Prevalence of gallbladder disease in American Indian populations: Findings from the Strong Heart Study

Prevalence of Gallbladder Disease in American Indian Populations: Findings From the Strong Heart Study James E. Everhart,1 Fawn Yeh,2 Elisa T. Lee,2 Michael C. Hill,3 Richard Fabsitz,4 Barbara V. Howard,5 and Thomas K. Welty6 American Indians are believed to be at high risk of gallbladder disease (GBD), but there has been no systematic evaluation of its prevalence among diverse groups of American Indians. Therefore, we determined the prevalence of GBD and associated risk factors among specified American Indian populations using ultrasonography of the gallbladder and standardized diagnostic criteria. Enrolled members, aged 47 years and older, of 13 American Indian tribes or communities in Arizona, Oklahoma, and South and North Dakota who participated in the Strong Heart Study were analyzed. GBD was the sum of gallstones (determined by ultrasound examination) and cholecystectomy (determined by ultrasound and self-report). The proportion of American Indian heritage was based on the heritage of the grandparents of participants. GBD prevalence was determined among 3,296 participants at the 3 sites. Among women, 17.8% had gallstones, and 46.3% had evidence of a cholecystectomy, for a total of 64.1% with GBD. Among men, 17.4% had gallstones, and 12.1% had evidence of a cholecystectomy, for a total of 29.5% with GBD. When figures were adjusted for age and Indian heritage, there was no significant difference in GBD prevalence across the 3 geographical areas. In multivariate logistic regression analysis, age, American Indian heritage, and waist circumference were associated with GBD among men, and age, American Indian heritage, diabetes, and parity were associated with GBD among women. Body mass index was not independently associated with GBD in either sex. In conclusion, GBD was found in epidemic proportions in diverse American Indian populations. (HEPATOLOGY 2002;35: 1507-1512.)

T

he prevalence of gallbladder disease (GBD) varies widely among racial and ethnic groups.1 It is generally believed that American Indians have the highest prevalence in the world, with as many as 50% of men and 80% of women affected.2 This conclusion, how-

Abbreviations: GBD, gallbladder disease; BMI, body mass index. From the 1National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; 2University of Oklahoma, Oklahoma City, OK; 3George Washington University, Washington, DC; 4National Heart, Lung, and Blood Institute, Bethesda, MD; 5MedStar Research Institute, Washington, DC; and 6Aberdeen Area Tribal Chairmen’s Health Board, Rapid City, SD. Received January 17, 2002; accepted March 4, 2002. Supported by cooperative agreements U01-HL41642, U01-HL41652, and U01-HL41654 from the National Heart, Lung, and Blood Institute with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center on Minority Health and Health Disparities (formerly Office of Research on Minority Health). Address reprint requests to: James Everhart, M.D., M.P.H., Chief, Epidemiology and Clinical Trials Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, 2 Democracy Plaza, Room 655, 6707 Democracy Boulevard MSC 5450, Bethesda, MD 20892-5450. E-mail: [email protected]; fax: 301-480-8300. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3506-0026$35.00/0 doi:10.1053/jhep.2002.33336

ever, has been drawn from relatively small studies performed decades ago without taking tribal diversity into account. These studies included an oral cholesystographic study of Pima Indians of Arizona in the late 1960s as well as small studies among the Chippewas, Micmacs, and Cree-Ojibwas.2-5 No multicenter ultrasonographic study of gallstone-related GBD has been performed among American Indians. The current study was conducted by using a common protocol to determine the extent of GBD among diverse groups of American Indians and to examine other factors associated with GBD.

Patients and Methods The study of GBD disease was carried out as part of the Strong Heart Study, a longitudinal study that began in 1989 of cardiovascular disease and its risk factors among members aged 45 years and older of 13 Indian tribes and communities.6,7 Participating tribes were the Pima, Maricopa, and T’ohono O’otham of central Arizona who live in the Gila River Indian Community, the Salt River Indian Community, and the Ak-Chin Indian Community, respectively; the 7 tribes of southwestern Oklahoma, 1507

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Fig. 1. Participating American Indian communities in the Strong Heart Study.

Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita; and the Oglala Sioux Tribe on the Pine Ridge Reservation, the Cheyenne River Sioux Tribe in the Eagle Butte area of South Dakota, and the Spirit Lake Tribe in the Fort Totten area of North Dakota (Fig. 1). The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the appropriate institutional review committees, the Indian Health Service, and the tribes. It was performed with the subjects’ informed, written consent. All participants and their medical care providers were notified of the results of their ultrasound studies, and those with gallstones were advised to seek medical evaluation. During the second round of examinations, between 1993 and 1995, echocardiography of the heart was performed to examine ventricular wall thickness and function.8 By using the same equipment (Acuson 128; Acuson, Inc., Mountain View, CA), gallbladder ultrasonography was performed after an overnight fast. The examinations were performed by registered sonographers, with the patient in both the supine and the left lateral decubitus positions. In South Dakota, all participants underwent the ultrasonography, whereas, in Arizona and Oklahoma, ultrasonography was performed only on participants who had not had cholecystectomy. Cholecystectomy was based on self-report or findings of an appropriate surgical scar and absent gallbladder on ultrasound. A medical records review of 25 participants who reported gallbladder surgery found that all had undergone cholecystectomy. All ultrasounds were videotaped and read by a radiologist specializing in abdominal ultrasound using the same criteria of intraluminal echoes with shadowing on 2 views as used in the third National Health and Nutrition Examination Survey (NHANES).9,10 Among 3,638 participants eligible for the examination, GBD data were obtained from 90.6%, or 3,296.

Reasons for insufficient GBD information were no interview (n ⫽ 206), interview but no examination (n ⫽ 22), poor-quality ultrasound (n ⫽ 5), and inability to find the gallbladder on ultrasound and no other evidence of gallbladder surgery (n ⫽ 109). Relative to the group with insufficient data, participants with GBD data were younger (59.9 vs. 61.6 years, P ⫽ .0001), were less likely to have full-Indian heritage (70.3% vs. 76.9%, P ⫽ .001), and had lower average body mass index (BMI; 31.1 kg/m2 vs. 32.0 kg/m2; P ⫽ .04), average waist circumference (106.3 cm vs. 108.8 cm, P ⫽ .01), and diabetes mellitus prevalence (54.5% vs. 63.3%; P ⫽ .003). Parity was similar between women with (n ⫽ 2,045) and without (n ⫽ 209) sufficient GBD information (mean 5.0 live births vs. 5.1 live births; P ⫽ 0.57). American Indian heritage was based on self-report according to the heritage of the grandparents. Self-reported American Indian heritage has been independently validated against genetic markers.11 Thirty percent of participants had less than full heritage, but only 7.4% reported less than 50% American Indian heritage. BMI equaled weight in kilograms divided by the square of height in meters. Waist circumference was measured at the level of the umbilicus while the participant was supine. Diabetes status was determined by World Health Organization criteria using a 2-hour, 75-g oral glucose tolerance test performed on all except for persons with known diabetes receiving hypoglycemic agents.12 The proportion with GBD was the sum of the proportion with gallstones and the proportion with cholecystectomy. Age-standardized results were computed by the direct method using the age distribution of the 1990 U.S. census population as the standard. Weighted analyses were used to compare age-standardized rates.13,14 Multivariate adjusted odds ratios for GBD were determined

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Table 1. Characteristics of Strong Heart Study Participants Dakotas

Women n ⫽ 634 Mean age (y) 60.0 ⬍75% Indian heritage (%) 33.1 75%-99% Indian heritage (%) 21.3 100% Indian heritage (%) 45.6 30.8 Mean body mass index (kg/m2) Mean waist circumference (cm) 104.4 Impaired glucose tolerance (%) 17.6 Diabetes (%) 51.9 Mean parity 5.5 Men n ⫽ 436 Mean age (y) 59.5 ⬍75% Indian heritage (%) 36.9 75%-99% Indian heritage (%) 18.8 100% Indian heritage (%) 44.3 Mean body mass index (kg/m2) 28.7 Mean waist circumference (cm) 101.5 Impaired glucose tolerance (%) 15.9 Diabetes (%) 35.0

Arizona Oklahoma

n ⫽ 713 59.8 2.7 3.9 93.4* 33.3* 112.9* 12.6 77.2* 5.2 n ⫽ 346 58.3* 3.2 4.0 92.8* 30.6* 104.6 12.4 67.9*

All Sites

n ⫽ 698 n ⫽ 2,045 60.9*† 60.2 19.9 18.0 6.5 10.2 73.6*† 71.8 31.4† 31.9 105.9† 107.9 18.3 16.1 48.8† 59.6 4.4*† 5.0 n ⫽ 469 n ⫽ 1,251 59.8† 59.3 22.8 22.3 5.8 9.8 71.4*† 67.9 30.5* 29.9 105.5* 103.8 15.1 14.7 41.1† 46.3

*Significantly different (P ⬍ .05) from Dakotas. †Significantly different (P ⬍ .05) from Arizona.

from logistic regression analyses. All statistical comparisons were derived with SAS.15

Results In total 3,296 participants were examined: 1,059 in Arizona, 1,116 in Oklahoma, and 1,070 in South and North Dakota. Potential risk factors differed across the sites (Table 1). Arizona participants had higher BMI and were more likely to have diabetes and full-Indian heritage (P ⬍ .005) than participants at the other sites. The prevalence of gallstones, cholecystectomy, and GBD is shown according to sex and geographic area in Table 2. The prevalence of GBD among women was about twice the prevalence among men at each site. Women with GBD were more likely to have had cholecystectomy than men with GBD (72.2% vs. 41.0%). More than half of the

Table 2. Prevalence (%) of Gallstones, Cholecystectomies, and Gallbladder Disease by Sex and Examination Site Among American Indians Women Gallstones Cholecystectomy Gallbladder disease 95% Confidence interval Men Gallstones Cholecystectomy Gallbladder disease 95% Confidence interval

Dakotas

Arizona

Oklahoma

All Sites

19.1 40.4 59.5 55.6-63.3

18.0 50.2 68.2 64.7-71.6

16.5 47.6 64.0 60.5-67.6

17.8 46.3 64.1 62.0-66.1

15.1 10.3 25.5 21.4-29.5

19.7 11.3 30.9 26.1-35.8

17.9 14.3 32.2 28.0-36.4

17.4 12.1 29.5 27.0-32.0

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Table 3. Age-Specific and Age-Standardized Prevalence (%) of Gallbladder Disease by Examination Site Among Women Age (y) 47-54 55-64 65 And older Age-standardized prevalence (overall) Indian heritage (%) ⬍75% 75-99% 100% Body mass index quartile 1 2 3 4 Waist circumference quartile 1 2 3 4 Glucose tolerance Normal Impaired Diabetes Parity 0 1-4 5-6 7 Or more

Dakotas

Arizona

Oklahoma

All Sites

50.5 60.0 69.6*

61.5 68.5 76.1*

50.8 65.0 74.6*

54.7 64.7 73.6*

61.3†

69.7

64.9

65.6

41.2 67.0‡ 73.9‡

54.0 71.9 70.3

45.9 61.2 70.5‡

43.7 66.3‡ 71.2‡

50.0 60.9 67.5‡ 71.7‡

72.7 64.1 70.7 69.4

61.3 60.3 67.8 70.2

60.5 61.6 69.1‡ 70.3‡

46.0 60.4‡ 68.6‡ 75.3‡

69.5 72.9 67.9 68.2

60.7 62.8 63.2 71.9

57.5 65.3 66.6‡ 71.2‡

42.8 66.1‡ 70.5‡

60.2 69.4 69.8

58.6 52.1 71.4‡

52.6 61.8 70.8‡

54.9 54.6 54.9 71.3

77.7 68.2 69.1 70.6

59.5 59.7 75.1 72.0

66.8 60.8 67.3 71.3

*P ⬍ 0.05 for test for trend across age groups. †Age-standardized prevalence significantly different (P ⬍ .05) from Arizona. ‡Age-standardized prevalence significantly different (P ⬍ .05) from lowest level (Indian heritage ⬍ 75%, first body mass index quartile, first waist circumference quartile, or normal glucose tolerance).

women aged 65 years and older (55.7%) had had cholecystectomy. GBD prevalence increased with age at each examination site (Tables 3 and 4). The highest prevalence of GBD was 76.1% found among Arizona women aged 65 years and older. Sixty percent of these women had had a cholecystectomy. Among women, the age-standardized prevalence of GBD was lower in the Dakotas than in Arizona (P ⫽ .001) but not Oklahoma (P ⫽ .18). In considering all sites together, GBD prevalence was higher with fullIndian heritage, with increasing BMI and waist circumference, and with diabetes. Among men, the agestandardized prevalence of GBD was lower in the Dakotas than in both Arizona (P ⫽ .03) and Oklahoma (P ⫽ .04). GBD prevalence was higher with full Indian heritage and diabetes. In multivariate logistic regression analysis, there were no differences in GBD across the geographic regions (Table 5). Older women and men and those with full-Indian heritage had substantially higher odds of GBD. There was

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Table 4. Age-Specific and Age-Standardized Prevalence of Gallbladder Disease (%) by Examination Site Among Men Age (y) 47-54 55-64 65 And older Age-standardized prevalence (overall) Indian heritage (%) ⬍75% 75-99% 100% Body mass index quartile 1 2 3 4 Waist circumference quartile 1 2 3 4 Glucose tolerance Normal Impaired Diabetes

Dakotas

Arizona

Oklahoma

All Sites

12.2 26.8 41.3*

27.3 25.8 46.7*

19.6 34.7 44.6*

19.6 29.4 43.9*

26.9†

33.9

32.9

31.2

18.0 21.7 34.9‡

5.1 21.3 34.6‡

18.4 24.6 38.2‡

18.0 22.7 36.3‡

27.1 23.1 26.1 34.2

28.1 35.6 31.4 37.5

31.1 40.6 34.1 25.8

28.7 32.6 30.7 31.0

22.6 26.0 26.8 36.7

28.3 39.0 30.7 34.6

33.8 33.6 29.7 34.4

27.6 31.7 29.2 35.8

21.8 22.9 35.0‡

27.6 31.7 37.4

32.4 43.0 31.9

26.8 32.9 34.8‡

*P ⬍ .05 for test for trend across age groups. †Age-standardized prevalence significantly different (P ⬍ .05) from Arizona and Oklahoma. ‡Age-standardized prevalence significantly different (P ⬍ .05) from lowest level (Indian heritage ⬍75% or normal glucose tolerance).

a stepwise increase in the odds of GBD with increasing Indian heritage. Among other potential risk factors, diabetes and parity showed a statistically significant relationship among women. Waist circumference was statistically significant among men, and diabetes was of borderline statistical significance. Because BMI and waist circumference are highly correlated, separate multivariate analyses were also performed that included one variable but not the other. Among women, both BMI (odds ratio ⫽ 1.02; 95% confidence interval ⫽ 1.01-1.04) and waist circumference (odds ratio ⫽ 1.01; 95% confidence interval ⫽ 1.00-1.02) were associated with GBD. Among men, BMI was not associated with GBD (odds ratio ⫽ 0.97; 95% confidence interval ⫽ 0.91-1.03), but waist circumference was associated (odds ratio ⫽ 1.01; 95% confidence interval ⫽ 1.00-1.02).

Discussion By using current diagnostic techniques, this study confirmed that American Indians have a remarkably high risk of GBD. The actual prevalence in these populations might be slightly higher, because the 10% of participants who did not have adequate GBD information had a risk profile of greater age, Indian admixture, waist circumfer-

ence, and diabetes that favored the condition. The most thorough previous examination of the prevalence of GBD in an American Indian community was among Pima Indians more than 25 years prior to the Strong Heart Study examinations. By using oral cholecystography, the prevalence of GBD among the Pima Indians aged 45 years and over was 56% for men and 76% for women.2 This prevalence was higher than that found in comparable age groups in the current study, particularly among men, but it was based on a much smaller sample size (310 persons). Thus, the prevalence of GBD among American Indians in this area of Arizona has been documented to be quite high over a period of nearly 3 decades. Although the Arizona sites had slightly higher ageadjusted prevalence, both the Oklahoma and the Dakota sites also had higher prevalence of GBD than any other population-based ultrasound study in any area of the world. The only closely comparable prevalence was in a study in Chile of Mapuche Indians, which found nearly a 50% prevalence of GBD among the native Mapuche Indian women but a prevalence of only 13% among men.16 American Indians may be at high risk of GBD because of a genetic predisposition common to persons with a shared heritage. Older studies found a high prevalence of GBD among American Indians but did not examine the extent to which American Indian ancestry influenced the risk of GBD. The current study directly supports a genetic influence on the risk of GBD by finding an increased risk of GBD among full-heritage American Indians while simultaneously controlling for other potentially explanatory factors. Importantly, this increased risk was found across 3 geographically and culturally diverse regions. The risk also increased in a stepwise fashion with increasing Indian heritage. The exact non-Indian admixture is un-

Table 5. Odds Ratios (95% Confidence Intervals) for Gallbladder Disease Among Men and Women Age (per 10 y) Examination site Dakotas Oklahoma Arizona Indian heritage (%) ⬍75% 75-99% 100% BMI (per kg/m2) Waist circumference (per cm) Glucose tolerance Normal Impaired Diabetes Parity (per child)

Women

Men

1.54 (1.35-1.75)

1.81 (1.54-2.14)

1 1.00 (0.78-1.28) 0.84 (0.64-1.10)

1 1.10 (0.80-1.51) 0.94 (0.65-1.34)

1 1.99 (1.39-2.87) 3.04 (2.32-3.99) 1.01 (0.98-1.04) 1.01 (0.99-1.02)

1 1.27 (0.73-2.19) 2.34 (1.62-3.39) 0.97 (0.91-1.03) 1.02 (1.00-1.05)

1 0.96 (0.71-1.29) 1.43 (1.14-1.80) 1.04 (1.00-1.08)

1 1.32 (0.89-1.96) 1.29 (0.96-1.72) —

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certain across the diverse Indian communities that participated in the Strong Heart Study. In one of the participating communities, the predominant non-Indian admixture was believed to be Mexican-American and European.17 The precise sources of genetic admixture may not be important, because the prevalence of GBD was quite similar at the 3 sites within each stratum of American Indian heritage. Thus, the increased risk of GBD among American Indians appears to be a consistent finding not limited to a small group of related tribes or a single region. Although the current study suggests that genetic susceptibility to GBD is increased among American Indians, we are not aware that human susceptibility genes for GBD have been identified. Nevertheless, inbred and gene-deleted mice have provided promising avenues for genetic investigation in humans.18-20 Genetic studies of GBD might be particularly appropriate among American Indians. Homogeneity of stone type (predominantly cholesterol stones21) and shared community environments would facilitate genetic studies. Most importantly, because of the high risk of GBD among American Indians, identification of genetic determinants potentially would directly benefit these populations. With regard to potential mechanisms for the high rate of gallstone formation among American Indians, studies from the 1970s found that young Pima Indians without gallstones had high biliary secretion of cholesterol without a compensatory increased secretion of bile acids. Hence, bile was supersaturated with cholesterol.21,22 In a different population with normal cholecystograms, more lithogenic bile was found among American Indian women than among white women.23 Studies of bile nucleation time and gallbladder motility have not been conducted among American Indians. Thus, considerable research opportunities exist among American Indians for understanding gallstone pathogenesis. As shown by the high prevalence across diverse groups in this study, these opportunities are not limited to American Indians in one area. An effect of American Indian genetic admixture has been inferred from studies of Hispanic Americans. Hispanic women of mixed heritage have a prevalence of GBD between the high prevalence found in the current study and the prevalence among non-Hispanic whites.10,16 However, increased risk with increasing American Indian genetic admixture has not previously been shown among men. In the third National Health and Nutrition Examination Survey, Mexican American and non-Hispanic white men had nearly the same prevalence of GBD, both before and after adjusting for numerous risk factors.10 In Chile, middle-aged Mapuche Indian men had the same prevalence of GBD as Hispanic men in Santiago, Chile.16

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Thus, the current study is the first population-based study that has shown an association in men of American Indian admixture with GBD risk. Risk factors other than genetic admixture were also of interest. In women, BMI and waist circumference were associated with GBD in age-adjusted but not multivariate analysis. However, these variables are highly correlated, and multivariate analysis that included one but not the other showed that each was associated with GBD. In men, BMI was not associated in either age-adjusted or multivariate analysis. In contrast, waist circumference was associated with GBD in multivariate analyses. These findings are consistent with a recent analysis of anthropometric associations with GBD in the U.S. population, in which waist to hip circumference was associated with GBD.24 As in other studies, BMI was found to have a stronger association with GBD in women than in men.10,25-28 As regards other risk factors, women with GBD were more likely to have diabetes and increased parity than women without GBD. Because the prevalence of both factors was high, these factors may be important determinants of the high prevalence of GBD in these populations. Because the Strong Heart Study did not include persons younger than age 45 years, there are limitations in possible inferences about the occurrence of GBD in these populations. Although the prevalence of GBD by middle age was similar across the study sites, we do not know the risk at younger ages. Because the age of onset of GBD was unknown, identifying risk factors is problematic. For example, BMI and glucose tolerance status were unknown at the time of gallstone occurrence. This study showed that GBD remains a highly prevalent condition and, therefore, a significant public health problem among American Indians. More than half of middle-aged and older men and women had GBD, and 3 of 5 persons with GBD had had a cholecystectomy. Whereas it can be presumed from this study that the risk of GBD is inherently high among American Indians, there are likely to be environmental influences that increase the risk of the disease. Furthermore, gallstones are the major identified risk factor for gallbladder cancer, and American Indians have the highest reported rates of gallbladder cancer of any ethnic group in the United States and one of the highest reported rates in the world.29,30 Further research into the identification of both the genetic and the environmental influences may be fruitful in populations that have such a high risk of disease. Acknowledgment: The authors acknowledge the assistance and cooperation of the participating tribes and the Indian Health Service facilities that serve those tribes. The

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authors also thank the study participants, the Directors of SHS clinics, Betty Jarvis, Martha Stoddart, Beverly Price, Marcia O’Leary, Dr. Tauqeer Ali, Alan Crawford and their staffs, and Dr. Tauqeer Ali, Helen Beaty, Joan Carter, Michael Cyl, and Neil Sikes for performance of the ultrasound studies. The opinions expressed in this report are those of the authors and not necessarily those of the Indian Health Service.

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14. Carriere KC, Roos LL. Comparing standardized rates of events. Am J Epidemiol 1994;140:472-482. 15. SAS Institiute Inc. SAS/STAT User’s Guide, Version 6, 4th ed. Cary, NC: SAS Institute Inc., 1989. 16. Miquel JF, Covarrubias C, Villaroel L, Mingrone G, Greco AV, Puglielli L, Carvallo P, et al. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 1998;115:937-946. 17. Williams RC, Knowler WC, Pettitt DJ, Long JC, Rokala DA, Polesky HF, Hackenberg RA, et al. The magnitude and origin of European-American admixture in the Gila River Indian Community of Arizona: a union of genetics and demography. Am J Hum Genet 1992;51:101-110. 18. Zanlungo S, Nervi F. The ACAT2 gene encodes a gatekeeper of intestinal cholesterol absorption that regulates cholesterolemia and gallstone disease. HEPATOLOGY 2001;33:760-761. 19. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000;6:1341-1347. 20. Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation: a murine gallstone map. Gastroenterology 2001;120:221-238. 21. Bennion LJ, Grundy SM. Risk factors for the development of cholelithiasis in man (first of two parts). N Engl J Med 1978;299: 1161-1167. 22. Bennion LJ, Knowler WC, Mott DM, Spagnola AM, Bennett PH. Development of lithogenic bile during puberty in Pima Indians. N Engl J Med 1979;300:873-876. 23. Thistle JL, Schoenfield LJ. Lithogenic bile among young Indian women. N Engl J Med 1971;284:177-181. 24. Ruhl CE, Everhart JE. Relationship of serum leptin concentration and other measures of adiposity with gallbladder disease. HEPATOLOGY 2001;34:877-883. 25. Rome group for the epidemiology and prevention of cholelithiasis (GREPCO). The epidemiology of gallstone disease in Rome, Italy: part I: prevalence data in men. HEPATOLOGY 1988;8:904906. 26. Barbara L, Sama C, Labate AMM, Taroni F, Rustucali AG, Festi D, Sapio C, et al. A population study on the prevalence of gallstone disease: the Sirmione study. HEPATOLOGY 1987;7:913-917. 27. Sichieri R, Everhart JE, Roth HP. Low incidence of hospitalization with gallbladder disease among blacks in the United States. Am J Epidemiol 1990;131:826-835. 28. Jørgensen T. Gall stones in a Danish population. Relation to weight, physical activity, smoking, coffee consumption, and diabetes mellitus. Gut 1989;30:528-534. 29. Everhart JE. Gallstones. In: Everhart JE, ed. Digestive Diseases in the United States: Epidemiology and Impact. Washington, DC: U.S. Government Printing Office, 1994;647-690. 30. Lowenfels AB, Maisonneuve P. Pancreatico-biliary malignancy: prevalence and risk factors. Ann Oncol 1999;10(Suppl 4):1-3.