A Genomewide Search Finds Major Susceptibility Loci for Gallbladder Disease on Chromosome 1 in Mexican Americans
2006; Elsevier BV; Volume: 78; Issue: 3 Linguagem: Inglês
10.1086/500274
ISSN1537-6605
AutoresSobha Puppala, Gerald D. Dodd, Sharon P. Fowler, Rector Arya, Jennifer L. Schneider, Vidya S. Farook, Richard Granato, Thomas D. Dyer, Laura Almasy, Christopher P. Jenkinson, Andrew K. Diehl, Michael P. Stern, John Blangero, Ravindranath Duggirala,
Tópico(s)Phytase and its Applications
ResumoGallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0–5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD ⩾1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans. Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0–5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD ⩾1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans. Gallbladder disease (GBD) is a common, economically burdensome digestive disease in the United States (Sandler et al. Sandler et al., 2002Sandler RS Everhart JE Donowitz M Adams E Cronin K Goodman C Gemmen E Shah S Rubin R The burden of selected digestive diseases in the United States.Gastroenterology. 2002; 122: 1500-1511Abstract Full Text Full Text PDF PubMed Google Scholar). An estimated 20 million Americans are affected with GBD, and >700,000 cholecystectomies are performed every year (Hall and Lawrence Hall and Lawrence, 1998Hall MJ Lawrence L Ambulatory surgery in the United States: advance data from vital and health statistics. No 300. National Center for Health Statistics, Hyattsville, MD1998Google Scholar; Everhart et al. 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Weiss et al., 1984bWeiss KM Ferrell RE Hanis CL Styne PN Genetics and epidemiology of gallbladder disease in New World native peoples.Am J Hum Genet. 1984; 36: 1259-1278PubMed Google Scholar; Diehl and Stern Diehl and Stern, 1989Diehl AK Stern MP Special health problems of Mexican-Americans: obesity, gallbladder disease, diabetes mellitus, and cardiovascular disease.Adv Intern Med. 1989; 34: 73-96PubMed Google Scholar; Everhart et al. Everhart et al., 2002Everhart JE Yeh F Lee ET Hill MC Fabsitz R Howard BV Welty TK Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study.Hepatology. 2002; 35: 1507-1512Crossref PubMed Scopus (64) Google Scholar; Méndez-Sánchez et al. 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The significant risk factors associated with GBD are age, female sex, obesity (especially central obesity), lipids, diet, parity, type 2 diabetes (T2DM), medications, and Mexican American ethnicity (Diehl Diehl, 1991Diehl AK Epidemiology of natural history of gallstone disease.Gastroenterol Clin North Am. 1991; 20: 1-19PubMed Google Scholar; Hanis et al. Hanis et al., 1993Hanis CL Hewett-Emmeett D Kubrusly LF Makland MN Douglas TC Mueller WH Barton SA Yoshimaru H Kubrusly DB Gonzalez R Schull WJ An ultrasound survey of gallbladder disease among Mexican Americans in Starr County, Texas: frequencies and risk factors.Ethn Dis. 1993; 3: 32-43PubMed Google Scholar; Misciagna et al. Misciagna et al., 1996Misciagna G Leoci C Guerra V Chiloiro M Elba S Petruzzi J Mossa A Noviello MR Coviello A Minutolo MC Mangini V Messa C Cavallini A De Michele G Giorgio I Epidemiology of cholelithiasis in southern Italy. 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Sahi et al., 1998Sahi T Paffenbarger Jr, RS Hsieh CC Lee IM Body mass index, cigarette smoking, and other characteristics as predictors of self-reported, physician diagnosed gall bladder disease in male college alumni.Am J Epidemiol. 1998; 147: 644-651Crossref PubMed Google Scholar; Leitzmann et al. Leitzmann et al., 1999Leitzmann MF Rimm EB Willet WC Spiegelman D Grodstein F Stampfer MJ Colditz GA Recreational physical activity and the risk of cholycystectomy in women.N Engl J Med. 1999; 341: 777-784Crossref PubMed Scopus (107) Google Scholar). The association between diabetes and GBD is controversial; some have suggested that hyperinsulinemia rather than diabetes may play a major role in the etiology of GBD (Haffner et al. Haffner et al., 1993Haffner SM Diehl AK Valdez R Mitchell BD Hazuda HP Morales P Stern MP Clinical gallbladder disease in NIDDM subjects.Diabetes Care. 1993; 16: 1276-1284Crossref PubMed Google Scholar; Everhart Everhart, 1995Everhart JE Digestive diseases and diabetes.in: Diabetes in America. 2nd ed. NIH publication no. 95-1468. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda1995: 457-483Google Scholar; Diehl Diehl, 2000Diehl AK Cholelithiasis and the insulin resistance syndrome.Hepatology. 2000; 31: 528-530Crossref PubMed Google Scholar; Ruhl and Everhart Ruhl and Everhart, 2000Ruhl CE Everhart JE Association of diabetes, serum insulin, and C-peptide with gallbladder disease.Hepatology. 2000; 31: 299-303Crossref PubMed Google Scholar). Also, it has been shown that duration of diabetes and blood sugar control are associated with impaired gallbladder function (Haffner et al. 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Factors such as hypersecretion of hepatic cholesterol, supersaturation of bile with cholesterol, cholesterol crystal nucleation time, and hypomotility of the gallbladder appear to influence the formation of gallstones (Pomeranz and Shaffer Pomeranz and Shaffer, 1985Pomeranz IS Shaffer EA Abnormal gallbladder emptying in a subgroup of patients with gallstone.Gastroenterology. 1985; 88: 787-791Abstract PubMed Google Scholar; Carey Carey, 1993Carey MC Pathogenesis of gallstones.Am J Surg. 1993; 165: 410-419Abstract Full Text PDF PubMed Google Scholar; Portincasa et al. Portincasa et al., 1995Portincasa P Stolk MFJ van Erpecum KJ Palasciano G van Berge-Henegouwen GP Cholesterol gallstone formation in man and potential treatments of the gallbladder motility defect.Scand J Gastroenterol Suppl. 1995; 212: 63-78Crossref PubMed Google Scholar; Méndez-Sánchez et al. 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Thus, the pathobiological mechanisms that underlie the phenotypic expression of GBD appear to be rather complex, and one or more defects could occur in genes that play critical roles in the diverse pathways leading to cholesterol gallstone formation. It is generally thought that GBD is a complex, multifactorial disease influenced by genetic and environmental factors and their interactions. The available information based on family data, albeit limited, suggests that genetic factors play a key role in the development of GBD (Kesaniemi et al Kesaniemi et al., 1989Kesaniemi YA Koskenvuo M Vuoristo Mittinen TA Biliary lipid composition in monozygotic and dizygotic pairs of twins.Gut. 1989; 30: 1750-1756Crossref PubMed Google Scholar; Sarin et al. Sarin et al., 1995Sarin SK Negi VS Dewan R Sasan S Saraya A High familial prevalence of gallstones in the first-degree relatives of gallstone patients.Hepatology. 1995; 22: 138-141PubMed Google Scholar; Duggirala et al. Duggirala et al., 1999bDuggirala R Mitchell BD Blangero J Stern MP Genetic determinants of variation in gallbladder disease in the Mexican-American population.Genet Epidemiol. 1999; 16: 191-204Crossref PubMed Scopus (36) Google Scholar; Nakeeb et al. Nakeeb et al., 2002Nakeeb A Comuzzie AG Martin L Sonnenberg GE Swartz-Basile D Kissebah AH Pitt HA Gallstones: genetics versus environment.Ann Surg. 2002; 235: 842-849Crossref PubMed Scopus (99) Google Scholar; Kosters et al. Kosters et al., 2003Kosters A Jirsa M Groen AK Genetic background of cholesterol gallstone disease.Biochim Biophys Acta. 2003; 1637: 1-19Crossref PubMed Scopus (31) Google Scholar). Using data from a large Swedish study of 43,141 twin pairs, Katsika et al. (Katsika et al., 2005Katsika D Grijbovski A Einarsson C Lammert F Lichtenstein P Marschall H-U Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs.Hepatology. 2005; 41: 1138-1143Crossref PubMed Scopus (113) Google Scholar) determined that genetic influences are major contributors to the variation in symptomatic gallstone disease. According to this study, genetic factors accounted for 25%, shared environmental factors for 13%, and unique environmental factors for 62% of the phenotypic variance among twins. In addition, varying prevalence on the basis of ethnicity has been considered to be indirect evidence of the genetic determination of GBD (Weiss et al. Weiss et al., 1984bWeiss KM Ferrell RE Hanis CL Styne PN Genetics and epidemiology of gallbladder disease in New World native peoples.Am J Hum Genet. 1984; 36: 1259-1278PubMed Google Scholar; Diehl and Stern Diehl and Stern, 1989Diehl AK Stern MP Special health problems of Mexican-Americans: obesity, gallbladder disease, diabetes mellitus, and cardiovascular disease.Adv Intern Med. 1989; 34: 73-96PubMed Google Scholar; Everhart et al. Everhart et al., 2002Everhart JE Yeh F Lee ET Hill MC Fabsitz R Howard BV Welty TK Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study.Hepatology. 2002; 35: 1507-1512Crossref PubMed Scopus (64) Google Scholar; Paigen and Carey Paigen and Carey, 2002Paigen B Carey MC Gallstones.in: King RA Rotter JI Motulsky AG The genetic basis of common diseases. 2nd ed. Oxford University Press, Oxford, United Kingdom2002: 298-335Google Scholar; Méndez-Sánchez et al. Méndez-Sánchez et al., 2004Méndez-Sánchez N King-Martinez AC Ramos MH Pichardo-Bahena R Uribe M The Amerindian's genes in the Mexican population are associated with development of gallstone disease.Am J Gastroenterol. 2004; 99: 2166-2170Crossref PubMed Scopus (23) Google Scholar). In fact, Weiss et al. (Weiss et al., 1984aWeiss KM Ferrell RE Hanis CL A New World syndrome of metabolic diseases with genetic and evolutionary basis.Yearbook Phys Anthropol. 1984; 27: 153-178Crossref Google Scholar) proposed that there might be a genetic susceptibility association among complex diseases such as GBD, diabetes, and obesity, which cluster to form a “New World Syndrome” in populations with Native American ancestry. Aside from these observations in human populations, several mouse models identified various Lith (i.e., lithogenic) loci influencing gallstone formation (Khanuja et al. Khanuja et al., 1995Khanuja B Cheah YC Hunt M Nishina PM Wang DQ Chen HW Billheimer JT Carey MC Paigen B Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.Proc Natl Acad Sci USA. 1995; 92: 7729-7733Crossref PubMed Scopus (154) Google Scholar; Paigen et al. Paigen et al., 2000Paigen B Schork NJ Svenson KL Cheah YC Mu JL Lammert F Wang DQ Bouchard G Carey MC Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice.Physiol Genomics. 2000; 4: 59-65Crossref PubMed Google Scholar; Lammert et al. Lammert et al., 2001Lammert F Carey MC Paigen B Chromosomal organization of candidate genes involved in cholesterol gallstone formation: a murine gallstone map.Gastroenterology. 2001; 120: 221-238Abstract Full Text Full Text PDF PubMed Google Scholar; Hillebrandt et al. 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Lyons et al., 2003Lyons MA Wittenburg H Li R Walsh KA Leonard MR Churchill GA Carey MC Paigen B New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice.Physiol Genomics. 2003; 14: 225-239PubMed Google Scholar, Lyons et al., 2005Lyons MA Korstanje R Li R Sheehan SM Walsh KA Rollins JA Carey MC Paigen B Churchill GA Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM.Mamm Genome. 2005; 16: 152-163Crossref PubMed Scopus (18) Google Scholar). Major susceptibility loci for GBD in human populations have not yet been identified. Therefore, we conducted a genetic epidemiologic investigation of GBD, using data from complex Mexican American families, as part of the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). Using a 10-cM map and ultrasound-based information on GBD occurrence, we employed a variance-components linkage technique, using a liability model to map susceptibility genes for GBD in the Mexican American population. Demographic and other phenotypic information was collected from 741 individuals drawn from 39 large Mexican American families that were enrolled in the San Antonio Family Gallbladder Study (SAFGS), a follow-up and extension of the San Antonio Family Diabetes Study (SAFDS). These studies are collectively referred to as the SAFDGS. The recruitment for the SAFGS was conducted between 1998 and 2001. Of these 741 individuals, 476 had been examined previously at baseline and/or follow-up in the SAFDS and were members of the 31 original SAFDS families (Duggirala et al. Duggirala et al., 1999aDuggirala R Blangero J Almasy L Dyer TD Williams KL Leach RJ O'Connell P Stern MP Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.Am J Hum Genet. 1999; 64: 1127-1140Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholara,Duggirala et al., 2001Duggirala R Blangero J Almasy L Arya R Dyer TD Williams KL Leach RJ O'Connell P Stern MP A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans.Am J Hum Genet. 2001; 68: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). An additional 265 individuals were recruited into the SAFGS; of these, 152 participants were newly recruited members of the original 31 SAFDS families, and 113 were members of 8 newly recruited SAFGS families. Recruitment of the new SAFGS families followed the same guidelines as were used originally in the SAFDS recruitment (Duggirala et al. Duggirala et al., 1999aDuggirala R Blangero J Almasy L Dyer TD Williams KL Leach RJ O'Connell P Stern MP Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.Am J Hum Genet. 1999; 64: 1127-1140Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Probands were recruited from a random sample of low-income Mexican American individuals who had been identified in the earlier San Antonio Heart Study as having T2DM. All of the probands' first-, second-, and third-degree relatives aged ⩾18 years were invited to participate in the study. Of the total 646 individuals who had taken part in the earlier SAFDS examinations, 54 died before SAFGS recruitment began. Of the 592 SAFDS survivors, 476 (∼80%) individuals participated in the present project. The Institutional Review Board of the University of Texas Health Science Center at San Antonio approved all procedures, and all subjects gave written informed consent. For each individual, a detailed medical history of previous gallbladder problems, including cholecystectomy, was obtained. Ultrasound examinations were conducted at the Frederic C. Bartter General Clinical Research Center (GCRC), South Texas Veterans Healthcare System, Audie L. Murphy Division, in San Antonio. Ultrasound is widely regarded as the test of choice for screening for gallstones because of its high sensitivity and specificity in detecting gallstones (Rosenthal et al. Rosenthal et al., 1994Rosenthal TC Siepel T Zubler J Horwitz M The use of ultrasonography to scan the abdomen of patients presenting for routine physical examinations.J Fam Pract. 1994; 38: 380-385PubMed Google Scholar). Each participant was asked to fast for a minimum of 12 h before the ultrasound scan. Gallbladder ultrasonograms were obtained using the GCRC's ATL 3000 ultrasound imaging unit (3.5 or 5.0 MHz transducer frequencies). Each ultrasonogram was performed by one of three technicians trained in screening gallbladder ultrasound, under supervision by an experienced radiologist. In each examination, the protocol included videotaped documentation of the gallbladder viewed in longitudinal and/or transverse views. Each view was obtained in supine and lateral positions, with both subcostal and intercostal approaches. To verify the technicians' work as part of ongoing quality control, ∼20% of the sonograms were chosen for review and verification by the radiologist. A participant was classified as having gallstones when one of the following three diagnostic criteria had been fulfilled: (1) gallbladder lumen with mobile nodular or dependent layering echoes that exhibited posterior acoustic shadowing, (2) gallbladder with hyperechoic shadowing material filling the gallbladder lumen with an appearance of the WES triad (i.e., the gallbladder wall, the echo of the stone, and the acoustic shadow—a specific ultrasonographic sign of gallstones used to make a reliable diagnosis of cholelithiasis [MacDonald et al. MacDonald et al., 1981MacDonald FR Cooperberg PL Cohen MM The WES triad: a specific sonographic sign of gallstones in the contracted gallbladder.Gastrointest Radiol. 1981; 6: 39-41Crossref PubMed Google Scholar; Rybicki Rybicki, 2000Rybicki FJ The WES sign.Radiology. 2000; 214: 881-882Crossref PubMed Google Scholar]), or (3) a history of cholecystectomy with no gallbladder lumen but with a scar consistent with a history of cholecystectomy. When the gallbladder lumen was found to have no echoes, the subject was considered unaffected. Because the reasons for cholecystectomy of 14 individuals were found to be ambiguous, we obtained medical records of these individuals for review by two physicians, to determine the indications for surgery. Of the 14 cases reviewed, GBD status was determined for 9 individuals. Individuals with cholecystectomies in the absence of gallstones were considered unaffected. Of the 741 examined individuals, the GBD status of 8 individuals was indeterminable either because of a lack of documentation about whether prior cholecystectomy had been due to stones or because of the uncertainty of the current diagnosis of stones. Hence, their phenotypes were considered to be unknown. The pedigree data used for this study, however, contained 715 individuals with GBD data available, because 18 unrelated individuals (mainly spouses) were excluded from the analyses. Two GBD phenotypes were defined for the analyses: (1) clinical GBD, the cases in which participants self-reported cholecystectomies due to symptomatic stones and the cholecystectomy was subsequently confirmed by ultrasound at the time of the study examination, and (2) total GBD, the clinically diagnosed cases plus asymptomatic persons found to have gallstones on ultrasound. For the SAFGS, a variety of metabolic, hemodynamic, anthropometric, and demographic variables were collected, by use of standard procedures, at the GCRC Laboratory. Blood samples were obtained after 12-h fasts, for the assessment of various metabolic traits, including fasting glucose concentrations, and they were collected again 2 h after a standardized oral glucose load, for the assessment of plasma glucose. T2DM was diagnosed in accordance with the 1999 criteria of the World Health Organization (World Health Organization World Health Organization, 1999World Health Organization Definition, diagnosis and classification of diabetes
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