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Blood lipid genetic scores, the HMGCR gene and cancer risk : A Mendelian randomization study

Orho-Melander, Marju LU ; Hindy, George LU ; Borgquist, Signe LU ; Schulz, Christina Alexandra LU ; Manjer, Jonas LU ; Melander, Olle LU and Stocks, Tanja LU (2018) In International Journal of Epidemiology 47(2). p.495-505
Abstract

Background: It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding. Methods: We applied Mendelian randomization analysis to genetic scores, comprising 26–41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in... (More)

Background: It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding. Methods: We applied Mendelian randomization analysis to genetic scores, comprising 26–41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR). Results: The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80–1.03] unadjusted, and 0.87 (95% CI: 0.78–0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01–1.18) for prostate cancer and 0.89 (95% CI: 0.82–0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder. Conclusions: Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cohort studies, Lipoproteins, Mendelian randomization analysis, Neoplasms, Triglycerides
in
International Journal of Epidemiology
volume
47
issue
2
pages
11 pages
publisher
Oxford University Press
external identifiers
  • scopus:85053570905
ISSN
0300-5771
DOI
10.1093/ije/dyx237
language
English
LU publication?
yes
id
3ad153c1-6107-41f5-935c-149c0c57d3d9
date added to LUP
2019-05-29 15:10:02
date last changed
2019-08-14 04:38:49
@article{3ad153c1-6107-41f5-935c-149c0c57d3d9,
  abstract     = {<p>Background: It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding. Methods: We applied Mendelian randomization analysis to genetic scores, comprising 26–41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR). Results: The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80–1.03] unadjusted, and 0.87 (95% CI: 0.78–0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01–1.18) for prostate cancer and 0.89 (95% CI: 0.82–0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder. Conclusions: Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.</p>},
  author       = {Orho-Melander, Marju and Hindy, George and Borgquist, Signe and Schulz, Christina Alexandra and Manjer, Jonas and Melander, Olle and Stocks, Tanja},
  issn         = {0300-5771},
  keyword      = {Cohort studies,Lipoproteins,Mendelian randomization analysis,Neoplasms,Triglycerides},
  language     = {eng},
  month        = {04},
  number       = {2},
  pages        = {495--505},
  publisher    = {Oxford University Press},
  series       = {International Journal of Epidemiology},
  title        = {Blood lipid genetic scores, the HMGCR gene and cancer risk : A Mendelian randomization study},
  url          = {http://dx.doi.org/10.1093/ije/dyx237},
  volume       = {47},
  year         = {2018},
}