Biology subjects

Rennert, G.

Publications and source records attributed to Rennert, G..

3 recordsLinked to original sources

bioRxiv2020

A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer

BackgroundEvidence for aspirins chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. MethodsHuman colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). ResultsAltered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively). ConclusionMCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirins reduction of metastasis. ImpactOur approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

cancer biology↗

bioRxiv2019

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg=0.098, p=2.3x10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg=0.137, p=2.0x10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR)=1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR=1.17, 1.01-1.35) and lung cancer in never smokers (OR=1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

genetics↗

bioRxiv2018

The association between low-density lipoprotein cholesterol predicted by HMGCR genetic variants and breast cancer risk may be mediated by body mass index

Orho-Melander et al. recently reported that lower low-density lipoprotein cholesterol (LDLC) as predicted by the T-allele of the variant rs12916 in HMGCR is associated with a decreased risk of developing breast cancer [odds ratio (OR) = 0.89; 95% confidence interval (CI): 0.82-0.96].1 This analysis was embedded in a wider Mendelian randomization (MR) study performed using genotype data from a prospective cohort of 26,589 individuals that included 16,022 women and 1176 incident breast cancer cases. HMGCR encodes 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme inhibited by statins. The T-allele of rs12916 is associated with reduced HMGCR expression and therefore, in principle, its effects should be analogous to the effects of lifelong statin administration starting at birth.2 The MR study of Orho-Melander et al. also found that a genome-wide LDLC score based on 32 independent LDLC-associated single nucleotide polymorphisms (SNPs) was not associated with breast cancer. In light of this finding, they suggest that the protective effect of the rs12916 T-allele on breast cancer may either be specific to LDLC lowering via genetic inhibition of HMGCR or be the result of a distinct mechanism that is regulated by rs12916 and HMGCR.

epidemiology↗