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      Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

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          Abstract

          Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25–1.49], P = 2.1 × 10 –12, MAF = 1%; Val98Ile: OR = 1.15 [1.10–1.20], P = 1.8 × 10 –10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.

          Abstract

          Genome-wide association studies have so far identified eight risk loci for gallstone disease. Here, the authors perform meta-analysis in cohorts from Iceland and the UK which reveals further 21 common and low-frequency risk variants that highlight the role of bile acid homeostasis in gallstone disease.

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          Most cited references52

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          Exome-wide association study of plasma lipids in >300,000 individuals

          We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.
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            Bile acid transporters.

            In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na(+) taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTalpha-OSTbeta. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers.
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              Gallstone disease: Epidemiology of gallbladder stone disease.

              Gallstone disease is common: >700,000 cholecystectomies and costs of approximately 6.5 billion dollars annually in the U.S. The burden of disease is epidemic in American Indians (60-70%); a corresponding decrease occurs in Hispanics of mixed Indian origin. Ten to fifteen per cent of white adults in developed countries harbour gallstones. Frequency is further reduced in Black Americans, East Asia and sub-Saharan Africa. In developed countries, cholesterol gallstones predominate; 15% are black pigment. East Asians develop brown pigment stones in bile ducts, associated with biliary infection or parasites, or in intrahepatic ducts (hepatolithiasis). Certain risk factors for gallstones are immutable: female gender, increasing age and ethnicity/family (genetic traits). Others are modifiable: obesity, the metabolic syndrome, rapid weight loss, certain diseases (cirrhosis, Crohn's disease) and gallbladder stasis (from spinal cord injury or drugs like somatostatin). The only established dietary risk is a high caloric intake. Protective factors include diets containing fibre, vegetable protein, nuts, calcium, vitamin C, coffee and alcohol, plus physical activity.
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                Author and article information

                Contributors
                patrick.sulem@decode.is
                kstefans@decode.is
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                30 November 2018
                30 November 2018
                2018
                : 9
                : 5101
                Affiliations
                [1 ]deCODE Genetics/Amgen, Inc., Reykjavik, 101 Iceland
                [2 ]ISNI 0000 0000 9894 0842, GRID grid.410540.4, Department of Clinical Biochemistry, , Landspítali University Hospital, ; Reykjavik, 101 Iceland
                [3 ]Laboratory in Mjódd (RAM), Reykjavik, 109 Iceland
                [4 ]GRID grid.440311.3, Department of Clinical Biochemistry, , Akureyri Hospital, ; Akureyri, 600 Iceland
                [5 ]ISNI 0000 0004 0640 0021, GRID grid.14013.37, Faculty of Medicine, , University of Iceland, ; Reykjavik, 101 Iceland
                [6 ]ISNI 0000 0000 9894 0842, GRID grid.410540.4, Department of Immunology, , Landspitali University Hospital, ; Reykjavik, 101 Iceland
                [7 ]ISNI 0000 0000 9894 0842, GRID grid.410540.4, Department of Internal Medicine, , Landspitali University Hospital, ; Reykjavik, 101 Iceland
                [8 ]ISNI 0000 0000 9894 0842, GRID grid.410540.4, Department of Obstetrics and Gynecology, , Landspitali University Hospital, ; Reykjavik, 101 Iceland
                [9 ]ISNI 0000 0004 0640 0021, GRID grid.14013.37, School of Engineering and Natural Sciences, , University of Iceland, ; Reykjavik, 101 Iceland
                Author information
                http://orcid.org/0000-0001-8090-7988
                http://orcid.org/0000-0002-4606-5163
                http://orcid.org/0000-0001-6571-423X
                http://orcid.org/0000-0001-7067-9862
                http://orcid.org/0000-0002-1806-2467
                http://orcid.org/0000-0003-0491-7046
                http://orcid.org/0000-0002-5222-9857
                http://orcid.org/0000-0001-7123-6123
                http://orcid.org/0000-0003-1676-864X
                Article
                7460
                10.1038/s41467-018-07460-y
                6269469
                30504769
                81051dc0-6dba-450b-a6b3-ced593d0c45b
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 May 2018
                : 1 November 2018
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