Avins ◽  
Michael Fredericson ◽  
...  
Keyword(s):  
Genetic Marker ◽  
Shoulder Dislocation ◽  
Dna Polymorphisms ◽  
European Ancestry ◽  
Shoulder Injuries ◽  
Ancestry Group ◽  
Environment And Health ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

AbstractShoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10−9; odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

scholarly journals Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

2017 ◽  
Author(s):  
Amit V. Khera ◽  
Mark Chaffin ◽  
Krishna G. Aragam ◽  
Connor A. Emdin ◽  
Derek Klarin ◽  
...  
Keyword(s):  
Coronary Disease ◽  
Fold Increase ◽  
Predictive Capacity ◽  
Cumulative Impact ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Artery Disease

AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

DGM1 may serve as a novel genetic biomarker of response to enzastaurin in glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2023-2023
Author(s):  
Nicholas A. Butowski ◽  
Ronald L. Shazer ◽  
Hong Sun ◽  
Isabel Han ◽  
Manoj A. Jivani ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Predictive Biomarker ◽  
Chromosome 8 ◽  
Newly Diagnosed ◽  
Genome Wide ◽  
Germline Polymorphism ◽  
A Genome ◽  
Genomic Marker ◽  
Daily Dose ◽  
Highly Correlated

2023 Background: Despite countless clinical trials being conducted, little has changed over the last decade in the chemotherapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. We discovered a novel pharmacogenomic biomarker for enzastaurin (enz) in treating lymphoma (lymph). We evaluated if this biomarker can be used to predict enz response in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples from a ph 3 enz lymph trial and confirmed in an independent ph 2 enz lymph trial. The biomarker was then evaluated for its predictability in GBM using the archived DNA samples from a prior ph 1/2 enz GBM trial. Results: A novel biomarker, Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymph trials. Using DNA extracted from blood of pts from the single-arm ph 1/2 study of newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. In addition, we found pts in the GBM study receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]; enz 500 mg/day was used in the lymph studies. Conclusions: These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymph and GBM. There is an ongoing biomarker-driven pivotal ph 3 study in lymph at 500 mg/day, and DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.

Two Genetic Variants Associated with Plantar Fascial Disorders

2018 ◽  
Vol 39 (04) ◽  
pp. 314-321 ◽  
Author(s):  
Stuart Kim ◽  
John Ioannidis ◽  
Marwa Ahmed ◽  
Andrew Avins ◽  
John Kleimeyer ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Plantar Fasciitis ◽  
Heel Pain ◽  
Tnf Alpha ◽  
Environment And Health ◽  
Genome Wide ◽  
A Genome ◽  
Dna Variants ◽  
Plantar Fibromatosis ◽  
Genome Wide Significance

AbstractPlantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10−8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

Two Genetic Loci associated with Medial Collateral Ligament Injury

2017 ◽  
Vol 38 (07) ◽  
pp. 501-507 ◽  
Author(s):  
Andrew Roos ◽  
Andy Avins ◽  
Marwa Ahmed ◽  
John Kleimeyer ◽  
Thomas Roos ◽  
...  
Keyword(s):  
Medial Collateral Ligament ◽  
Ligament Injury ◽  
Genetic Loci ◽  
Collateral Ligament ◽  
Environment And Health ◽  
Medial Collateral Ligament Injury ◽  
Genome Wide ◽  
A Genome ◽  
Competitive Athletes ◽  
Using Data

AbstractMedial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10−8) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

scholarly journals Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

2018 ◽  
Vol 25 (4) ◽  
pp. 565-573 ◽  
Author(s):  
Dorothea Buck ◽  
Till FM Andlauer ◽  
Wilmar Igl ◽  
Eva-Maria Wicklein ◽  
Mark Mühlau ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Variants ◽  
Neutralizing Antibodies ◽  
Genome Wide Association Study ◽  
Phase Iii ◽  
Interferon Β ◽  
Hla Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

scholarly journals Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population

2021 ◽  
Vol 118 (11) ◽  
pp. e2004199118
Author(s):  
Marina Penova ◽  
Shuji Kawaguchi ◽  
Jun-ichirou Yasunaga ◽  
Takahisa Kawaguchi ◽  
Tomoo Sato ◽  
...  
Keyword(s):  
Amino Acid ◽  
Association Study ◽  
Proviral Load ◽  
Odds Ratio ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

HTLV-1–associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10−9) and class II (P = 1.21 × 10−8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10−5), HLA-B*07:02 (P = 4.97 × 10−10), HLA-DRB1*01:01 (P = 1.15 × 10−9) and HLA-DQB1*05:01 (P = 2.30 × 10−9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10−5), HLA-DRB1*15:01 (P = 1.06 × 10−5) and HLA-DQB1*06:02 (P = 1.78 × 10−6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10−10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

scholarly journals The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

2015 ◽  
Vol 5 (4) ◽  
pp. e553-e553 ◽  
Author(s):  
J M Biernacka ◽  
K Sangkuhl ◽  
G Jenkins ◽  
R M Whaley ◽  
P Barman ◽  
...  
Keyword(s):  
Association Study ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Genome Wide Association Study ◽  
Transmembrane Domain ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Research Network ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Abstract Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

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