Author + information
- Matthew J.J. D’Mello, MSc,
- Stephanie A. Ross, PhD,
- Sonia S. Anand, MD, PhD,
- Hertzel Gerstein, MD, MSc,
- Matthew McQueen, MD, PhD,
- Salim Yusuf, DPhil and
- Guillaume Paré, MD, MSc∗ ()
- ↵∗Hamilton Health Sciences–General Site, Population Health Research Institute, C3-103, 237 Barton Street East, Hamilton, Ontario, L8L 2X2, Canada
Telomeres are repetitive, gene-poor regions that cap the ends of chromosomes. Over time, telomeres shorten due to natural cellular aging, oxidative stress, and chronic inflammation (1). Consequently, it has been suggested that telomere length (TL) may be a marker of age-related diseases, such as cardiovascular disease (CVD). Previous research on the association between shorter TL and the risk of CVD has yielded inconsistent results, with the majority of studies only being conducted with white Europeans (2). We examined the relationship between TL and myocardial infarction (MI) in a large, multiethnic MI case-control study, the INTERHEART study (3).
The INTERHEART subjects were recruited within 24 h of presenting with an acute MI. Control subjects had no history of CVD and were age (±5 years) and sex matched. Data were collected on patient demographic characteristics (ethnicity) and CVD risk factors: diabetes, hypertension, smoking history, physical activity, alcohol consumption, fruit and vegetable consumption, general stress, waist-to-hip ratio, and apolipoprotein B/apolipoprotein A-I ratio.
Using a validated qualitative polymerase chain reaction method, we measured leukocyte TL in peripheral blood samples from 3,972 subjects and 4,321 control subjects (4). Leukocyte TL is highly correlated with TL in various somatic tissues (5). Measured TL was loge transformed and multiplied by −1 for regression models in order to provide effect estimates based on decreasing TL. Logistic regression was used to evaluate the association between TL and MI. All models were adjusted for age, sex, ethnicity, and CVD risk factors, where appropriate. The chi-square test was used to assess heterogeneity. Two-sided p values <0.05 were considered significant, and statistical analyses were performed using the R statistical package (R Foundation, Vienna, Austria).
The INTERHEART subjects had a significantly shorter TL than control subjects (p = 3.37 × 10−21). When assessed as a continuous variable, each unit decrease in TL was associated with an increased risk of MI (odds ratio [OR]: 2.24, 95% confidence interval [CI]: 1.88 to 2.67). The relationship between TL and MI was linear when categorizing TL in tertiles (p for trend = 6.51 × 10−19), with an OR of 1.36 (95% CI: 1.20 to 1.54) for comparison of middle versus longest tertile and an OR of 1.78 (95% CI: 1.56 to 2.02) for the shortest versus longest tertile. The PAR (population attributable risk) for shortest tertile versus longest 2 tertiles was 14.0% (95% CI: 10.6% to 17.3%). The addition of TL to CVD risk factors significantly improved discriminability of the regression model (IDI [integrated discrimination improvement] = 0.01, p = 1.00 × 10−5). Diabetes status, physical activity, hypertensive status, smoking status, age group, and ethnicity did not modify the association (Figure 1).
In this investigation, we report a significant 2.24 times increase in risk of MI per 1-unit decrease in TL. Our results are consistent with those of previous studies and provide robust evidence because of the large number of events observed (n = 3,972), the use of an optimized high-throughput TL assay on centrally stored samples, and the multiethnic study population. The linear trend identified between shorter tertiles of TL and increasing risk of MI suggests that TL has a graded effect. Moreover, the improved discriminability with TL underscores its added predictive value above traditional CVD risk factors. On a tissue level, the association between TL and MI is compelling because vascular tissue senescence is a key initiator of atherosclerosis. Shorter telomeres, a marker of senescence, are present in vascular tissue with atherosclerotic lesions.
An important finding was the consistency of the association between short TL and MI across various ethnic groups. To date, most TL-CVD studies have been conducted in a single ethnic group, precluding generalization to ethnically diverse populations. Ethnicity is a critical consideration because there is marked regional variation in the prevalence of MI. This variation may result from differences in the prevalence of MI risk factors or a stronger or weaker association of TL (or other CVD risk factors) with MI. Our study provides evidence that the TL-MI association is consistent across ethnic groups (p for heterogeneity = 0.17). However, the limitation of our investigation is that TL is reported as a standardized (telomere/single-copy gene) ratio as opposed to nucleotide bases. Therefore, risk cannot be estimated with respect to absolute base differences.
In summary, our study supports the use of TL as an independent marker of MI. This association is demonstrated across many subgroups of participants and notably across 6 ethnic groups. Further prospective studies of multiethnic populations are needed to confirm results.
Please note: The INTERHEART study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the International Clinical Epidemiology Network; and through unrestricted grants from several pharmaceutical companies (major contributions from AstraZeneca, Novartis, Sanofi, Knoll Pharmaceuticals [now Abbott], Bristol-Myers Squibb, and King Pharma). Sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the letter. Dr. Gerstein receives consulting fees from Sanofi, Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; and support for research or continuing education through his institution from Sanofi, Eli Lilly, Takeda, Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. Dr. Anand is a recipient of the Heart and Stroke Michael G. DeGroote Chair in Population Health Research and a Canada Research Chair in Ethnicity and Cardiovascular Disease. Dr. Paré receives support from Canada Research Chair in Genetic and Molecular Epidemiology and CISCO Professorship in Integrated Health Systems. Dr. Yusuf is funded by the Marion Burke Chair of the Heart and Stroke Foundation of Canada. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation