Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals

Alexander Scheller Madrid; Line Rode; Børge Grønne Nordestgaard; Stig Egil Bojesen

doi:10.1373/clinchem.2016.258566

Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals

Alexander Scheller Madrid, Line Rode, Børge Grønne Nordestgaard, Stig Egil Bojesen

59 Citationer (Scopus)

Abstract

BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.

METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.

RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99-1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06-1.14).

CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically.

Originalsprog	Engelsk
Tidsskrift	Clinical Chemistry
Vol/bind	62
Udgave nummer	8
Sider (fra-til)	1140-1149
Antal sider	10
ISSN	0009-9147
DOI	https://doi.org/10.1373/clinchem.2016.258566
Status	Udgivet - aug. 2016

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10.1373/clinchem.2016.258566

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Citationsformater

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title = "Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals",

abstract = "BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99-1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06-1.14).CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically.",

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author = "Madrid, {Alexander Scheller} and Line Rode and Nordestgaard, {B{\o}rge Gr{\o}nne} and Bojesen, {Stig Egil}",

note = "{\textcopyright} 2016 American Association for Clinical Chemistry.",

year = "2016",

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doi = "10.1373/clinchem.2016.258566",

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T1 - Short Telomere Length and Ischemic Heart Disease

T2 - Observational and Genetic Studies in 290 022 Individuals

AU - Madrid, Alexander Scheller

AU - Rode, Line

AU - Nordestgaard, Børge Grønne

AU - Bojesen, Stig Egil

PY - 2016/8

Y1 - 2016/8

N2 - BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99-1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06-1.14).CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically.

AB - BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.METHODS: We genotyped 3 genetic variants in OBFC1 (oligonucleotide/oligosaccharide binding fold containing 1), TERT (telomerase reverse transcriptase), and TERC (telomerase RNA component), which code for proteins and RNA involved in telomere maintenance. We studied 105 055 individuals from Copenhagen; 17 235 of these individuals were diagnosed with ischemic heart disease between 1977 and 2013, and 66 618 had telomere length measured. For genetic studies, we further included the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) consortium dataset, which included up to 184 967 participants and 60 837 cases of ischemic heart disease. We conducted multivariable adjusted Cox proportional hazard models for observational estimates, using logistic and instrumental variable analysis for genetic estimates.RESULTS: Observationally, a 200-bp-shorter telomere length was associated with a multivariable adjusted hazard ratio for ischemic heart disease of 1.02 (95% CI, 1.01-1.03). Per allele, telomeres were shorter by 67 bp (73-60). In meta-analyses of all 4 studies combined, odds ratios for ischemic heart disease were 1.05 (1.03-1.08) for OBCF1, 1.04 (1.02-1.06) for TERT, and 1.01 (0.99-1.03) for TERC. A genetically determined 200-bp-shorter telomere length was associated with an odds ratio for ischemic heart disease of 1.10 (1.06-1.14).CONCLUSIONS: Shorter telomeres were associated with a higher risk of ischemic heart disease, both observationally and genetically.

KW - Journal Article

U2 - 10.1373/clinchem.2016.258566

DO - 10.1373/clinchem.2016.258566

M3 - Journal article

C2 - 27259814

SN - 0009-9147

VL - 62

SP - 1140

EP - 1149

JO - Clinical Chemistry

JF - Clinical Chemistry

IS - 8

ER -

Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals

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