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Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus

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Harvard

Antikainen, AAV, Sandholm, N, Trëgouet, D-A, Charmet, R, McKnight, AJ, Ahluwalia, TS, Syreeni, A, Valo, E, Forsblom, C, Gordin, D, Harjutsalo, V, Hadjadj, S, Maxwell, AP, Rossing, P & Groop, P-H 2021, 'Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus', Cardiovascular Research, vol. 117, no. 2, cvaa045, pp. 600-612. https://doi.org/10.1093/cvr/cvaa045

APA

Antikainen, A. A. V., Sandholm, N., Trëgouet, D-A., Charmet, R., McKnight, A. J., Ahluwalia, T. S., Syreeni, A., Valo, E., Forsblom, C., Gordin, D., Harjutsalo, V., Hadjadj, S., Maxwell, A. P., Rossing, P., & Groop, P-H. (2021). Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus. Cardiovascular Research, 117(2), 600-612. [cvaa045]. https://doi.org/10.1093/cvr/cvaa045

CBE

Antikainen AAV, Sandholm N, Trëgouet D-A, Charmet R, McKnight AJ, Ahluwalia TS, Syreeni A, Valo E, Forsblom C, Gordin D, Harjutsalo V, Hadjadj S, Maxwell AP, Rossing P, Groop P-H. 2021. Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus. Cardiovascular Research. 117(2):600-612. https://doi.org/10.1093/cvr/cvaa045

MLA

Vancouver

Author

Antikainen, Anni A V ; Sandholm, Niina ; Trëgouet, David-Alexandre ; Charmet, Romain ; McKnight, Amy Jayne ; Ahluwalia, Tarunveer S ; Syreeni, Anna ; Valo, Erkka ; Forsblom, Carol ; Gordin, Daniel ; Harjutsalo, Valma ; Hadjadj, Samy ; Maxwell, Alexander P ; Rossing, Peter ; Groop, Per-Henrik. / Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus. In: Cardiovascular Research. 2021 ; Vol. 117, No. 2. pp. 600-612.

Bibtex

@article{ba585cd1814d462eb6e00256d6963bd4,
title = "Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus",
abstract = "AIMS: Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the function of these discoveries and to study the role of the known risk loci in type 1 diabetes.METHODS AND RESULTS: We performed the largest genome-wide association study to date for coronary artery disease in type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR = 1.32, p=1.50 × 10-8), and rs6055069 on DEFB127 promoter (OR = 4.17, p=2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (p=0.04) when adjusted for diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (p<1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with type 1 diabetes with the known susceptibility loci. General population risk variants were modestly but significantly associated with coronary artery disease also in type 1 diabetes (p=4.21 × 10-7).CONCLUSIONS: While general population coronary artery disease risk loci had limited effect on the risk in type 1 diabetes, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with coronary artery disease in individuals with type 1 diabetes. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility and coronary artery disease, although pending on future confirmation.TRANSLATIONAL PERSPECTIVE: Genetic association studies enable the discovery of novel genes and genetic pathways associated with the disease. Thus, this study provides an insight into coronary artery disease mechanisms specific to type 1 diabetes. The DEFB127 discovery may lead to a therapeutic target and improve patient care, if replicated in the future. Furthermore, genetic studies on coronary artery disease in type 1 diabetes are required for accurate personalized treatment plans achieved through genetic data for those with type 1 diabetes.",
keywords = "Cardiovascular disease, Coronary artery disease, Genetics, Genome-wide association study, Type 1 diabetes",
author = "Antikainen, {Anni A V} and Niina Sandholm and David-Alexandre Tr{\"e}gouet and Romain Charmet and McKnight, {Amy Jayne} and Ahluwalia, {Tarunveer S} and Anna Syreeni and Erkka Valo and Carol Forsblom and Daniel Gordin and Valma Harjutsalo and Samy Hadjadj and Maxwell, {Alexander P} and Peter Rossing and Per-Henrik Groop",
note = "Publisher Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. {\textcopyright} The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",
year = "2021",
month = jan,
day = "21",
doi = "10.1093/cvr/cvaa045",
language = "English",
volume = "117",
pages = "600--612",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

RIS

TY - JOUR

T1 - Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus

AU - Antikainen, Anni A V

AU - Sandholm, Niina

AU - Trëgouet, David-Alexandre

AU - Charmet, Romain

AU - McKnight, Amy Jayne

AU - Ahluwalia, Tarunveer S

AU - Syreeni, Anna

AU - Valo, Erkka

AU - Forsblom, Carol

AU - Gordin, Daniel

AU - Harjutsalo, Valma

AU - Hadjadj, Samy

AU - Maxwell, Alexander P

AU - Rossing, Peter

AU - Groop, Per-Henrik

N1 - Publisher Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2021/1/21

Y1 - 2021/1/21

N2 - AIMS: Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the function of these discoveries and to study the role of the known risk loci in type 1 diabetes.METHODS AND RESULTS: We performed the largest genome-wide association study to date for coronary artery disease in type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR = 1.32, p=1.50 × 10-8), and rs6055069 on DEFB127 promoter (OR = 4.17, p=2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (p=0.04) when adjusted for diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (p<1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with type 1 diabetes with the known susceptibility loci. General population risk variants were modestly but significantly associated with coronary artery disease also in type 1 diabetes (p=4.21 × 10-7).CONCLUSIONS: While general population coronary artery disease risk loci had limited effect on the risk in type 1 diabetes, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with coronary artery disease in individuals with type 1 diabetes. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility and coronary artery disease, although pending on future confirmation.TRANSLATIONAL PERSPECTIVE: Genetic association studies enable the discovery of novel genes and genetic pathways associated with the disease. Thus, this study provides an insight into coronary artery disease mechanisms specific to type 1 diabetes. The DEFB127 discovery may lead to a therapeutic target and improve patient care, if replicated in the future. Furthermore, genetic studies on coronary artery disease in type 1 diabetes are required for accurate personalized treatment plans achieved through genetic data for those with type 1 diabetes.

AB - AIMS: Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the function of these discoveries and to study the role of the known risk loci in type 1 diabetes.METHODS AND RESULTS: We performed the largest genome-wide association study to date for coronary artery disease in type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR = 1.32, p=1.50 × 10-8), and rs6055069 on DEFB127 promoter (OR = 4.17, p=2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (p=0.04) when adjusted for diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (p<1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with type 1 diabetes with the known susceptibility loci. General population risk variants were modestly but significantly associated with coronary artery disease also in type 1 diabetes (p=4.21 × 10-7).CONCLUSIONS: While general population coronary artery disease risk loci had limited effect on the risk in type 1 diabetes, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with coronary artery disease in individuals with type 1 diabetes. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility and coronary artery disease, although pending on future confirmation.TRANSLATIONAL PERSPECTIVE: Genetic association studies enable the discovery of novel genes and genetic pathways associated with the disease. Thus, this study provides an insight into coronary artery disease mechanisms specific to type 1 diabetes. The DEFB127 discovery may lead to a therapeutic target and improve patient care, if replicated in the future. Furthermore, genetic studies on coronary artery disease in type 1 diabetes are required for accurate personalized treatment plans achieved through genetic data for those with type 1 diabetes.

KW - Cardiovascular disease

KW - Coronary artery disease

KW - Genetics

KW - Genome-wide association study

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85100279849&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvaa045

DO - 10.1093/cvr/cvaa045

M3 - Journal article

C2 - 32077919

VL - 117

SP - 600

EP - 612

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

M1 - cvaa045

ER -

ID: 59467257