Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study

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Zhan, Y.Karolinska Institutet (author)

Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease : A Network Mendelian Randomization Study

Article/chapterEnglish2017

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Lippincott Williams and Wilkins,2017
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LIBRIS-ID:oai:DiVA.org:hj-41594
https://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-41594URI
https://doi.org/10.1161/CIRCRESAHA.116.310517DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:136254723URI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Rationale: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.Objective: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design.Methods and Results: Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis - an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality - was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04).Conclusions: Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
body mass index
cardiovascular diseases
coronary disease
diabetes mellitus
insulin
glucose
hemoglobin A1c
low density lipoprotein cholesterol
triacylglycerol
glucose blood level
Article
body mass
cholesterol blood level
controlled study
genetic association
genetic trait
genetic variability
genome-wide association study
hemoglobin blood level
human
insulin blood level
ischemic heart disease
major clinical study
priority journal
risk factor
telomere length
triacylglycerol blood level
waist circumference
waist hip ratio
blood
female
genetic variation
genetics
male
Mendelian randomization analysis
metabolism
physiology
procedures
single nucleotide polymorphism
telomere
telomere homeostasis
Blood Glucose
Humans
Polymorphism
Single Nucleotide

Added entries (persons, corporate bodies, meetings, titles ...)

Karlsson, Ida K.Karolinska Institutet,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden(Swepub:hj)karida (author)
Karlsson, R.Karolinska Institutet (author)
Tillander, A. (author)
Reynolds, C. A. (author)
Pedersen, Nancy L.Karolinska Institutet (author)
Hägg, S.Karolinska Institutet (author)
Karolinska InstitutetDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (creator_code:org_t)

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In:Circulation Research: Lippincott Williams and Wilkins121:3, s. 214-2190009-73301524-4571

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

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