Dataset Information

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

ABSTRACT:

Background

Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

Objectives

This analysis used summary statistics from a prior genome-wide association study to derive a new GPS_CAD for South Asians.

Methods

This GPS_CAD was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS_CAD reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS_CAD reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

Results

The GPS_CAD, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPS_CAD distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each).

Conclusions

The new GPS_CAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

SUBMITTER: Wang M

PROVIDER: S-EPMC7592606 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

Wang Minxian M Menon Ramesh R Mishra Sanghamitra S Patel Aniruddh P AP Chaffin Mark M Tanneeru Deepak D Deshmukh Manjari M Mathew Oshin O Apte Sanika S Devanboo Christina S CS Sundaram Sumathi S Lakshmipathy Praveena P Murugan Sakthivel S Sharma Krishna Kumar KK Rajendran Karthikeyan K Santhosh Sam S Thachathodiyl Rajesh R Ahamed Hisham H Balegadde Aniketh Vijay AV Alexander Thomas T Swaminathan Krishnan K Gupta Rajeev R Mullasari Ajit S AS Sigamani Alben A Kanchi Muralidhar M Peterson Andrew S AS Butterworth Adam S AS Danesh John J Di Angelantonio Emanuele E Naheed Aliya A Inouye Michael M Chowdhury Rajiv R Vedam Ramprasad L RL Kathiresan Sekar S Gupta Ravi R Khera Amit V AV

Journal of the American College of Cardiology 20200801 6

<h4>Background</h4>Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.<h4>Objectives</h4>This analysis used summary statistics from a prior genome-wide association study to derive a new GPS<sub>CAD</sub> for South Asians.<h4>Methods</h4>This GPS<sub>CAD</sub> was ...[more]

PMID: 32762905

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Project description:BackgroundThe value of polygenic risk scores (PRSs) towards improving guideline-recommended clinical risk models for coronary artery disease (CAD) prediction is controversial. Here we examine whether an integrated polygenic risk score improves the prediction of CAD beyond pooled cohort equations. METHODS: An observation study of 291,305 unrelated White British UK Biobank participants enrolled from 2006 to 2010 was conducted. A case-control sample of 9499 prevalent CAD cases and an equal number of randomly selected controls was used for tuning and integrating of the polygenic risk scores. A separate cohort of 272,307 individuals (with follow-up to 2020) was used to examine the risk prediction performance of pooled cohort equations, integrated polygenic risk score, and PRS-enhanced pooled cohort equation for incident CAD cases. The performance of each model was analyzed by discrimination and risk reclassification using a 7.5% threshold.ResultsIn the cohort of 272,307 individuals (mean age, 56.7 years) used to analyze predictive accuracy, there were 7036 incident CAD cases over a 12-year follow-up period. Model discrimination was tested for integrated polygenic risk score, pooled cohort equation, and PRS-enhanced pooled cohort equation with reported C-statistics of 0.640 (95% CI, 0.634-0.646), 0.718 (95% CI, 0.713-0.723), and 0.753 (95% CI, 0.748-0.758), respectively. Risk reclassification for the addition of the integrated polygenic risk score to the pooled cohort equation at a 7.5% risk threshold resulted in a net reclassification improvement of 0.117 (95% CI, 0.102 to 0.129) for cases and - 0.023 (95% CI, - 0.025 to - 0.022) for noncases [overall: 0.093 (95% CI, 0.08 to 0.104)]. For incident CAD cases, this represented 14.2% correctly reclassified to the higher-risk category and 2.6% incorrectly reclassified to the lower-risk category.ConclusionsAddition of the integrated polygenic risk score for CAD to the pooled cohort questions improves the predictive accuracy for incident CAD and clinical risk classification in the White British from the UK Biobank. These findings suggest that an integrated polygenic risk score may enhance CAD risk prediction and screening in the White British population.

Project description:ImportanceThe clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established.ObjectiveTo investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk.Design, setting, and participantsThis was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022.ExposuresPolygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), or high risk (≥20%).Main outcomes and measuresMyocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death).ResultsA total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age <50 years: hazard ratio [HR] per 1 SD of PRS, 1.72; 95% CI, 1.56-1.89; age 50-60 years: HR, 1.46; 95% CI, 1.38-1.53; age >60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction <.001). In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased associated risk of MI compared with those in the low PRS category. A significant interaction between CAD PRS and age was replicated in Biobank Japan. When CAD PRS testing was added to the clinical ASCVD risk score in individuals younger than 50 years, 591 of 4373 patients (20%) with borderline risk were risk stratified into intermediate risk, warranting initiation of statin therapy and 3198 of 7477 patients (20%) with both borderline or intermediate risk were stratified as low risk, thus not warranting therapy.Conclusions and relevanceResults of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.

Dataset Information

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

Background

Objectives

Methods

Results

Conclusions

Publications

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

Similar Datasets

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