The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study

Abstract

Background Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa. Methods and findings Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings. Conclusions We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.

Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study

“…Furthermore, genetically proxied PCSK9 exhibited the strongest magnitude of association with the risk of early onset prostate cancer than that of overall prostate cancer, and there is weak evidence for association with advanced disease. This is consistent with the association between Lp(a) and the risk of prostate cancer outcomes identified in the recent multivariable MR [27]. Although our findings suggest that Lp(a) may play a mediatory role along the pathway between PCSK9 inhibition and prostate cancer risk, further functional work is required to robustly demonstrate this.…”

“…Our results found little evidence for associations for mediatory effects from genetically proxied inhibition of PCSK9 on these two risk factors. Moreover, a higher levels of Lp(a) has previously been reported to associate with poor prognosis of prostate cancer [67] as well as a higher risk of overall and early onset prostate cancer [27]. Our results provided strong evidence that PCSK9 inhibition may lower levels of Lp(a), and there is weak evidence for a similar effect from the inhibition of NPC1L1 or HMGCR.…”

“…The effect of LDL-c lowering drugs, LDLR expression and circulating LDL-c on advanced prostate cancer and early-onset prostate cancer was also investigated. Finally, we evaluated the genetically proxied effects of LDL-c lowering drugs on several traits previously implicated to play a role in prostate cancer risk (body mass index (BMI) [24][25][26], lipoprotein A (Lp(a)) [27] and testosterone [28,29]) to discern whether they may reside along the pathways between therapeutic targets and risk of prostate cancer.…”

Lipoprotein(a) and cardiovascular and valvular diseases: A genetic epidemiological perspective

“…Lp(a) levels may have been elevated in response to undiagnosed cancer and concomitant inflammation [74]. This limitation does, however, not apply to the very recent finding of an association of LPA genetic variants with increased risk of prostate cancer in the UK Biobank and PRAC-TICAL consortium [75]. Thus, an odds ratio for prostate cancer of 1.09 (95% CI:1.03-1.16) per 1 standard deviation increase in genetically predicted Lp(a) levels was reported while testing for associations with several other genetically predicted lipid parameters yielding null findings.…”

Can Diet Prevent Urological Cancers? An Update on Carotenoids as Chemopreventive Agents

“…It has been shown that increased fat consumption results in amplifying the MYC-dependent transcriptional cascade [ 28 ]. Blood lipids, and especially high lipoprotein A concentrations, seem to be associated with increased PCa risk and advanced disease [ 29 ], and lipoprotein A is known to promote inflammation. On the other hand, high levels of chronic inflammatory markers are associated with high-risk, aggressive PCa [ 30 ].…”