Gallstones, Body Mass Index, C‐Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data

Abstract

Background & aims: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here we investigate the causal effects of risk factors considered in current GBC prevention programmes as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach & results: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (p = 9 × 10-5) and Europeans (p = 9 × 10-5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (p = 0.03), while higher CRP concentrations increased GBC risk in Europeans (p = 4.1 × 10-6). European results suggest causal effects of BMI on gallstone disease (p = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions: Two risk factors considered in the current Chilean programme for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

“…The number of MR studies based on independent study samples for each disease category was two for diabetes mellitus [ 7 , 8 ], 13 for circulatory system diseases [ 9 – 21 ], three for respiratory diseases [ 8 , 22 , 23 ], six for digestive system diseases [ 24 – 29 ], five for musculoskeletal system diseases [ 30 – 34 ] plus FinnGen consortium (for osteoporosis), five for nervous system diseases [ 35 – 39 ], and 14 for neoplasms [ 40 – 53 ]. Among the selected studies, six studies included East-Asian (Chinese [ 11 , 25 , 42 ] and Japanese [ 48 , 50 ]) or Chilean [ 53 ] individuals, whereas the remaining studies included individuals of European ancestry or mixed (trans-ancestry) populations. Details and results of published MR studies included in the meta-analyses as well as results from de novo MR analyses of FinnGen data are provided in Additional file 1 : Table S2.…”

“…These observational findings [ 1 – 6 ] may represent the causal effect of obesity on disease risk or confounding from other risk factors, such as a poor diet and physical inactivity. During the last years, an increasing number of Mendelian randomization (MR) studies of adiposity, mostly defined by body mass index (BMI), in relation to chronic diseases have been published [ 7 – 53 ]. MR is an instrumental variable analysis that exploits genetic variants with a robust impact on the exposure (e.g., BMI) as proxy markers for the exposure to test whether the exposure has a causal relationship with disease risk [ 54 ].…”

Systematic review of Mendelian randomization studies on risk of cancer

“…Transferrin saturation showed increased risk of liver cancer, but transferrin levels presented a decreased risk [ 311 ]. The rest of the robust associations pertained to age at menarche with ovarian (total and serous; decreased risk) [ 260 ], alcohol use disorder diagnostic codes with ovarian serous (decreased risk) [ 317 ], endometriosis with ovarian [ 261 ] and with endometriosis-uterine leiomyoma [ 235 ] (both increased risk), gallstone disease with gallbladder (increased risk) [ 264 ], insulin-like growth factor 1 (IGF-1) with breast (increased risk) [ 295 ], obstructive sleep apnea syndrome with breast (increased risk) [ 271 ], polycystic ovary syndrome with ovarian endometrioid (decreased risk) [ 237 ], stem cell growth factor beta (SCGF-β) with prostate (decreased risk) [ 304 ], schizophrenia with breast (total, ER+, ER−; increased risk) [ 210 ], standardized forced expiratory volume in 1 s with lung SCC (increased risk) [ 281 ], thyroid-stimulating hormone with cancer overall (decreased risk) [ 313 ], type 2 diabetes with esophageal (decreased risk) [ 312 ], and vitiligo with non-melanoma skin, melanoma, and ovarian (decreased risk) [ 306 ].…”

Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

“…65 Obesity is associated with increased bile acid (BA) synthesis, which provokes supersaturation of BA in the gallbladder and subsequently gallstone formation (cholelithiasis). [66][67][68] Cholecystitis, an inflammation of the gallbladder most often developed by a gallstone, 68,69 was causally associated with increased adiposity along with cholelithiasis in our results (Figures 2 and 3). The result was in concordance with a previous MR-based phenomewide association study that reported the causal effect of BMI on cholecystitis.…”