{
  "abstract": "Objective Gallstone carriers have elevated cardiovascular disease (CVD) risk. Shared lifestyle risk factors only partly explain the observed association. Gallstone-driven inflammation may contribute to CVD with cholecystectomy offering protection. A triangulation study using observational, genetic and interventional data was undertaken.Design Cox proportional hazards analysis of UK Biobank data assessed 10-year CVD risk in gallstone cases versus healthy controls and gallstone carriers versus post-cholecystectomy individuals. Data were meta-analysed with other published cohorts. Gallstone state was additionally modelled as a time-varying covariate with states: gallstone-free, gallstone-carrier, gallstone-related inflammation and post cholecystectomy. Finally, Mendelian randomisation (MR) analyses were undertaken using 41 gallstone-promoting single nucleotide polymorphisms (SNPs) to assess causal effects of gallstones on CVD.Results In UK Biobank (gallstones=32,528, controls=424,520) and meta-analysis (gallstones=202,055, controls=1,256,861), gallstones were associated with CVD (adjusted HR (aHR) 1·28 (1·20 to 1·36), meta-analysis aHR 1·23 (1·18 to 1·29)). Cholecystectomy was associated with reduced CVD risk compared with gallstone carriers (aHR 0·71 (0·62 to 0·82)). Time-varying analysis supported elevated CVD risk with inflammation and reduced CVD following cholecystectomy. MR analyses required handling of pleiotropic cholesterol-lowering SNPs that affect CVD risk independently of gallstones. Multivariable MR adjusting for the impact of SNPs on lipids showed no significant association of CVD and gallstones.Conclusion Gallstones are associated with elevated CVD risk, which increased with gallstone-related inflammation but diminished post cholecystectomy. The benefits of cholecystectomy indicate a potential causal pathway. However, as cholecystectomy interrupts exposure to gallstones, the effects of gallstone-promoting SNPs on CVD are likely attenuated by cholecystectomy, meaning MR analyses cannot detect an underlying causal effect.",
  "authors": [
    {
      "affiliations": [
        "Centre for Medical Informatics, Usher Institute, The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK"
      ],
      "name": "Cameron J Fairfield"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "Thomas Drake"
    },
    {
      "affiliations": [
        "Centre for Medical Informatics, Usher Institute, The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK"
      ],
      "name": "Riinu Pius"
    },
    {
      "affiliations": [
        "University of Leeds Leeds Institute of Health Sciences, Leeds, UK"
      ],
      "name": "William A Cambridge"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "David W Clark"
    },
    {
      "affiliations": [
        "The University of Edinburgh Department of Clinical Surgery, Edinburgh, UK"
      ],
      "name": "Lydia Charlotte Cullen"
    },
    {
      "affiliations": [
        "Centre for Inflammation Research, Univeristy of Edinburgh, Edinburgh, UK"
      ],
      "name": "Jonathan Andrew Fallowfield"
    },
    {
      "affiliations": [
        "The University of Edinburgh Centre for Genomic and Experimental Medicine, Edinburgh, UK"
      ],
      "name": "Caroline Hayward"
    },
    {
      "affiliations": [
        "MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK"
      ],
      "name": "Neil C Henderson"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "Andrii Iakovliev"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "Peter K Joshi"
    },
    {
      "affiliations": [
        "Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK"
      ],
      "name": "Nicholas L Mills"
    },
    {
      "affiliations": [
        "Centre for Inflammation Research, University of Edinburgh Division of Clinical and Surgical Sciences, Edinburgh, UK"
      ],
      "name": "Prakash Ramachandran"
    },
    {
      "affiliations": [
        "Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK"
      ],
      "name": "Robert K Semple"
    },
    {
      "affiliations": [
        "Department of Clinical Surgery, The University of Edinburgh, Edinburgh, UK",
        "Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK"
      ],
      "name": "Catherine A Shaw"
    },
    {
      "affiliations": [
        "Centre for Medical Informatics, Usher Institute, The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK"
      ],
      "name": "Cathie LM Sudlow"
    },
    {
      "affiliations": [
        "Institute of Genetics and Cancer, The University of Edinburgh MRC Human Genetics Unit, Edinburgh, UK",
        "Usher Institute, The University of Edinburgh Centre for Global Health Research, Edinburgh, UK"
      ],
      "name": "Paul Timmers"
    },
    {
      "affiliations": [
        "Institute of Genetics and Cancer, The University of Edinburgh MRC Human Genetics Unit, Edinburgh, UK",
        "Usher Institute, The University of Edinburgh Centre for Global Health Research, Edinburgh, UK"
      ],
      "name": "James F Wilson"
    },
    {
      "affiliations": [
        "Department of HPB and Liver Transplant Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK"
      ],
      "name": "Stephen J Wigmore"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "Athina Spiliopoulou"
    },
    {
      "affiliations": [
        "The University of Edinburgh Usher Institute, Edinburgh, UK"
      ],
      "name": "Ewen Harrison"
    }
  ],
  "title": "Gallstones: a driver of cardiovascular disease? A triangulation study",
  "uid": "cf492d70-8fe9-57b0-829b-bfc0221efdb2"
}