Genetic Predisposition to Gallbladder Stones

ABSTRACT

Geographic and ethnic differences in gallstone prevalence rates and familial clustering of cholelithiasis imply that genetic factors influence the risk of gallstone formation. Recently, twin, family, and linkage studies confirmed a genetic predisposition to the development of symptomatic gallstones. In rare instances, mutations in single genes confer a substantial risk for the formation of gallstones. However, in the majority of cases gallstones might develop as a result of lithogenic polymorphisms in several genes and their interactions with multiple environmental factors, rendering gallstones generally a complex genetic disorder. Some of the rare monogenic forms of cholelithiasis were unraveled but the lithogenic genes that increase the susceptibility to cholelithiasis in the majority of gallstone carriers remain elusive. Identification of these lithogenic genes will provide novel means of risk assessment, strategies for prevention, and targets for nonsurgical management of cholelithiasis, which currently is one of the most expensive digestive disorders.

KEYWORDS

Association study - cholelithiasis - complex genetic disorder - gallstones - LITH gene

REFERENCES

• 1 Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease.  Lancet. 2006;  368 230-239
• 2 Cahalane M J, Neubrand M W, Carey M C. Physical-chemical pathogenesis of pigment gallstones.  Semin Liver Dis. 1988;  8 317-328
• 3 Robins S J, Fasulo J M, Patton G M. Lipids of pigment gallstones.  Biochim Biophys Acta. 1982;  712 21-25
• 4 Wosiewitz U, Schenk J, Sabinski F, Schmack B. Investigations on common bile duct stones.  Digestion. 1983;  26 43-52
• 5 Friedman G D. Natural history of asymptomatic and symptomatic gallstones.  Am J Surg. 1993;  165 399-404
• 6 Sandler R S, Everhart J E, Donowitz M et al.. The burden of selected digestive diseases in the United States.  Gastroenterology. 2002;  122 1500-1511
• 7 Kratzer W, Mason R A, Kachele V. Prevalence of gallstones in sonographic surveys worldwide.  J Clin Ultrasound. 1999;  27 1-7
• 8 Lammert F, Sauerbruch T. Mechanisms of disease: the genetic epidemiology of gallbladder stones.  Nat Clin Pract Gastroenterol Hepatol. 2005;  2 423-433
• 9 Paigen B, Carey M C. Gallstones. In: King RA, Rotter JF, Motulsky AG The Genetic Basis of Common Diseases. 2nd ed. New York; Oxford University Press 2002: 298-335
• 10 Sampliner R E, Bennett P H, Comess L J, Rose F A, Burch T A. Gallbladder disease in Pima Indians: demonstration of high prevalence and early onset by cholecystography.  N Engl J Med. 1970;  283 1358-1364
• 11 Everhart J E, Yeh F, Lee E T et al.. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study.  Hepatology. 2002;  35 1507-1512
• 12 Everhart J E, Khare M, Hill M, Maurer K R. Prevalence and ethnic differences in gallbladder disease in the United States.  Gastroenterology. 1999;  117 632-639
• 13 Mendez-Sanchez N, King-Martinez A C, Ramos M H, 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 2166-2170
• 14 Miquel J F, Covarrubias C, Villaroel L et al.. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris.  Gastroenterology. 1998;  115 937-946
• 15 Carey M C, Paigen B. Epidemiology of the American Indians' burden and its likely genetic origins.  Hepatology. 2002;  36 781-791
• 16 Neel J V. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”?.  Am J Hum Genet. 1962;  14 353-362
• 17 Attili A F, Capocaccia R, Carulli N et al.. Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis.  Hepatology. 1997;  26 809-818
• 18 Tsai C J, Leitzmann M F, Willett W C, Giovannucci E L. Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women.  Gastroenterology. 2005;  129 105-112
• 19 Lowenfels A B. Gallstones and glaciers: the stone that came in from the cold.  Lancet. 1988;  1 1385-1386
• 20 Barbara L, Sama C, Morselli Labate A M et al.. A population study on the prevalence of gallstone disease: the Sirmione Study.  Hepatology. 1987;  7 913-917
• 21 Nakeeb A, Comuzzie A G, Martin L et al.. Gallstones: genetics versus environment.  Ann Surg. 2002;  235 842-849
• 22 Katsika D, Grjibovski A, Einarsson C et al.. Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs.  Hepatology. 2005;  41 1138-1143
• 23 Duggirala R, Mitchell B D, Blangero J, Stern M P. Genetic determinants of variation in gallbladder disease in the Mexican-American population.  Genet Epidemiol. 1999;  16 191-204
• 24 Kullak-Ublick G A, Stieger B, Meier P J. Enterohepatic bile salt transporters in normal physiology and liver disease.  Gastroenterology. 2004;  126 322-342
• 25 Hofmann A F. Bile acid secretion, bile flow and biliary lipid secretion in humans.  Hepatology. 1990;  12 17S-22S discussion 22S-25S
• 26 Baiocchi L, LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte bile secretion.  J Hepatol. 1999;  31 179-191
• 27 Wang P, Kim R B, Chowdhury J R, Wolkoff A W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport.  J Biol Chem. 2003;  278 20695-20699
• 28 Bosma P J, Seppen J, Goldhoorn B et al.. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.  J Biol Chem. 1994;  269 17960-17964
• 29 Nies A T, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2).  Pflugers Arch. 2006;  , July 18 (Epub ahead of print)
• 30 Robins S J, Fasulo J M. High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.  J Clin Invest. 1997;  99 380-384
• 31 Cooper A D. Hepatic uptake of chylomicron remnants.  J Lipid Res. 1997;  38 2173-2192
• 32 Hillebrant C G, Nyberg B, Einarsson K, Eriksson M. The effect of plasma low density lipoprotein apheresis on the hepatic secretion of biliary lipids in humans.  Gut. 1997;  41 700-704
• 33 Caroli-Bosc F X, Le Gall P, Pugliese P et al.. Role of fibrates and HMG-CoA reductase inhibitors in gallstone formation: epidemiological study in an unselected population.  Dig Dis Sci. 2001;  46 540-544
• 34 Tall A R, Wang N, Mucksavage P. Is it time to modify the reverse cholesterol transport model?.  J Clin Invest. 2001;  108 1273-1275
• 35 Ji Y, Wang N, Ramakrishnan R et al.. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile.  J Biol Chem. 1999;  274 33398-33402
• 36 Lammert F, Wang D Q. New insights into the genetic regulation of intestinal cholesterol absorption.  Gastroenterology. 2005;  129 718-734
• 37 Yu L, Hammer R E, Li-Hawkins J et al.. Disruption of Abcg5 and Abcg8 in mice reveals the crucial role in biliary cholesterol secretion.  Proc Natl Acad Sci USA. 2002;  99 16237-16242
• 38 Wang R, Salem M, Yousef I M et al.. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci USA. 2001;  98 2011-2016
• 39 Smit J J, Schinkel A H, Oude Elferink R P et al.. Homozygous disruption of the murine mdr2 gene P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell. 1993;  75 451-462
• 40 Kalaany N Y, Mangelsdorf D J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism.  Annu Rev Physiol. 2006;  68 159-191
• 41 Admirand W H, Small D M. The physicochemical basis of cholesterol gallstone formation in man.  J Clin Invest. 1968;  47 1043-1052
• 42 Carey M C. Critical tables for calculating the cholesterol saturation of native bile.  J Lipid Res. 1978;  19 945-955
• 43 Portincasa P, Di Ciaula A, vanBerge-Henegouwen G P. Smooth muscle function and dysfunction in gallbladder disease.  Curr Gastroenterol Rep. 2004;  6 151-162
• 44 Wang D Q, Schmitz F, Kopin A S, Carey M C. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis.  J Clin Invest. 2004;  114 521-528
• 45 Marks J W, Bonorris G G, Albers G, Schoenfield L J. The sequence of biliary events preceding the formation of gallstones in humans.  Gastroenterology. 1992;  103 566-570
• 46 Wilhelmi M, Jungst C, Mock M et al.. Effect of gallbladder mucin on the crystallization of cholesterol in bile.  Eur J Gastroenterol Hepatol. 2004;  16 1301-1307
• 47 Vandenhaute B, Buisine M P, Debailleul V et al.. Mucin gene expression in biliary epithelial cells.  J Hepatol. 1997;  27 1057-1066
• 48 Lammert F, Carey M C, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation: a murine gallstone map.  Gastroenterology. 2001;  120 221-238
• 49 Maurer K J, Ihrig M M, Rogers A B et al.. Identification of cholelithogenic enterohepatic helicobacter species and their role in murine cholesterol gallstone formation.  Gastroenterology. 2005;  128 1023-1033
• 50 Lyons M A, Wittenburg H. Susceptibility to cholesterol gallstone formation: evidence that LITH genes also encode immune-related factors.  Biochim Biophys Acta. 2006;  1761 1133-1147
• 51 Trotman B W, Bernstein S E, Balistreri W F, Wirt G D, Martin R A. Hemolysis-induced gallstones in mice: increased unconjugated bilirubin in hepatic bile predisposes to gallstone formation.  Gastroenterology. 1981;  81 232-236
• 52 Soloway R D, Trotman B W, Maddrey W C, Nakayama F. Pigment gallstone composition in patients with hemolysis or infection/stasis.  Dig Dis Sci. 1986;  31 454-460
• 53 Vitek L, Carey M C. Enterohepatic cycling of bilirubin as a cause of “black” pigment gallstones in adult life.  Eur J Clin Invest. 2003;  33 799-810
• 54 Broderick A L, Wittenburg H, Lyons M A et al.. Cystic fibrosis transmembrane conductance regulator gene mutations cause “black” pigment gallstone formation: new insights from mouse models and implications for therapeutic interventions in cystic fibrosis. In: Adler G, Blum HE, Fuchs M, Stange EF Gallstones: Pathogenesis and Treatment. Dordrecht/Boston/London; Kluwer Academics Publishers 2004: 24-27
• 55 Angelico M, Gandin C, Canuzzi P et al.. Gallstones in cystic fibrosis: a critical reappraisal.  Hepatology. 1991;  14 768-775
• 56 Fevery J, Blanckaert N, Heirwegh K P, Preaux A M, Berthelot P. Unconjugated bilirubin and an increased proportion of bilirubin monoconjugates in the bile of patients with Gilbert's syndrome and Crigler-Najjar disease.  J Clin Invest. 1977;  60 970-979
• 57 Wasmuth H E, Keppeler H, Herrmann U et al.. Coinheritance of Gilbert syndrome-associated UGT1A1 mutation increases gallstone risk in cystic fibrosis.  Hepatology. 2006;  43 738-741
• 58 del Giudice E M, Perrotta S, Nobili B et al.. Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis.  Blood. 1999;  94 2259-2262
• 59 Chaar V, Keclard L, Diara J P et al.. Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia.  Haematologica. 2005;  90 188-199
• 60 Premawardhena A, Fisher C A, Fathiu F et al.. Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia.  Lancet. 2001;  357 1945-1946
• 61 Conte D, Fraquelli M, Fornari F et al.. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.  Arch Intern Med. 1999;  159 49-52
• 62 Conte D, Barisani D, Mandelli C et al.. Prevalence of cholelithiasis in alcoholic and genetic haemochromatotic cirrhosis.  Alcohol Alcohol. 1993;  28 581-584
• 63 Zoller H, Cox T M. Hemochromatosis: genetic testing and clinical practice.  Clin Gastroenterol Hepatol. 2005;  3 945-958
• 64 Walshe J M. Hepatic Wilson's disease: initial treatment and long-term management.  Curr Treat Options Gastroenterol. 2005;  8 467-472
• 65 Oude Elferink R P, Paulusma C C, Groen A K. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases.  Gastroenterology. 2006;  130 908-925
• 66 Jacquemin E, De Vree J M, Cresteil D et al.. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.  Gastroenterology. 2001;  120 1448-1458
• 67 van Mil S W, van der Woerd W L, van der Brugge G et al.. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.  Gastroenterology. 2004;  127 379-384
• 68 Rosmorduc O, Hermelin B, Boelle P-Y et al.. ABCB4 gene mutation-associated cholelithiasis in adults.  Gastroenterology. 2003;  125 452-459
• 69 Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.  Gastroenterology. 2001;  120 1459-1467
• 70 Lammert F, Wang D Q, Hillebrandt S et al.. Spontaneous cholecysto- and hepatolithiasis in Mdr2 - / - mice: a model for low phospholipid-associated cholelithiasis.  Hepatology. 2004;  39 117-128
• 71 Pullinger C R, Eng C, Salen G et al.. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype.  J Clin Invest. 2002;  110 109-117
• 72 Pullinger C R, Eng C, Malloy M J, Kane J P. Cholesterol 7alpha-hydroxylase (CYP7A1) gene mutation: another cause for gallstone formation?. In: Adler G, Blum HE, Fuchs M, Stange EF Gallstones: Pathogenesis and Treatment. Dordrecht/Boston/London; Kluwer Academics Publishers 2004: 14-23
• 73 Miyake J H, Duong-Polk X T, Taylor J M et al.. Transgenic expression of cholesterol-7-alpha-hydroxylase prevents atherosclerosis in C57BL/6J mice.  Arterioscler Thromb Vasc Biol. 2002;  22 121-126
• 74 Lancellotti S, Zaffanello M, Di Leo E et al.. Pediatric gallstone disease in familial hypobetalipoproteinemia.  J Hepatol. 2005;  43 188-191
• 75 Miller L J, Holicky E L, Ulrich C D, Wieben E D. Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity.  Gastroenterology. 1995;  109 1375-1380
• 76 Schneider H, Sanger P, Hanisch E. In vitro effects of cholecystokinin fragments on human gallbladders: evidence for an altered CCK-receptor structure in a subgroup of patients with gallstones.  J Hepatol. 1997;  26 1063-1068
• 77 Miyasaka K, Takata Y, Funakoshi A. Association of cholecystokinin A receptor gene polymorphism with cholelithiasis and the molecular mechanisms of this polymorphism.  J Gastroenterol. 2002;  37 102-106
• 78 Krejs G J, Orci L, Conlon J M et al.. Somatostatinoma syndrome: biochemical, morphologic and clinical features.  N Engl J Med. 1979;  301 285-292
• 79 Moschetta A, Stolk M F, Rehfeld J F et al.. Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.  Aliment Pharmacol Ther. 2001;  15 181-185
• 80 Puppala S, Dodd G D, Fowler S et al.. A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans.  Am J Hum Genet. 2006;  78 377-392
• 81 Cohen J C, Kiss R S, Pertsemlidis A et al.. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.  Science. 2004;  305 869-872
• 82 Jiang Z Y, Han T Q, Suo G J et al.. Polymorphisms at cholesterol 7alpha-hydroxylase, apolipoproteins B and E and low density lipoprotein receptor genes in patients with gallbladder stone disease.  World J Gastroenterol. 2004;  10 1508-1512
• 83 Han T, Jiang Z, Suo G, Zhang S. Apolipoprotein B-100 gene Xba I polymorphism and cholesterol gallstone disease.  Clin Genet. 2000;  57 304-308
• 84 Juvonen T, Savolainen M J, Kervinen K et al.. Polymorphism at the apoB, apoA-I, and the cholesterol ester transfer protein gene loci in patients with gallbladder disease.  J Lipid Res. 1995;  36 804-812
• 85 Singh M K, Pandey U B, Ghoshal U C et al.. Apolipoprotein B-100 XbaI gene polymorphism in gallbladder cancer.  Hum Genet. 2004;  114 280-283
• 86 Schafmayer C, Tepel J, Franke A et al.. Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease.  Hepatology. 2006;  44 650-657
• 87 Weintraub M S, Eisenberg S, Breslow J L. Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E.  J Clin Invest. 1987;  80 1571-1577
• 88 Juvonen T, Kervinen K, Kairaluoma M I, Lajunen L H, Kesaniemi Y A. Gallstone cholesterol content is related to apolipoprotein E polymorphism.  Gastroenterology. 1993;  104 1806-1813
• 89 Bertomeu A, Ros E, Zambon D et al.. Apolipoprotein E polymorphism and gallstones.  Gastroenterology. 1996;  111 1603-1610
• 90 Venneman N G, vanBerge-Henegouwen G P, Portincasa P et al.. Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.  J Hepatol. 2001;  35 10-16
• 91 van Erpecum K J, Portincasa P, Dohlu M H, van Berge-Henegouwen G P, Jungst D. Biliary pronucleating proteins and apolipoprotein E in cholesterol and pigment stone patients.  J Hepatol. 2003;  39 7-11
• 92 Niemi M, Kervinen K, Rantala A et al.. The role of apolipoprotein E and glucose intolerance in gallstone disease in middle aged subjects.  Gut. 1999;  44 557-562
• 93 Hasegawa K, Terada S, Kubota K et al.. Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone.  Am J Gastroenterol. 2003;  98 1605-1609
• 94 Dixit M, Choudhuri G, Mittal B. Association of APOE-C1 gene cluster polymorphisms with gallstone disease.  Dig Liver Dis. 2006;  38 397-403
• 95 Dixit M, Choudhuri G, Mittal B. Association of lipoprotein receptor, receptor-associated protein, and metabolizing enzyme gene polymorphisms with gallstone disease: a case-control study.  Hepatol Res. 2006;  36 61-69
• 96 Mella J G, Schirin-Sokhan R, Rigotti A et al.. Apolipoprotein E polymorphisms and cholesterol gallstone disease in two high-risk populations: genetic evidence that ApoE4 is not a relevant lithogenic risk factor. 2006 (submitted)
• 97 Lyons M A, Wittenburg H. Cholesterol gallstone susceptibility loci: a mouse map, candidate gene evaluation, and guide to human LITH genes.  Gastroenterology. 2006;  131 1943-1970
• 98 Nadeau J H, Taylor B A. Lengths of chromosomal segments conserved since divergence of man and mouse.  Proc Natl Acad Sci USA. 1984;  81 814-818
• 99 Sugiyama F, Churchill G A, Higgins D C et al.. Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci.  Genomics. 2001;  71 70-77
• 100 DiPetrillo K, Wang X, Stylianou I M, Paigen B. Bioinformatics toolbox for narrowing rodent quantitative trait loci.  Trends Genet. 2005;  21 683-692
• 101 Wang X, Ishimori N, Korstanje R, Rollins J, Paigen B. Identifying novel genes for atherosclerosis through mouse-human comparative genetics.  Am J Hum Genet. 2005;  77 1-15
• 102 Hillebrandt S, Wasmuth H E, Weiskirchen R et al.. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.  Nat Genet. 2005;  37 835-843
• 103 Wang X, Ria M, Kelmenson P M et al.. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility.  Nat Genet. 2005;  37 365-372
• 104 Schafmayer C, Franke A, Egberts J et al.. Investigation of the Lith6 candidate genes ABOBEC1 and PPARG in human symptomatic gallstone disease. 2006 (submitted)
• 105 Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease.  Scand J Gastroenterol Suppl. 1994;  204 27-31
• 106 Hou L, Xu J, Gao Y T et al.. CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China.  Int J Cancer. 2006;  118 2847-2853
• 107 Coelho J C, Vizzoto A O, Salvalaggio P R, Tolazzi A R. Laparoscopic cholecystectomy to treat patients with asymptomatic gallstones.  Dig Surg. 2000;  17 344-347
• 108 Paumgartner G, Sauter G H. Extracorporeal shock wave lithotripsy of gallstones: 20th anniversary of the first treatment.  Eur J Gastroenterol Hepatol. 2005;  17 525-527
• 109 Shiffman M L, Kaplan G D, Brinkman-Kaplan V, Vickers F F. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program.  Ann Intern Med. 1995;  122 899-905
• 110 Moschetta A, Bookout A L, Mangelsdorf D J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model.  Nat Med. 2004;  10 1352-1358
• 111 Van Der Veere C N, Schoemaker B, Bakker C et al.. Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia.  Hepatology. 1996;  24 620-626
• 112 Hafkamp A M, Havinga R, Sinaasappel M, Verkade H J. Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats.  Hepatology. 2005;  41 526-534
• 113 Mendez-Sanchez N, Roldan-Valadez E, Flores M A, Cardenas-Vazquez R, Uribe M. Zinc salts precipitate unconjugated bilirubin in vitro and inhibit enterohepatic cycling of bilirubin in hamsters.  Eur J Clin Invest. 2001;  31 773-780
• 114 Vitek L, Muchova L, Zelenka J, Zadinova M, Malina J. The effect of zinc salts on serum bilirubin levels in hyperbilirubinemic rats.  J Pediatr Gastroenterol Nutr. 2005;  40 135-140
• 115 Hofmann A F, Zakko S F, Lira M et al.. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans.  Hepatology. 2005;  42 1391-1398
• 116 Witt H. Chronic pancreatitis and cystic fibrosis.  Gut. 2003;  52 ii31-ii41
• 117 Harada L M, Amigo L, Cazita P M et al.. CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion.  Atherosclerosis. 2006;  , June 24 (Epub ahead of print)
• 118 Willnow T E, Armstrong S A, Hammer R E, Herz J. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo.  Proc Natl Acad Sci USA. 1995;  92 4537-4541