Pulse lineResearch With Heart Logo

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

TitleAssociation Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.
Publication TypeJournal Article
Year of Publication2017
AuthorsHaycock PC, Burgess S, Nounu A, et al.
Corporate AuthorsTelomeres Mendelian Randomization Collaboration
JournalJAMA Oncol
Volume3
Issue5
Pagination636-651
Date Published2017 May 01
ISSN2374-2445
KeywordsAdult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis
Abstract

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

DOI10.1001/jamaoncol.2016.5945
Alternate JournalJAMA Oncol
PubMed ID28241208
PubMed Central IDPMC5638008
Grant ListR01 DK106621 / DK / NIDDK NIH HHS / United States
Z99 EY999999 / ImNIH / Intramural NIH HHS / United States
G1001158 / MRC_ / Medical Research Council / United Kingdom
ZIA EY000403-10 / ImNIH / Intramural NIH HHS / United States
P50 CA102701 / CA / NCI NIH HHS / United States
Z01 EY000403-06 / ImNIH / Intramural NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
R33 HL120770 / HL / NHLBI NIH HHS / United States
ZIA EY000403-15 / ImNIH / Intramural NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
ZIA EY000403-12 / ImNIH / Intramural NIH HHS / United States
P20 GM103534 / GM / NIGMS NIH HHS / United States
P01 HL092870 / HL / NHLBI NIH HHS / United States
MC_UU_12013/3 / MRC_ / Medical Research Council / United Kingdom
ZIA EY000403-13 / ImNIH / Intramural NIH HHS / United States
U01 HG006382 / HG / NHGRI NIH HHS / United States
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
R01 HL077612 / HL / NHLBI NIH HHS / United States
ZIA EY000403-14 / ImNIH / Intramural NIH HHS / United States
ZIA EY000403-11 / ImNIH / Intramural NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
G0700491 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
P30 CA023108 / CA / NCI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_UU_00002/7 / MRC_ / Medical Research Council / United Kingdom
MC_EX_MR/L012286/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
MR/M012816/1 / MRC_ / Medical Research Council / United Kingdom
P50 CA097257 / CA / NCI NIH HHS / United States
ZIA EY000403-09 / ImNIH / Intramural NIH HHS / United States
ZIA EY000403-08 / ImNIH / Intramural NIH HHS / United States
MC_UU_12013/4 / MRC_ / Medical Research Council / United Kingdom
Z01 EY000403-07 / ImNIH / Intramural NIH HHS / United States
P30 AR070549 / AR / NIAMS NIH HHS / United States
R01 HL064310 / HL / NHLBI NIH HHS / United States
R01 HL097163 / HL / NHLBI NIH HHS / United States
UM1 CA182883 / CA / NCI NIH HHS / United States
P30 AR047363 / AR / NIAMS NIH HHS / United States
R01 CA052689 / CA / NCI NIH HHS / United States
MC_UU_12013/2 / MRC_ / Medical Research Council / United Kingdom