Multiple SNP testing improves risk prediction of first venous thrombosis

Haan, Hugoline G. de; Bezemer, Irene D.; Doggen, Carine J.M.; Cessie, Saskia le; Reitsma, Pieter H.; Arellano, André R.; Tong, Carmen H.; Devlin, James J.; Bare, Lance A.; Rosendaal, Frits R.; Vossen, C. Y.

doi:10.1182/blood-2011-12-397752

Cited by 136 publications

(212 citation statements)

References 35 publications

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“…12,16,17 Genotyping of individual DNA samples was performed with kPCR assays using 0.3 ng of DNA or using multiplexed oligo ligation assays. 18,19 Genotyping accuracy of both systems have been assessed in previous studies, and the concordance of the genotype calls from these methods was >99%.…”

Section: Genotype Determinationmentioning

confidence: 99%

“…We previously showed that the more risk alleles or genotypes are present of 31 common thrombosis associated single nucleotide polymorphisms (SNPs), the higher the risk of a first venous thrombosis. 12 A parsimonious risk score based on 5 SNPs led to an over 20-fold difference in risk between those with none versus those with ≥6 risk alleles, and an area-underthe-curve of 0.82 for the receiver operating characteristic (ROC) curve when the score was combined with information on acquired factors.…”

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confidence: 99%

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Genetic Variations Associated With Recurrent Venous Thrombosis

Vlieg

Flinterman

Bare

et al. 2014

Circ Cardiovasc Genet

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Background— The prediction of recurrent venous thrombosis using individual genetic risk predictors has proven to be challenging. The aim of this study was to assess whether multiple genetic single nucleotide polymorphism (SNP) analysis would predict recurrent venous thrombosis. Methods and Results— Patients with a first venous thrombosis were followed for a recurrent venous thrombosis up to 2009 (MEGA follow-up study), which occurred in 608 out of 4100 patients (2.7%/year). Thirty-one common thrombosis-associated single nucleotide polymorphisms (SNPs) were associated with the risk of recurrence. A genetic risk score (GRS) for each individual was calculated by summing the number of risk-increasing alleles for each of the 31 SNPs and for a simplified model consisting of 5 SNPs: rs6025, rs1799963, rs8176719, rs2066865, and rs2036914. The risk of recurrence associated with the GRS was calculated continuously and after stratification in a low and high score. All individual SNPs were at most mildly associated with recurrence risk. Regarding the 31-SNP GRS, recurrence risk was highest in patients with ≥31 and lowest in patients with <21 risk alleles. The discriminative power of the 5-SNP GRS was similar to that of the 31-SNP GRS. The 6-year cumulative incidence of recurrence was high for individuals with ≥5 (20.3%; 95% confidence interval, 16.5–24.1) and low for individuals with ≤1 (9.4%; 95% confidence interval, 6.7–12.1) risk alleles. Predictive power improved after stratification into provoked and unprovoked first events and sex. Conclusions— Multiple genetic SNP analysis is useful in the prediction of recurrent thrombosis, even more so when combining this model with clinical risk factors.

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Section: Genotype Determinationmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic Variations Associated With Recurrent Venous Thrombosis

Vlieg

Flinterman

Bare

et al. 2014

Circ Cardiovasc Genet

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“…This suggests that easy-to-find high-penetrance mutations probably do not exist or are rare. In contrast, accumulating evidence from other malignancies (10)(11)(12) and multifactorial diseases and traits (13)(14)(15)(16) suggests that the genetic predisposition often consists of a multitude of low-penetrance alleles (16,17). The first few years of GWASs appear to have amply confirmed this assumption.…”

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confidence: 99%

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

Liyanarachchi

Wójcicka

et al. 2013

Thyroid

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Background: Two recent genome-wide association studies (GWASs) identified five single nucleotide polymorphisms (SNPs; rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs. Methods: We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio and 1795 PTC cases and 2090 controls from Poland. Cumulative genetic risk scores were calculated using unweighted and weighted approaches. Results: All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls ( p < 2.2 · 10 Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to three weighted risk score groups, low ( £ 2), medium (2-5), and high (>5). Individuals in the high group were significantly more susceptible to PTC compared with individuals in the low group with an odds ratio of 8.7 [95% CI 5.8, 13.3] in Ohio and 4.24 [95% CI 3.10, 5.84] in Poland. Almost identical results were obtained when follicular variant PTCs and microPTCs were omitted. These five SNPs explained 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort. Conclusion: As the genetic risk score increases, the risk of having PTC increases. However, the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected.

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“…56 Genetic risk scores have been developed using multiple SNVs identified in GWASs associated with VTE with an ultimate goal of personalizing anticoagulation therapy for prevention of recurrent VTE. [57][58][59] Considerably more refinement and validation is needed before such genetic testing would be applied to treatment approaches.…”

Section: Medicine In Thrombosis 2667mentioning

confidence: 99%

Personalized medicine in thrombosis: back to the future

Nagalla

Bray

2016

Blood

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Most physicians believe they practiced personalized medicine prior to the genomics era that followed the sequencing of the human genome. The focus of personalized medicine has been primarily genomic medicine, wherein it is hoped that the nucleotide dissimilarities among different individuals would provide clinicians with more precise understanding of physiology, more refined diagnoses, better disease risk assessment, earlier detection and monitoring, and tailored treatments to the individual patient. However, to date, the “genomic bench” has not worked itself to the clinical thrombosis bedside. In fact, traditional plasma-based hemostasis-thrombosis laboratory testing, by assessing functional pathways of coagulation, may better help manage venous thrombotic disease than a single DNA variant with a small effect size. There are some new and exciting discoveries in the genetics of platelet reactivity pertaining to atherothrombotic disease. Despite a plethora of genetic/genomic data on platelet reactivity, there are relatively little actionable pharmacogenetic data with antiplatelet agents. Nevertheless, it is crucial for genome-wide DNA/RNA sequencing to continue in research settings for causal gene discovery, pharmacogenetic purposes, and gene-gene and gene-environment interactions. The potential of genomics to advance medicine will require integration of personal data that are obtained in the patient history: environmental exposures, diet, social data, etc. Furthermore, without the ritual of obtaining this information, we will have depersonalized medicine, which lacks the precision needed for the research required to eventually incorporate genomics into routine, optimal, and value-added clinical care.

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Multiple SNP testing improves risk prediction of first venous thrombosis

Cited by 136 publications

References 35 publications

Genetic Variations Associated With Recurrent Venous Thrombosis

Genetic Variations Associated With Recurrent Venous Thrombosis

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

Personalized medicine in thrombosis: back to the future

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