Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: a Mendelian randomization study

Author:

Gormley MarkORCID,Yarmolinsky JamesORCID,Dudding TomORCID,Burrows KimberleyORCID,Martin Richard MORCID,Thomas Steven,Tyrrell JessicaORCID,Brennan Paul,Pring MirandaORCID,Boccia StefaniaORCID,Olshan Andrew F,Diergaarde BrendaORCID,Hung Rayjean J.,Liu GeoffreyORCID,Legge DannyORCID,Tajara Eloiza H,Severino PatriciaORCID,Lacko Martin,Ness Andrew R,Smith George DaveyORCID,Vincent Emma EORCID,Richmond Rebecca CORCID

Abstract

AbstractIntroductionHead and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk.Methods and findingsWe conducted two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk.The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis.We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p= 9.31 ×10−05), with good concordance between GAME-ON and UK Biobank (I2= 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p= 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings.ConclusionWe found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects, but further replication of this finding is required.Author summaryWhy was this study done?To determine if genetically-proxied cholesterol-lowering drugs (such as statins which target HMGCR) reduce oral and oropharyngeal cancer risk.To determine if genetically-proxied circulating lipid traits (e.g. low-density lipoprotein cholesterol) have a causal effect on oral and oropharyngeal cancer risk.What did the researchers do and find?There was little evidence that genetically-proxied inhibition of HMGCR (target of statins), NPC1L1 (target of ezetimibe) and CETP (target of CETP inhibitors) influences oral or oropharyngeal cancer risk.There was little evidence of an effect of circulating lipid traits on oral or oropharyngeal cancer risk.There was some evidence that genetically-proxied inhibition of PCSK9 increases, while lipid-lowering variants in LDLR reduces oral and oropharyngeal cancer risk.What do these findings mean?These findings suggest that the results of previous observational studies examining the effect of statins on oral and oropharyngeal risk may have been confounded.Given we found little evidence of an effect of other cholesterol lowering therapies, the mechanism of action of PCSK9 may be independent of cholesterol-lowering. Further replication of this finding in other head and neck cancer datasets is required.

Publisher

Cold Spring Harbor Laboratory

Reference78 articles.

1. Global epidemiology of oral and oropharyngeal cancer

2. Gender and ethnic disparities in incidence and survival of squamous cell carcinoma of the oral tongue, base of tongue, and tonsils: a surveillance, epidemiology and end results program-based analysis;Oncology,2011

3. Cancer Research UK (CRUK). Head and neck cancer statistics 2019 [cited 2019 11/04/2019]. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/head-and-neck-cancers#heading-Two.

4. Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines;J Laryngol Otol,2016

5. Physical and Psychosocial Correlates of Head and Neck Cancer: A Review of the Literature

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3