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Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

ABSTRACT: BACKGROUND AND PURPOSE:Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. METHODS:The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ?55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. RESULTS:In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: ?joint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: ?joint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). CONCLUSIONS:The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

SUBMITTER: Ibrahim-Verbaas CA

PROVIDER: S-EPMC3955258 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

Ibrahim-Verbaas Carla A CA Fornage Myriam M Bis Joshua C JC Choi Seung Hoan SH Psaty Bruce M BM Meigs James B JB Rao Madhu M Nalls Mike M Fontes Joao D JD O'Donnell Christopher J CJ Kathiresan Sekar S Ehret Georg B GB Fox Caroline S CS Malik Rainer R Dichgans Martin M Schmidt Helena H Lahti Jari J Heckbert Susan R SR Lumley Thomas T Rice Kenneth K Rotter Jerome I JI Taylor Kent D KD Folsom Aaron R AR Boerwinkle Eric E Rosamond Wayne D WD Shahar Eyal E Gottesman Rebecca F RF Koudstaal Peter J PJ Amin Najaf N Wieberdink Renske G RG Dehghan Abbas A Hofman Albert A Uitterlinden André G AG Destefano Anita L AL Debette Stephanie S Xue Luting L Beiser Alexa A Wolf Philip A PA Decarli Charles C Ikram M Arfan MA Seshadri Sudha S Mosley Thomas H TH Longstreth W T WT van Duijn Cornelia M CM Launer Lenore J LJ

Stroke 20140116 2

<h4>Background and purpose</h4>Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.<h4>Methods</h4>The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphi ...[more]

PMID: 24436238

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Project description:BACKGROUND:The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS:Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS:The accuracy of the %EBWL logistic prediction model - including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) - significantly increased after the inclusion of PRS186 (?AUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005-0.038) but not PRS11 (?AUCadj= 0.008; 95% CIdiff= -0.003-0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (-2 log-likelihood = 12.3; P = 0.002) and PRS11 (-2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (? = -0.003; P = 0.008) and PRS11 (? = -0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION:These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING:Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).

Dataset Information

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

Publications

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

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