Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies

Liu, Yu-Peng; Zhang, Yuxue; Li, Pengfei; Cheng, Cheng; Zhao, Yashuang; Li, Dapeng; Du, Chen

doi:10.1158/1055-9965.epi-14-1329

Cited by 82 publications

(83 citation statements)

References 34 publications

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“…Meta‐analyses of observational studies and randomized controlled trials present heterogeneous findings for associations of cholesterol with prostate cancer, making it difficult to conclude whether cholesterol plays a role in prostate cancer. The most recent and comprehensive assessment of observational data did not show any association between HDL and LDL and prostate cancer, but could not draw definitive conclusions on high‐grade prostate cancer due to limited data . Our Mendelian randomization approach has several advantages over conventional observational epidemiology: it eliminates the problem of reverse causality, as prostate cancer status cannot alter one's germline genetic makeup; genetic risk scores represent an individual's exposure to lipid traits over their lifetime, reducing biological and technical sources of measurement error that arise from one‐off blood sampling at one point in a person's life; and confounding by behavioral, lifestyle, and other related intermediate traits should be minimized as individuals are effectively randomly allocated to a low or high level of exposure based on their genotype, randomly generated at conception (Mendel's second law of independent assortment) .…”

Section: Discussionmentioning

confidence: 99%

“…are the product of confounding by common causes of both cholesterol levels and prostate cancer (e.g., aspects of diet), bias, or reverse causality (the cancer causing altered cholesterol metabolism) [5]. As serum cholesterol levels can be modified by lifestyle changes [6] and statin therapy [7], clarifying the causality of this association could inform the development of prevention interventions for prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Blood lipids and prostate cancer: a Mendelian randomization analysis

Bull¹,

Bonilla²,

Holly³

et al. 2016

Cancer Medicine

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Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high‐ (≥7 Gleason score) versus low‐grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916‐T variant in 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blood lipids and prostate cancer: a Mendelian randomization analysis

Bull¹,

Bonilla²,

Holly³

et al. 2016

Cancer Medicine

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“…It is not surprising, therefore, that inhibitors of HMG-CoA-reductase (HMGCR) (statins), drugs that block cholesterol synthesis and reduce serum cholesterol and inhibit PC cell growth in vitro (11,12), are associated with reduced PC progression following treatment with surgical prostatectomy (13) or brachytherapy (14) and have been shown in population studies to be associated with a lower risk of developing metastatic or fatal PC (15-18). Given these positive data, it is noteworthy that not all studies have linked hypercholesterolemia with higher PC risk (19). Likewise, the data on statins are not universally positive in terms of their association with PC risk and/or PC progression with several studies finding no such association or with increased risk (20-23).…”

Section: Introductionmentioning

confidence: 99%

CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer

Alfaqih

Nelson

et al. 2017

Cancer Research

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In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 (SREBP2) and downregulating low-density lipoprotein receptor (LDLR) expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis.

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“…In addition to the roles in cellular structure and function, cholesterol is a precursor of several steroid hormones such as estrogen and androgen, and can synthesize bile acids in the liver. Thus, cholesterol was thought to be involved in the etiology of certain cancers including breast cancer, prostate cancer and colorectal cancer . However, several of these findings were inconsistent and have been controversial.…”

mentioning

confidence: 99%

Association of total cholesterol, low‐density lipoprotein cholesterol, and non‐high‐density lipoprotein cholesterol with atherosclerotic cardiovascular disease and cancer in a Chinese male population

Guan

Yang

et al. 2017

Intl Journal of Cancer

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This prospective study included 68,759 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Subjects were divided into four categories based on the quartiles of TC, LDL-C and non-HDL-C. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53; HR 1.16; HR 1.55); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR0.84; HR 0.82; HR 0.80) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. In a word, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers.

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Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies

Cited by 82 publications

References 34 publications

Blood lipids and prostate cancer: a Mendelian randomization analysis

Blood lipids and prostate cancer: a Mendelian randomization analysis

CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer

Association of total cholesterol, low‐density lipoprotein cholesterol, and non‐high‐density lipoprotein cholesterol with atherosclerotic cardiovascular disease and cancer in a Chinese male population

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