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Kharazmi, M., Michaëlsson, K., Schilcher, J., Eriksson, N., Melhus, H., Wadelius, M. & Hallberg, P. (2019). A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture. Calcified Tissue International, 105(1), 51-67
Open this publication in new window or tab >>A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
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2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed) Published
Abstract [en]

Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Genome-wide association study, Atypical fractures, Bisphosphonate, Drug-related side effects and adverse reactions, Pharmacogenetics
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-386428 (URN)10.1007/s00223-019-00546-9 (DOI)000469477400005 ()31006051 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440; 521-2014-337; 2015-035270Swedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceErik, Karin och Gösta Selanders FoundationÖstergötland County Council
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Patel, R. S., Schmidt, A. F., Tragante, V., McCubrey, R. O., Holmes, M. V., Howe, L. J., . . . Asselbergs, F. W. (2019). Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data. Circulation: Genomic and Precision Medicine, 12(4), Article ID e002471.
Open this publication in new window or tab >>Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data
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2019 (English)In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002471Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Keywords
chromosome, genetic, variation, myocardial infarction, risk factor, secondary prevention
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:uu:diva-383874 (URN)10.1161/CIRCGEN.119.002471 (DOI)000466741600005 ()30897348 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201668EU, European Research Council, 294609EU, Horizon 2020, 01KL1802NIH (National Institute of Health)EU, Horizon 2020, 692145Wellcome trustEU, FP7, Seventh Framework Programme, 223004Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2019-06-14 Created: 2019-06-14 Last updated: 2019-06-14Bibliographically approved
Kessler, T., Wolf, B., Eriksson, N., Kofink, D., Mahmoodi, B. K., Rai, H., . . . Schunkert, H. (2019). Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention. Cardiovascular Research, 115(10), 1512-1518
Open this publication in new window or tab >>Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention
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2019 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 115, no 10, p. 1512-1518Article in journal (Refereed) Published
Abstract [en]

Aim A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. Methods and results The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU.min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203AU.min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered. Conclusion We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2019
Keywords
On-aspirin platelet reactivity, Genetic variation, Stent thrombosis, Genome-wide association studies, Platelet aggregation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-397295 (URN)10.1093/cvr/cvz015 (DOI)000492854700015 ()30768153 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456EU, European Research Council, ERC 261053
Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2019-11-25Bibliographically approved
Karlsson Sundbaum, J., Eriksson, N., Hallberg, P., Lehto, N., Wadelius, M. & Baecklund, E. (2019). Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice. INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, 22(7), 1226-1232
Open this publication in new window or tab >>Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice
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2019 (English)In: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, no 7, p. 1226-1232Article in journal (Refereed) Published
Abstract [en]

Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis.

Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
liver toxicity, liver transaminases, methotrexate, non-alcoholic fatty liver disease, rheumatoid arthritis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-391959 (URN)10.1111/1756-185X.13576 (DOI)000476560400008 ()31012257 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved
Hailer, N. P., Garland, A., Gordon, M., Karrholm, J., Skoldenberg, O., Eriksson, N., . . . Holmberg, L. (2019). No generally increased risk of cancer after total hip arthroplasty performed due to osteoarthritis. International Journal of Cancer
Open this publication in new window or tab >>No generally increased risk of cancer after total hip arthroplasty performed due to osteoarthritis
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Previous studies on the risk of cancer after total hip arthroplasty (THA) contradict each other, and many are hampered by small cohort sizes, residual confounding, short observation times or a mix of indications underlying the THA procedure. We evaluated the risk of cancer after total hip arthroplasty due to osteoarthritis in a nationwide cohort by comparing cancer incidences in individuals exposed to total hip arthroplasty due to osteoarthritis and in unexposed, sex-, age- and residence matched individuals. To address some previous studies' shortcomings, information on comorbidity and socioeconomic background were obtained and adjusted for. We included 126,276 patients exposed to a cemented THA between 1992 and 2012, and 555,757 unexposed individuals. Follow-up started on the day of surgery for exposed individuals and respective date for matched, unexposed individuals, and ended on the day of death, emigration, censuring or December 31st, 2012, whichever came first. The Swedish Hip Arthroplasty Registry (SHAR), the Swedish Cancer Registry, the Swedish National Patient Registry and Statistics Sweden were accessed to obtain information on procedural details of the THA, cancer diagnoses, comorbidities, and socioeconomic background. The primary outcome measure was the occurrence of any cancer after the index date. Exposed individuals had a slightly lower adjusted risk of developing any cancer than unexposed individuals (hazard ratio [HR] 0.97; CI 0.95-0.99). The only cancer with a statistically significant risk increase in exposed individuals was skin melanoma (HR 1.15; CI 1.05-1.24). We attained similar risk estimates in analyses stratified by sex, in individuals with minimum 5 years of follow-up, in an analysis including individuals with a history of previous cancer, and in patients with cementless THA. In this study on a large and well-defined population with long follow-up, we found no increased overall risk of cancer after THA. These reassuring findings could be included in the guidelines on preoperative information given to THA patients.

Keywords
total hip replacement, total hip arthroplasty, cancer, nationwide, Sweden
National Category
Cancer and Oncology Orthopaedics
Identifiers
urn:nbn:se:uu:diva-397670 (URN)10.1002/ijc.32711 (DOI)000494074900001 ()31595487 (PubMedID)
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Hallberg, P., Smedje, H., Eriksson, N., Kohnke, H., Daniilidou, M., Öhman, I., . . . Wadelius, M. (2019). Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. EBioMedicine, 40, 595-604
Open this publication in new window or tab >>Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

Keywords
(MeSH), Autoimmune diseases, Drug-related side effects and adverse reactions, Genetic variation, Genome-wide association study, Glial cell line-derived neurotrophic factor, H1N1 subtype, Influenza A virus, Influenza vaccines, Narcolepsy, Pharmacogenetics, RNA, long noncoding
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-377169 (URN)10.1016/j.ebiom.2019.01.041 (DOI)000460696900067 ()30711515 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningSwedish Research Council, 2017-00641
Available from: 2019-02-15 Created: 2019-02-15 Last updated: 2019-05-13Bibliographically approved
Patel, R. S., Tragante, V., Schmidt, A. F., McCubrey, R. O., Holmes, M. V., Howe, L. J., . . . Asselbergs, F. W. (2019). Subsequent Event Risk in Individuals With Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium. Circulation: Genomic and Precision Medicine, 12(4), Article ID e002470.
Open this publication in new window or tab >>Subsequent Event Risk in Individuals With Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium
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2019 (English)In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002470Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Keywords
coronary artery disease, genetics, myocardial infarction, prognosis, secondary prevention
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-383875 (URN)10.1161/CIRCGEN.119.002470 (DOI)000466741600004 ()30896328 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201668EU, FP7, Seventh Framework Programme, 305739EU, European Research Council, 294609Swedish Research CouncilSwedish Foundation for Strategic Research EU, European Research Council, 294609EU, Horizon 2020, 01KL1802NIH (National Institute of Health), R0133169NIH (National Institute of Health), R01ES021801NIH (National Institute of Health), R01MD010358NIH (National Institute of Health), R01ES025786NIH (National Institute of Health), R01HL103866NIH (National Institute of Health), R01DK106000NIH (National Institute of Health), R01HL126827NIH (National Institute of Health), P20HL113452NIH (National Institute of Health), P01HL098055NIH (National Institute of Health), P01HL076491NIH (National Institute of Health), R01HL103931NIH (National Institute of Health), AG051633NIH (National Institute of Health), 5P01HL101398-02NIH (National Institute of Health), 1P20HL113451-01NIH (National Institute of Health), 1R56HL126558-01NIH (National Institute of Health), 1RF-1AG051633-01NIH (National Institute of Health), R01 NS064162-01NIH (National Institute of Health), R01 HL89650-01NIH (National Institute of Health), HL095479-01NIH (National Institute of Health), 1U10HL110302-01NIH (National Institute of Health), 1DP3DK094346-01NIH (National Institute of Health), 2P01HL086773-06A1EU, Horizon 2020, 692145Wellcome trust, 072960/Z/03/ZWellcome trust, 084726/Z/08/ZWellcome trust, 084727/Z/08/ZWellcome trust, 085475/Z/08/ZWellcome trust, 085475/B/08/ZSwedish Heart Lung FoundationThe Crafoord FoundationKnut and Alice Wallenberg FoundationEU, FP7, Seventh Framework Programme, 223004Forte, Swedish Research Council for Health, Working Life and WelfareNIH (National Institute of Health), R01 NR013396
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-06-12Bibliographically approved
Parker, W. A., Eriksson, N., Becker, R. C., Voora, D., Åkerblom, A., Himmelmann, A., . . . Storey, R. F. (2018). Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study. Platelets, 30(5), 579-588
Open this publication in new window or tab >>Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study
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2018 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 30, no 5, p. 579-588Article in journal (Refereed) Published
Abstract [en]

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y12 inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.

Keywords
Acute coronary syndrome, adenosine, equilibrative nucleoside transporter 1, thrombosis, ticagrelor
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-374178 (URN)10.1080/09537104.2018.1478404 (DOI)000469424700005 ()29851527 (PubMedID)
Funder
AstraZeneca
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-12-09Bibliographically approved
Wadelius, M., Eriksson, N., Smedje, H., Yue, Q.-Y. -., Magnusson, P. K. & Hallberg, P. (2018). Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF). Paper presented at First Nordic Conference on Personalized Medicine (NORPM 2018), May 30th ‐ June 1st 2018, Nyborg, Denmark.. Basic & Clinical Pharmacology & Toxicology, 123(S1), 12-13
Open this publication in new window or tab >>Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)
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2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-362656 (URN)10.1111/bcpt.13020 (DOI)000434060000033 ()
Conference
First Nordic Conference on Personalized Medicine (NORPM 2018), May 30th ‐ June 1st 2018, Nyborg, Denmark.
Note

Meeting Abstract: NorPM-O5

Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2018-10-16Bibliographically approved
Goel, K., Baheti, S., Åkerblom, A., Eriksson, N., Wallentin, L., Goodman, S., . . . Pereira, N. (2018). Novel Cyp2C19 Genetic Variants associated with Stent Thrombosis: a Next Generation Sequencing Study. Paper presented at 67th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), MAR 10-12, 2018, Orlando, FL. Journal of the American College of Cardiology, 71(11), 1205-1205
Open this publication in new window or tab >>Novel Cyp2C19 Genetic Variants associated with Stent Thrombosis: a Next Generation Sequencing Study
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2018 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, no 11, p. 1205-1205Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background

Commonly tested Loss-of-function (LOF) alleles in CYP2C19 are present in 30-40% of patients who experience stent thrombosis. The objective of this study was to identify novel genetic variants in CYP2C19 gene associated with stent thrombosis.

Methods

We included 70 patients with definite stent thrombosis while on clopidogrel who had stored DNA samples in our institutional (n=12) or PLATO trial (n=70) biorepository. Cases were matched 1:1 with controls for age, race, sex, diabetes, type of stent, and presentation. All controls were on clopidogrel and free of recurrent events. Clinical Pharmacogenetics (PGx) Implementation Consortium (CPIC) guidelines were used to determine the list of known PGx variants and dbSNP version 142 was used to assess novel variants. Whole exome sequencing was performed using the protocol for Agilent's SureSelect Human All Exon v5 + UTRs 75 MB kit and additional custom primers were designed to cover the entire CYP2C19 gene.

Results

Mean age was 63 ± 12 years, and 71% were male. We identified a total of 456 single nucleotide variants (SNV) in the CYP2C19 gene (cases: 376; controls: 288), of which 5 were synonymous, 6 non-synonymous, 46 indels and 449 intronic SNVs. There were 168 vs. 80 novel CYP2C19 variants and 10 vs. 5 indels in cases vs. controls, respectively. Four SNVs (3 missense and 1 synonymous) were present only in cases, whereas 3 SNVs (1 misssense, 1 synonymous and 1 intron) were unique to controls. There were no detectable differences in the frequency of LOF CYP2C19*2 allele (cases 34% vs. controls 31%) or other CPIC annotated PGx variants in cases and controls. After excluding the known PGx variants, there were 10 indels (all intronic) out of which 7 were novel in cases and were not present in controls.

Conclusion

We describe several novel genetic variants in the CYP2C19 gene in patients treated with clopidogrel after coronary stenting. We identified 168 novel SNVs and 10 novel indels in the CYP2C19 gene of patients with stent thrombosis. Four SNVs and 9 indels were unique to cases. Functional validation of these CYP2C19 genetic variants may provide important insights of CYP2C19 and the pathophysiology of stent thrombosis in clopidogrel treated patients.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-357331 (URN)10.1016/S0735-1097(18)31746-7 (DOI)000429659702455 ()
Conference
67th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), MAR 10-12, 2018, Orlando, FL
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2152-4343

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