Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals.
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.
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;
Alexander
A
Scheller Madrid
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark;
Line
L
Rode
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
Børge G
BG
Nordestgaard
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark. Stig.Egil.Bojesen@regionh.dk.
Stig E
SE
Bojesen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics*; D011446:Prospective Studies; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics; D055815:Young Adult
C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase