Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Nicole D. Armstrong; Vinodh Srinivasasainagendra; Amit Patki; Rikki M. Tanner; Bertha A. Hidalgo; Hemant K. Tiwari; Nita A. Limdi; Ethan M. Lange; Leslie A. Lange; Donna K. Arnett; Marguerite R. Irvin

doi:10.3389/fgene.2021.781451

Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Nicole D. Armstrong, Vinodh Srinivasasainagendra, Amit Patki, Rikki M. Tanner, Bertha A. Hidalgo, Hemant K. Tiwari, Nita A. Limdi, Ethan M. Lange, Leslie A. Lange, Donna K. Arnett, Marguerite R. Irvin

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.

Original language	English
Article number	781451
Journal	Frontiers in Genetics
Volume	12
DOIs	https://doi.org/10.3389/fgene.2021.781451
State	Published - Dec 21 2021

Bibliographical note

Funding Information:
The study was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123782 (MI) and R01HL136666 (MI, LL). NA was supported by an NIH NHLBI T32 Fellowship (T32HL007457). The Warfarin Pharmacogenomics Cohort was supported by NHLBI grant R01HL092173 (NL). The REGARDS study is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, U.S. Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data.

Publisher Copyright:
Copyright © 2021 Armstrong, Srinivasasainagendra, Patki, Tanner, Hidalgo, Tiwari, Limdi, Lange, Lange, Arnett and Irvin.

Keywords

antihypertensives
disparities
genome wide association studies
hypertension
incident stroke
polygenic risk score

ASJC Scopus subject areas

Molecular Medicine
Genetics
Genetics(clinical)

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Armstrong, N. D., Srinivasasainagendra, V., Patki, A., Tanner, R. M., Hidalgo, B. A., Tiwari, H. K., Limdi, N. A., Lange, E. M., Lange, L. A., Arnett, D. K., & Irvin, M. R. (2021). Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies. Frontiers in Genetics, 12, Article 781451. https://doi.org/10.3389/fgene.2021.781451

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title = "Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies",

abstract = "Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.",

keywords = "antihypertensives, disparities, genome wide association studies, hypertension, incident stroke, polygenic risk score",

author = "Armstrong, {Nicole D.} and Vinodh Srinivasasainagendra and Amit Patki and Tanner, {Rikki M.} and Hidalgo, {Bertha A.} and Tiwari, {Hemant K.} and Limdi, {Nita A.} and Lange, {Ethan M.} and Lange, {Leslie A.} and Arnett, {Donna K.} and Irvin, {Marguerite R.}",

note = "Funding Information: The study was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123782 (MI) and R01HL136666 (MI, LL). NA was supported by an NIH NHLBI T32 Fellowship (T32HL007457). The Warfarin Pharmacogenomics Cohort was supported by NHLBI grant R01HL092173 (NL). The REGARDS study is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, U.S. Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data. Publisher Copyright: Copyright {\textcopyright} 2021 Armstrong, Srinivasasainagendra, Patki, Tanner, Hidalgo, Tiwari, Limdi, Lange, Lange, Arnett and Irvin.",

year = "2021",

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Armstrong, ND, Srinivasasainagendra, V, Patki, A, Tanner, RM, Hidalgo, BA, Tiwari, HK, Limdi, NA, Lange, EM, Lange, LA, Arnett, DK & Irvin, MR 2021, 'Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies', Frontiers in Genetics, vol. 12, 781451. https://doi.org/10.3389/fgene.2021.781451

Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies. / Armstrong, Nicole D.; Srinivasasainagendra, Vinodh; Patki, Amit et al.
In: Frontiers in Genetics, Vol. 12, 781451, 21.12.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension

T2 - A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

AU - Armstrong, Nicole D.

AU - Srinivasasainagendra, Vinodh

AU - Patki, Amit

AU - Tanner, Rikki M.

AU - Hidalgo, Bertha A.

AU - Tiwari, Hemant K.

AU - Limdi, Nita A.

AU - Lange, Ethan M.

AU - Lange, Leslie A.

AU - Arnett, Donna K.

AU - Irvin, Marguerite R.

N1 - Funding Information: The study was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123782 (MI) and R01HL136666 (MI, LL). NA was supported by an NIH NHLBI T32 Fellowship (T32HL007457). The Warfarin Pharmacogenomics Cohort was supported by NHLBI grant R01HL092173 (NL). The REGARDS study is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, U.S. Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data. Publisher Copyright: Copyright © 2021 Armstrong, Srinivasasainagendra, Patki, Tanner, Hidalgo, Tiwari, Limdi, Lange, Lange, Arnett and Irvin.

PY - 2021/12/21

Y1 - 2021/12/21

N2 - Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.

AB - Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.

KW - antihypertensives

KW - disparities

KW - genome wide association studies

KW - hypertension

KW - incident stroke

KW - polygenic risk score

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JO - Frontiers in Genetics

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Armstrong ND, Srinivasasainagendra V, Patki A, Tanner RM, Hidalgo BA, Tiwari HK et al. Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies. Frontiers in Genetics. 2021 Dec 21;12:781451. doi: 10.3389/fgene.2021.781451

Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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