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Medicine » "Updates in Gallbladder Diseases", book edited by Hesham Mohamed Abdeldayem, ISBN 978-953-51-3088-8, Print ISBN 978-953-51-3087-1, Published: April 26, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 2

Immunogenetic Basis of Cholecystitis

By Batool Mutar Mahdi
DOI: 10.5772/67365

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Formation of cholesterol gallstone [9].
Figure 1. Formation of cholesterol gallstone [9].
Major histocompatibility complex on chromosome 6: class I, class II and class III.
Figure 2. Major histocompatibility complex on chromosome 6: class I, class II and class III.

Immunogenetic Basis of Cholecystitis

Batool Mutar Mahdi
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Cholecystitis is an inflammation of the gallbladder caused by many causes like stone that is cholesterol gallstone and sometimes the cause is due to bacterial infection also known as acalculous cholecystitis. The risk factors for this disease are female, 40, fatty, fair, aging, diabetes mellitus, pregnancy, oral contraceptive and the most common factor is the interaction between genetic and environmental factors. Genetic factors include human leukocyte antigens, ethnicity, race and single nucleotide polymorphism in genes involved in the synthesis of cholesterol, transport and excretion.

Keywords: cholecystitis, genetic, stone, HLA, ethnicity

1. Introduction

Cholecystitis is an inflammation of the gallbladder, originated from Greek word—cholecyst means “gallbladder,” combined with the suffix -itis means “inflammation,” means inflammation of the gallbladder, which occurs due to calculous in 90% of the cases and the rest 10% known as acalculous cholecystitis [1]. The most common presenting symptom is upper abdominal colicky pain frequently begins in the epigastric region that may radiate to the right shoulder and then localizes to the right upper quadrant of the abdomen associated with nausea and vomiting while acalculous cholecystitis may present with fever and sepsis only [2], jaundice may occur suggesting choledocholithiasis [3]. Immunocompromised patients and elderly patients may have vague symptoms that may not include fever or localized tenderness [4]. The pathogenesis of cholecystitis is blockage of the cystic duct with one or multiple gallstones form when substances in the bile form crystal-like particles. They can range from the size of a grain of sand to the size of a golf ball resulting in accumulation of bile and increased pressure within the gallbladder. Many factors contribute in the pathogenesis such as concentrated bile, increased pressure inside the gallbladder and secondary bacterial infection by gut organisms, predominantly Escherichia coli and Bacteroides species irritate and damage the gallbladder wall, causing inflammation and swelling of the gallbladder. This leads to reduce normal blood flow to areas of the gallbladder, leading in cell death due to insufficient oxygen supply to tissues [5]. The importance of chronic inflammation of the gallbladder (chronic cholecystitis) and cholelithiasis is related to its association with gallbladder cancer [6]. Thus, it is important to deal with its etiogenesis.

2. Causes

Cholecystitis is a gallbladder inflammation, which is most commonly caused by gallstones, tumor or scarring of the bile duct [7]. The greatest risk factor for calculous cholecystitis is gallstones and the risk factors for gallstones include female sex, increasing age more than 60, pregnancy, oral contraceptives, obesity, diabetes mellitus, ethnicity like Native North American or Mexican American ethnicity, rapid weight loss and drugs like hormonal replacement therapy in women during menopause. Cholesterol gallstones, accountable for about 90% of gallstones, due to supersaturation of bile with cholesterol stand for a multifactorial disease with a significant genetic component (Figure 1) [8].


Figure 1.

Formation of cholesterol gallstone [9].

A genetic factor in the vulnerability to gallstones was recognized as early as 1937 [10]. These stones were formed due to interactions of lithogenic alleles of gallstone susceptibility genes in DNA and many environmental factors [11]. The genetic cause may be due to fibroblast growth factor receptor 4 (FGFR4) polymorphism, which is a genetic risk factor contributing to aggravation of gallstone disease by maintaining bile acid homeostasis by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1). The Gly388Arg (G-388R) had a greater inhibitory activity against bile acid biosynthesis and polymorphism in it affects stabilization and activation of FGFR4 and overexpression of FGFR4, especially the G-388R mutant of FGFR4 that inhibits luciferase activity of CYP7A1 reporter [12]. Acalculous cholecystitis is related to conditions associated with biliary stasis such as critical illness, major surgery or severe trauma/burns, sepsis, long-term total parenteral nutrition, prolonged fasting, myocardial infarction, sickle cell disease, Salmonella infections, diabetes mellitus and patients with AIDS who have cytomegalovirus, cryptosporidiosis or microsporidiosis [13]. Genetic factors play an important role in causation of disease because around 50–70% of cholecystitis patients have a positive family history of the disease [14]. In addition to that, epidemiologic studies have showed that environmental factors and genetic elements are contributed in gallstone formation through many studies on twins, families and ethnicities with gallstone formation [15].

2.1. Genetic factor

Cholecystitis had been found in certain area of the world and had an epidemiological distribution raises an issue of genetic or chromosomal factors associated with it [16]. The frequency of diseases of the gallbladder, gallstones (cholelithiasis), cancer of the gallbladder and other biliary tract system diseases is more common in western countries (North America, Europe and Africa) [17]. This may be due to general response to some dietary or other environmental risk factor, suggesting a gene-environment interaction. The role of diet was attributed to the consumption of high-calorie, high-fat, low-fiber diets and insufficient exercise [18]. There was an epidemic of gallbladder disease among Amerindians and peoples genetically related to them [19]. The existence of this epidemic indicates a genetic basis of this disease. In addition to that, the prevalence of cholecystitis in geographically associated distribution may be related to genes of aboriginal Amerindian origin, the degree of Amerindian admixture. The person from New World genotype will do cholecystectomy by age 85 years and this constitutes about 40% in Mexican-American females and increased the risk of gallbladder cancer. Thus, genetic factor can be considered as Carcinogenic reason in New World peoples as any major environmental exposure [20]. The genetic effect in gallbladder diseases starts from chromosomal changes in gallbladder cells that leads to gallbladder cancer either acquired or inherent genetic instability in normal cells of the gallbladder causing mutational events that result in neoplastic transformation of normal cells and provide such cells with a selective growth over normal cells that leads to carcinoma of the gallbladder [21].The cause was due to loss of heterozygosity in the 3p, 8p, 9q and 22q chromosomal regions of cancer patients [22]. Other study demonstrated chromosomal aberrations were confined on chromosome 1’s long arm and translocation from the long arm of chromosome 4 to the long arm of chromosome 6. These aberrations constitutes about 16.6% and may be due to environmental effects, infections and inflammation [16]. The frequency of gallbladder disease was increased in Eastern populations like China, this may be due to the diet of the Chinese in Taiwan is already Westernized and differences among genetic populations [23]. The effect of genetic factor in the development of acute acalculous cholecystitis was manifested by infection with Epstein–Barr virus and development of disease [24]. Other microorganism that causes acalculous cholecystitis is Lactococcus garvieae that is recognized as a freshwater fish bacteria, is now regarded as zoonotic microorganism in human. The genome sequence of L. garvieae is draft genome sequence of L. garvieae LG-ilsanpaik-gs201105, with a total genome size of 1,960,261 bp in 53 contigs and a 38.1% average G-C content [25]. These extracellular bacteria phagocytosed by antigen presenting cells like macrophages, dendritic cells and B cells that processed them and presented with Major histocompatibility complex class II molecules to T cells. Human leukocytes antigens (HLA) (Figure 2) is one of the genetic factor that cause cholecystitis, studies into the genetic characteristics of patients with chronic cholecystitis made the significance of hereditary load in the development of cholecystitis and to identify genetic markers (B (III) blood group), type Hp 1-1, HLA-A3, HLA-A30 and HLA-B5, and genetic protectors (O (I) blood group), HLA-B8 and HLA-B14 of the disease [26].


Figure 2.

Major histocompatibility complex on chromosome 6: class I, class II and class III.

The class II molecule of HLA is a heterodimer consisting of two chains, an alpha (DRA) and a beta chain (DRB), both anchored in the membrane of the cell wall. HLA DRB1 plays a central role in the immune system by presenting peptides derived from extracellular proteins and the class II molecules are expressed in cell wall of antigen presenting cells B lymphocytes, dendritic cell and macrophages. The beta chain is approximately 26–28 kDa and is encoded by six exons. Exon 1 encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms of HLA that specifying the peptide binding specificities. Allelic variants of DRB1 are linked with many diseases [27]. Cholecystitis patients and control groups were typed for identifying the DRB1* alleles using DNA-based methodology (PCR-SSOP). Allele’s frequencies of HLA-DRB1 for cholecystitis patients and control group. There was an increased frequency of HLA-DRB1*03:01 in patients with cholecystitis compared with healthy controls (p = 0.0442, odd ratio = 4.1111, 95% CI: 1.0372–16.2949); also there is an increase in the HLA-DRB1*13:01 in patients with cholecystitis while the control group did not have this allele, thus this allele is predisposing allele to diseases development. The highest frequencies belong to HLADRB1*03:01 and HLA-DRB1*13:01 that are 0.14 and 0.16, respectively. This demonstrated the role of chromosome 6 in gallbladder disease by HLA typing. Thus, HLA-DRB1*13:01 is significantly higher than control group [28]. In other populations, HLA A3, HLA A30, HLA B5, HLA B8 and HLA B14 are associated with this disease [29]. Human leukocyte antigens are important in determining immune response whether cellular or humeral. The HLA-DR antigen expression on macrophages and monocytes plays an important role in antigen presentation to T-helper lymphocytes [29]. In fact, these cells require both HLA-DR and exogenic antigens on the macrophage surface to initiate proliferation. Thus, HLA-DR is a major histocompatibility complex class II cell surface receptor that is up-regulated in response to signaling during an infection. Therefore, decrease of human leukocyte antigen-DR leading to increased gallbladder inflammation and sepsis [20]. The cholecystitis pattern of genotypic variability in an admixed population is a function of the gene frequencies of the original contributing parental populations, the number of loci involved in a trait of interest, the mating pattern relative to those loci and the amount of admixture between populations. Native peoples of the New World, including Amerindians and admixed Latin Americans such as Mexican-Americans, are highly susceptible to cholecystitis. This pattern differs from that generally associated with Westernization, which suggests a gene-environment interaction [30]. Among women with cholecystitis, the risk is highest among American Indians, followed by Hispanics, non-Hispanic whites and non-Hispanic blacks. Men differ from women by having lower risk in all ethnic groups and by having a similar prevalence between Hispanics and non-Hispanic whites. Genetic markers have not been identified that would explain differences in risk among ethnic groups. Patients with HLA typing haplotype HLAB*07 and DRB1*15 have a higher level of IgG4 in patients with primary sclerosing cholangitis [31]. Allele like HLA-DRB1*13:119 and 14:57 are either new alleles or ambiguous allele that assign with high number. According to IMGT/HLA, these two alleles occur in Native Indian.

Occurrence of genetic alterations is risk factors have been associated with gallbladder disease like cholecystitis, chronic inflammation of the gallbladder, congenital biliary abnormalities and polyps. Genetic predisposing factors associated with cancer of gallbladder like mutations in KRAS, TP53, p16/CDKN2A, microsatellite instability, overexpression of COX2, VEGF, hTERT and ERBB2 genes in gallbladder cancer (GBC) [32, 33]. Chronic inflammation of the gallbladder and biliary tract infections or irritation by gallstones and progression to invasive carcinoma, tracks at the molecular level, with tumor suppressor gene silencing by DNA methylation, together with global and gene-specific loss of methylation [34]. There are different studies about lesions’ methylome and gene-specific promoter methylation alterations in the following genes (APC, CDKN2A, ESR1, MCAM, MGMT, PGP9.5, RARβ and SSBP2) of DNA of the patients with cholecystitis. The acquisition of hypermethylation at gene-promoter sites (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2 and p73) may lead to loss of gene function and chronically inflamed gallbladder and cancer and this hypermethylation differ in different parts of the world [35]. In addition to that, aberrant methylation of 5′ gene promoter regions is an epigenetic phenomenon that is a main method for silencing of genes, which is absent in chronic cholecystitis, whereas it is present in gallbladder disease [36]. The methylation levels seem to play an important role in the progression of chronic cholecystitis without metaplasia to chronic cholecystitis with metaplasia [37].

2.2. Genetic cause of calculous cholecystitis disease

Gallstone disease is a very common biliary tract disease in the world. Gallstones are one of the most common and mainly costly digestive diseases in the developed countries. Geographic and ethnic differences in its occurrence imply that genetic factors influence risk of gallstone formation [14]. Its prevalence in the western countries was 48% [38], whereas in Asian ones was 5.9–21.9% [39]. It is a most common cause for cholecystitis, acute cholangitis and biliary pancreatitis. It is formed due to genetic-environmental factors interactions. Genetic factors that influence gallstone formation by its implication in different metabolic pathways, have been involved from linkage studies of twins, families study and ethnicities, it had been found that this disease is more common in siblings and other family members of affected persons than spouses or unrelated controls in a ratio 3:1 [40]. Twin studies have provided a clue into the genetic effect on disease development; the rates of this disease in monozygotic twins of both sexes were higher than in dizygotic twins [41]. This involves the genetic effects of multiple LITH genes of susceptible alleles that interact with environmental factors. The genetic defect either oligogenic (mutations in single genes) or polygenic (mutation in multiple genes) that affect the molecular pathophysiology of cholesterol gallstone formation, defect in the physical-chemistry of bile and the physiology of biliary lipid secretion [4244]. One of these metabolic pathways defect is MDR3 which is the phosphatidylcholine translocator across the hepatocyte canalicular membrane because phospholipids are a carrier and a solvent of cholesterol in hepatic bile. Thus a defect in the MDR3 gene due to mutations involving a conserved amino acid region represents a genetic factor involved in the formation of cholesterol gallstone disease in adults and familial intrahepatic cholestasis type-3 that characterized by production bile acid-rich toxic bile that damages the intrahepatic bile ducts [45]. Other genetic pathway disease is caused by defects of canalicular secretion of bile salts. Most of bile salts were absorbed in terminal ileum while in the liver, there is a transporter at the basolateral sinusoidal membrane called sodium-dependent taurocholate transporter and the bile salt export pump at this membrane-mediated hepatic uptake and canalicular secretion of bile salts. When there is impairment in the bile flow leads to impairment in the metabolism of cholesterol and bile acids by expression of transporter proteins and enzymes of the cytochrome P-450 system. This stimulates or inhibits the transcription of genes encoding transporters and enzymes involved in their metabolism leading to a hepatoprotective dysfunction and familial intrahepatic cholestasis type-1 results from mutations in various genes encoding hepatobiliary transport proteins while type-2 results from mutations in the bile salt export pump gene [46]. There is other genetic defect that leads to cholelithiasis, which is a mutation in ABCB4 gene (adenosine triphosphate-binding cassette (ABC), subfamily B, member 4) a major genetic risk factor in a symptomatic and recurring form of cholelithiasis in young adults [47]. Pullinger et al. [48] showed that a deletion mutation in cholesterol 7 alpha-hydroxylase enzyme (CYP7A1) was related to hypercholesterolemia resistant to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that lead to a loss of enzyme function which results in decrease in bile salt synthesis. This ends in increase of bile stone formation and calculus cholecystitis. Other monogenic disorder is mutations in the ATP-binding cassette (ABC) 1 gene that leads to a defect in cellular cholesterol efflux ends in Tangier disease [49, 50]. Other cause was defect in splicing of cholecystokinin A receptor (CCK-1R) resulted in non-functional receptor and stasis of bile in gallbladder [51]. Additional defect was mutations in the ATB7B gene leads to copper accumulation and Wilson’s disease [52]. A genome-wide association (GWA) study of more than 500,000 SNP identified a coding variant rs11887534 (D19H) of the sterol transporters ABCG5/G8 on the canalicular membrane of hepatocytes as a risk factor for cholesterol gallstone development [10]. In addition to that, polymorphisms of the apolipoprotein (APO)-E (three allelic variants, e2, e3 and e4) e4 genotype is a genetic risk factor for cholelithiasis [53], Apo-B and the cholesteryl ester transfer protein are result in familial type III hyperlipoproteinemia (HLP III) [54].

Thus, in conclusion, there are a large number of genetic polymorphisms (SNPs) that causing calculus cholecystitis starting from cholesterol transporter [55], plasma transport [56], cholesteryl ester transfer protein [57] and cholesterol uptake [58], bile acid synthesis [59], transporter [60] and bilirubin excretion [61], mucin affect the formation of the gallstone genetically [62], gallbladder motility [63] and hormone receptor [64]. Thus, genetic study provided an insight toward the pathogenesis of the calculus cholecystitis.

2.3. Immunologic causes

The role of immune system on development of calculus and cholecystitis is manifested by cell-mediated immunity (Th1 cell) exerting its effect on formation of cholesterol gallstone and local inflammation [65]). It was first be confirmed by Lee and coworkers [66]. The proinflamatory cytokines had an effect on mucin production. Regarding immunoglobulins (particularly IgM and IgG), it had been found that they promote crystal nucleation [67]. This immune mechanism in the biliary system was altered due to the presence of multiple microbial flora [68] and other bacteria like enterohepatic Helicobacter spp. as H. pylori [69].This bacteria-induced disease through stimulation of adaptive immunity by Th1-mediated proinflammatory immune response and secretion of cytokines [70] and increased immunoglobulines production that alters mucin production [71]. In addition to that innate immunity also had an important role in defense mechanism against cholecystitis represented by Toll-like receptors by initiating and directing immune response to bacteria, lower expression of TLR4 in chronic cholecystitis in the glandular and luminal epithelium of gallbladder enhancing cholecystitis [72]. CXCL16 (membrane-bound molecule) was detected on gallbladder epithelia, CXCR6(+)/CD8(+) T cells and CXCR6(+)/CD68(+) macrophages were upregulated due to E. coli infection through Toll-like receptor 4. This is due to role of the scavenger receptor class A on macrophages that phagocytes E. coli followed by foamy changes and that bacterial infection causes the upregulation of CXCL16 in gallbladder epithelia, leading to the chemoattraction of more macrophages via CXCL16-CXCR6 interaction [73].

3. Conclusions

Inflammation of the gallbladder whether calculus or acalculous is a complex process mediated by genetic and environmental factors. Cholecystitis required a strong involvement of a genetic factor whether in the immune response infection against pathogen, formation of a stone and defense mechanism against inflammation. Understanding the concept of genetic factor leads to a novel diagnostic tools, treatments and preventive measures.

Conflict of interest

The author confirms that there are no conflicts of interest.


1 - Huffman JL, Schenker S. Acute acalculous cholecystitis—a review. Clin Gastroenterol Hepatol. 2010; 8:15–22.
2 - Strasberg SM. Clinical practice. Acute calculous cholecystitis. N Engl J Med. 2008:358: 2804–11.
3 - Friedman LS. Liver, biliary tract, & pancreas disorders. In Papadakis MA, McPhee SJ, Rabow MW (Eds), Current Medical Diagnosis & Treatment, 2015. Chapter 16, pp:658–715.
4 - Demehri FR, Alam HB. Evidence-based management of common gallstone-related emergencies. J Int Care Med. 2016:31(1) 3–13.
5 - Glasgow RE, Mulvihill SJ. Treatment of gallstone disease. In Feldman M, Friedman LS, Brandt LJ (Eds), Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadelphia, PA: Saunders Elsevier; 2010: Chap. 66.
6 - Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. Cancer J Clin. 2001:51:349–64.
7 - Greenberger NJ, Paumgartner G. Chapter 311. Diseases of the Gallbladder and Bile Ducts. In Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J (Eds), ‘Harrison’s Principles of Internal Medicine, 18e.Retrieved November 08, 2014.
8 - Casper M, Lammert F. Gallstone disease: Basic mechanisms, diagnosis and therapy. Praxis (Bern 1994). 2011:16:1403–12.
9 -
10 - Buch S, Schafmayer C, Volzke H, Becker C, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet. 2007:39:995–9.
11 - Wittenburg H. Hereditary liver disease: Gallstones. Best Pract Res Clin Gastroenterol. 2010:24:747–56.
12 - Chuang SC, Hsi E, Lee KT. Genetics of gallstone disease. Adv Clin Chem. 2013:60:143–85.
13 - Forbes LE, Bajaj M, McGinn T, et al. Perihepatic abscess formation in diabetes: A complication of silent gallstones. Am J Gastroenterol. 1996:91:786–8.
14 - Chuang S-C, His E, Lee K-T. Genetics of gallstone disease Chapter five. Adv Clin Chem. 2013:60, 143–85. Elsevier Inc.
15 - Evseeva IV. The determination in the polyclinic of the genetic risk for the development of chronic cholecystitis. Ter Arkh. 1994:66:67–70.
16 - Dixit R, Kumar P, Tripathi R, Baus S, Mishra R, Shukla VK. Chromosomal structural analysis in carcinoma of the gallbladder. World J Surg Oncol. 2012:10:198.
17 - Heaton K. Gallstones. In Trowell H, Burkitt D (Eds), Western Diseases. Cambridge, MA: Harvard Press, 1981, 47–60.
18 - Trowell H, Burkitt D. Western Diseases: Their Emergence and Prevention. Cambridge, MA: Harvard Press, 1981.
19 - Sampliner R, Bennett P, Comess L, Rose F, Burch T. Gallbladder disease in Pima Indians: Demonstration of high prevalence and early onset by cholecystography. N Engl J Med. 1970:283:1358–64.
20 - Weiss KM, Ferrell RE, Hanis CL, Styne PN. Genetics and epidemiology of gallbladder disease in New World native peoples. Am J Hum Genet. 1984:36:1259–78.
21 - Matsuo K, Kuroki T, Kitaoka F, Tajima Y, Kanematsu T. Loss of heterozygosity of chromosome 16q in gallbladder carcinoma. J Surg Res. 2002:102:133–6.
22 - Wistuba II, Maitra A, Carrasco R, Tang M, Troncoso P, Minna JD, Gazdar AF. High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma. Br J Cancer. 2002:87:432–40.
23 - Chen J, Hsu C, Liu J, Tung T. Clinical predictors of incident gallstone disease in a Chinese population in Taipei, Taiwa. BMC Gastroenterol. 2014:14:83.
24 - Koufakis T, Gabranis I. Another report of acalculous cholecystitis in a Greek patient with infectious mononucleosis: A matter of luck or genetic predisposition? Case Report Hepatol. 2016:1–3.
25 - Kim JH, Kang DH, Park SC. Draft genome sequence of human-pathogenic Lactococcus garvieae LG-ilsanpaik-gs201105 that caused acute acalculous cholecystitis. Genome Announc. 2015:3:e00464–15.
26 - Festi D, Dormi A, Capodicasa S, Staniscia T, Attili AF, Loria P, et al. Incidence of gallstone disease in Italy: Results from a multicenter, population-based Italian study (the MICOL project). World J Gastroenterol. 2008:14:5282–9.
27 - Neefjes JJ, Ploegh HL. Intracellular transport of MHC class II molecules. Immunol Today. 1992:13:179–84.
28 - Al-Marzook TJ, Mutar Mahdi B, Raouf H, Zalzala HH, Abid LA, Nehad Z. The effect of HLA-DRB1 on cholecystitis. Iran J Immunol. 2015:12:149–55.
29 - Sista F, Schietroma M, Santis GD, Mattei A, Cecilia EM, Piccione F, Leardi S, Carlei F, Amicucci G. Systemic inflammation and immune response after laparotomy vs laparoscopy in patients with acute cholecystitis, complicated by peritonitis. World J Gastrointest Surg. 2013:5:73–82.
30 - Everhart JE. Gallstones and ethnicity in the Americas. J Assoc Acad Minor Phys. 2001:12:137–43.
31 - Berntsen NL, Klingenberg O, Juran BD, Benito de Valle M, Lindkvist B, Lazaridis KN, et al. Association between HLA haplotypes and increased serum levels of IgG4 in patients with primary sclerosing cholangitis. Gastroenterol. 2015:148:924–7.
32 - Eslick GD. Epidemiology of gallbladder cancer. Gastroenterol Clin N Am. 2010:39:307–30.
33 - Goldin RD, Roa JC. Gallbladder cancer: A morphological and molecular update. Histopathol. 2009:55:218–29.
34 - Letelier P, Brebi P, Tapia O, Roa JC. DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer. Clin Epigenet. 2012:4:11.
35 - House MG, Wistuba Ii, Argani P, et al. Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. Ann Surg Oncol. 2003:10:882–9.
36 - Takahashi T, Shivapurkar N, Riquelme E, et al. Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res. 2004:10(18 Pt 1):6126–33.
37 - Garcia P, Manterola C, Araya JC, et al. Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Mol Carcinog. 2009:48:79–89.
38 - Everhart JE, Yeh F, Lee ET, et al. Prevalence of gallbladder disease in American Indian populations: Findings from the Strong Heart Study. Hepatology. 2002:35:1507–12.
39 - Lammert F, Sauerbruch T. Mechanisms of disease: The genetic epidemiology of gallbladder stones. Nat Clin Pract Gastroenterol Hepatol. 2005:2:423–33.
40 - Attili AF, De Santis A, Attili F, Roda E, Festi D, Carulli N. Prevalence of gallstone disease in first-degree relatives of patients with cholelithiasis. World J Gastroenterol. 2005:11:6508–11.
41 - Antero Kesaniemi Y, Koskenvuo M, Vuoristo M, Miettinen TA. Biliary lipid composition in monozygotic and dizygotic pairs of twins. Gut. 1989:30:1750–6.
42 - Hernández-Nazará A, Curiel-López F, Martínez-López E, Hernández-Nazará Z, Panduro A. Genetic predisposition of cholesterol gallstone disease. Ann Hepatol. 2006:5:140–9.
43 - Kosters A, Jirsa M, Groen AK. Genetic background of cholesterol gallstone disease. Biochim Biophys Acta. 2003:1637:1–19.
44 - Wang HH, Portincasa P, Wang DQ. Molecular pathophysiology and physical chemistry of cholesterol gallstones. Front Biosci. 2008:1:401–23.
45 - Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001:120:1459–67.
46 - Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int. 2003:23:315–22.
47 - Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology. 2003:125:452–9.
48 - Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest. 2002:110:109–17.
49 - Marcil M, Brooks-Wilson A, Clee SM, et al. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet. 1999:354:1341–6.
50 - Grunhage F, Acalovschi M, Tirziu S, et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology. 2007:46:793–801.
51 - King RA, Rotter JI, Motulsky AG, The Genetic Basis of Common Diseases, 2nd ed. Oxford, NY: Oxford University Press, 2002.
52 - Wang DQ, Schmitz F, Kopin AS, Carey MC. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J Clin Invest. 2004:114:521–8.
53 - Bertomeu A, Ros E, Zambon D, et al. Apolipoprotein E polymorphism and gallstones. Gastroenterol. 1996:111:1603–10.
54 - Lohse P, Brewer HB, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res. 1992:33:1583–90.
55 - Srivastava A, Srivastava K, Choudhuri G, Mittal B, Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India. J Gastroenterol Hepatol. 2010:25:1758–62.
56 - Dixit M, Choudhuri G, Saxena R, Mittal B. Association of apolipoprotein A1-C3 gene cluster polymorphisms with gallstone disease. Can J Gastroenterol. 2007:21:569–75.
57 - Baez S, Tsuchiya Y, Calvo A, et al. Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women. World J Gastroenterol. 2010:16:372–8.
58 - Dixit D, Choudhuri G, Keshri LJ, Mittal B, Association of low density lipoprotein receptor related protein-associated protein (LRPAP1) gene insertion/deletion polymorphism with gallstone disease. J Gastroenterol Hepatol. 2006:21:847–9.
59 - Chen Q, Li WJ, Wan YY, Yu CD, Li W. Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population. Genet Mol Res. 2012:8:548–55.
60 - Srivastava A, Srivastava N, Choudhuri G, Mittal B, Organic anion transporter 1B1(SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CAgenotype in female patients in North India, Hepatol Res. 2011; 41: 71–8.
61 - Heeney MM, Howard TA, Zimmerman SA, Ware RE, UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia, J Lab Clin Med. 2003;141: 279–82.
62 - Chuang SC, Juo SH, His E, et al., Multiple mucin genes polymorphisms are associated with gallstone disease in Chinese men, Clin Chim Acta. 2011;412:599–603.
63 - Klass DM, Lauer N, Hay B, Kratzer W, Fuchs M. Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation. Am J Gastroenterol. 2007:102:2482–7.
64 - Kitsiou-Tzeli S, Giannatou E, Spanos I, et al. Steroid hormones polymorphisms and cholelithiasis in Greek population. Liver Int. 2007:27:61–8.
65 - Whary MT, Morgan TJ, Dangler CA, Gaudes KJ, Taylor NS, Fox JG. Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response. Infect Immun. 1998:66:3142–8.
66 - Lee SP, Carey MC, LaMont JT. Aspirin prevention of cholesterol gallstone formation in prairie dogs. Science. 1981:211:1429–31.
67 - Miquel JF, Nunez L, Rigotti A, Amigo L, Brandan E, Nervi F. Isolation and partial characterization of cholesterol pronucleating hydrophobic glycoproteins associated to native biliary vesicles. FEBS Lett. 1993:318:45–9.
68 - Abayli B, Colakoglu S, Serin M, Erdogan S, Isiksal YF, Tuncer I, Koksal F, Demiryurek H. Helicobacter pylori in the etiology of cholesterol gallstones. J Clin Gastroenterol. 2005:39:134–7.
69 - Fox JG. Other helicobacters involved in human diseases. Acta Gastroenterol Belg. 2002:65:24–32.
70 - Eaton KA, Mefford M, Thevenot T. The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice. J Immunol. 2001:166:7456–61.
71 - Harvey PR, Upadhya GA, Strasberg SM. Immunoglobulins as nucleating proteins in the gallbladder bile of patients with cholesterol gallstones. J Biol Chem. 1991:266:13996–4003.
72 - Huan P, Maosheng T, Zhiqian H, Long C, Xiaojun Y. TLR4 expression in normal gallbladder, chronic cholecystitis and gallbladder carcinoma. Hepatogastroenterol. 2012:59:42–6.
73 - Sawada S, Harada K, Isse K, Sato Y, Sasaki M, Kaizaki Y, Nakanuma Y. Involvement of Escherichia coli in pathogenesis of xanthogranulomatous cholecystitis with scavenger receptor class A and CXCL16-CXCR6 interaction. Pathol Int. 2007:57:652–63.