The Impact of Homocysteine on the Risk of Hormone-Related Cancers: A Mendelian Randomization Study

Abstract

Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.

Mendelian randomization analysis does not reveal a causal influence of mental diseases on osteoporosis

“…Fourthly, any ambiguous or palindromic SNPs that were ambiguous with non-concordant alleles (e.g., A/G vs. A/C) or with an ambiguous strand (i.e., A/T or G/C) were excluded. Finally, using the PhenoScanner tool ( http://www.phenoscanner.medschl.cam.ac.uk/ ) ( 30 – 32 ), we excluded any SNPs associated with the confounding factor of the outcome, and we used the F -statistic to indicate the strength of the genetic instrumental variants.…”

Causal Relationships between Homocysteine and the Polycystic Ovary Syndrome: A Mendelian Randomization Analysis

“…To ensure that the specifed SNPs only infuenced the outcome through the exposure, we used the PhenoScanner V2 website (https://www.phenoscanner.medschl.cam.ac.uk) to kick out the SNP associated with any potential confounders of PCOS and rs548987 was removed because of pleiotropic efect on BMI. Tree [32] SNPs (rs7422339, rs234709, and rs2851391) were not available in the FinnGen datasets and did not get a replacement with proxy SNPs (r 2 > 0.8). Lastly, a total of 14 (11 in FinnGen) SNPs were selected (Table 1), explaining 5.9% of the variation in the Hcy plasma levels [31], and these SNPs were selected by the previous studies to predict the serum level of Hcy [32][33][34].…”

One-Carbon and Polyamine Metabolism as Cancer Therapy Targets

“…However, because a very high Hcy concentration may potentially be lethal to the cancer cells, advanced-stage cancer cells may release Hcy. Clinically, the situation is less clear—in some studies, there is no evidence of a correlation between Hcy levels and cancer risk [ 94 ]. Further investigations are required to reveal the precise mechanism of how cancer patients deal with Hcy metabolism.…”