Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis

Seamus C Harrison; Michael V Holmes; Stephen Burgess; Folkert W Asselbergs; Gregory T Jones; Annette F Baas; F N van 't Hof; Paul I W de Bakker; Jan D Blankensteijn; Janet T Powell; Athanasios Saratzis; Gert J de Borst; Daniel I Swerdlow; Yolanda van der Graaf; Andre M van Rij; David J Carey; James R Elmore; Gerard Tromp; Helena Kuivaniemi; Robert D Sayers; Nilesh J Samani; Matthew J Bown; Steve E Humphries

doi:10.1001/jamacardio.2017.4293

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis

Seamus C Harrison
, Michael V Holmes
, Stephen Burgess
, Folkert W Asselbergs
, Gregory T Jones
, Annette F Baas
, F N van 't Hof
, Paul I W de Bakker
, Jan D Blankensteijn
, Janet T Powell
, Athanasios Saratzis
, Gert J de Borst
, Daniel I Swerdlow
, Yolanda van der Graaf
, Andre M van Rij
, David J Carey
, James R Elmore
, Gerard Tromp
, Helena Kuivaniemi
, Robert D Sayers

Nilesh J Samani, Matthew J Bown, Steve E Humphries

Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, England.
National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, England.
Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, England.
Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, England.
Department of Surgery, University of Otago, Dunedin, New Zealand.
Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, The Netherlands; SEIN - Stichting Epilepsy Instellingen Nederland, Heemstede, The Netherlands.
Vascular Surgery Research Group, Imperial College Charing Cross Hospital, London, England.
National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit and Department of Cardiovascular Sciences, University of Leicester, Leicester, England.
Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Medicine, Imperial College London, Hammersmith Hospital, London, England.
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania.
Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, Pennsylvania.
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
Department of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, England.

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

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Abstract

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.

Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.

Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.

Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).

Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.

Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28).

Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.

Original language	English
Pages (from-to)	26-33
Number of pages	8
Journal	JAMA cardiology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1001/jamacardio.2017.4293
Publication status	Published - 1 Jan 2018

Keywords

Journal Article

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10.1001/jamacardio.2017.4293

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Harrison, S. C., Holmes, M. V., Burgess, S., Asselbergs, F. W., Jones, G. T., Baas, A. F., van 't Hof, F. N., de Bakker, P. I. W., Blankensteijn, J. D., Powell, J. T., Saratzis, A., de Borst, G. J., Swerdlow, D. I., van der Graaf, Y., van Rij, A. M., Carey, D. J., Elmore, J. R., Tromp, G., Kuivaniemi, H., ... Humphries, S. E. (2018). Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis. JAMA cardiology, 3(1), 26-33. https://doi.org/10.1001/jamacardio.2017.4293

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title = "Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis",

abstract = "Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95\% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95\% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95\% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95\% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95\% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95\% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95\% CI, 0.92-1.02; P = .28).Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.",

keywords = "Journal Article",

author = "Harrison, \{Seamus C\} and Holmes, \{Michael V\} and Stephen Burgess and Asselbergs, \{Folkert W\} and Jones, \{Gregory T\} and Baas, \{Annette F\} and \{van 't Hof\}, \{F N\} and \{de Bakker\}, \{Paul I W\} and Blankensteijn, \{Jan D\} and Powell, \{Janet T\} and Athanasios Saratzis and \{de Borst\}, \{Gert J\} and Swerdlow, \{Daniel I\} and \{van der Graaf\}, Yolanda and \{van Rij\}, \{Andre M\} and Carey, \{David J\} and Elmore, \{James R\} and Gerard Tromp and Helena Kuivaniemi and Sayers, \{Robert D\} and Samani, \{Nilesh J\} and Bown, \{Matthew J\} and Humphries, \{Steve E\}",

year = "2018",

month = jan,

day = "1",

doi = "10.1001/jamacardio.2017.4293",

language = "English",

volume = "3",

pages = "26--33",

journal = "JAMA cardiology",

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Harrison, SC, Holmes, MV, Burgess, S, Asselbergs, FW, Jones, GT, Baas, AF, van 't Hof, FN, de Bakker, PIW, Blankensteijn, JD, Powell, JT, Saratzis, A, de Borst, GJ, Swerdlow, DI, van der Graaf, Y, van Rij, AM, Carey, DJ, Elmore, JR, Tromp, G, Kuivaniemi, H, Sayers, RD, Samani, NJ, Bown, MJ & Humphries, SE 2018, 'Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis', JAMA cardiology, vol. 3, no. 1, pp. 26-33. https://doi.org/10.1001/jamacardio.2017.4293

TY - JOUR

T1 - Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm

T2 - A Meta-analysis

AU - Harrison, Seamus C

AU - Holmes, Michael V

AU - Burgess, Stephen

AU - Asselbergs, Folkert W

AU - Jones, Gregory T

AU - Baas, Annette F

AU - van 't Hof, F N

AU - de Bakker, Paul I W

AU - Blankensteijn, Jan D

AU - Powell, Janet T

AU - Saratzis, Athanasios

AU - de Borst, Gert J

AU - Swerdlow, Daniel I

AU - van der Graaf, Yolanda

AU - van Rij, Andre M

AU - Carey, David J

AU - Elmore, James R

AU - Tromp, Gerard

AU - Kuivaniemi, Helena

AU - Sayers, Robert D

AU - Samani, Nilesh J

AU - Bown, Matthew J

AU - Humphries, Steve E

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28).Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.

AB - Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28).Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.

KW - Journal Article

U2 - 10.1001/jamacardio.2017.4293

DO - 10.1001/jamacardio.2017.4293

M3 - Article

SN - 2380-6583

VL - 3

SP - 26

EP - 33

JO - JAMA cardiology

JF - JAMA cardiology

IS - 1

ER -

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis

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