PMID: 21274884

Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A
Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population.
Hepatology. 2011 Feb;53(2):640-8. doi: 10.1002/hep.24046. Epub 2010 Dec 28., [PubMed]
Sentences
No. Mutations Sentence Comment
1 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:1:91
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:1:101
status: VERIFIED
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To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 801 years. Login to comment
6 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:6:45
status: VERIFIED
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The fraction of all gallstones attributed to D19H was 11%. Login to comment
8 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:8:54
status: VERIFIED
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The fraction of all biliary cancers attributed to the D19H genotype was 27%. Login to comment
9 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:9:9
status: VERIFIED
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Finally, D19H genotype associated with stepwise increases in plasma levels of alanine aminotransferase and gamma glutamyltransferase of up to 14% and 25% in HH homozygotes, and with corresponding stepwise reductions in plasma levels of total and low-density lipoprotein cholesterol of up to 5% versus noncarriers (all comparisons, P for trend <0.001). Login to comment
10 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:10:53
status: VERIFIED
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Conclusion: In this general population cohort, ABCG8 D19H genotype was an important predictor of both symptomatic gallstone disease and biliary cancer. Login to comment
20 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:20:336
status: VERIFIED
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640 A recent genomewide association scan identified the sterol transporter adenosine triphosphate-binding cassette transporter G8 (ABCG8) as a susceptibility factor for gallstone disease in humans.6 The association was attributed to a common variant that leads to the substitution of aspartate with histidine at amino acid residue 19 (D19H; rs11887534). Login to comment
21 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:21:30
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:21:278
status: VERIFIED
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It has been hypothesized that D19H constitutes a gain-of-function variant that increases hepatobiliary cholesterol efflux, resulting in precipitation of cholesterol gallstones.6-8 Gallstone disease is a risk factor for biliary cancer, a rare but highly lethal disease.9 Whether D19H affects the risk of gallstone disease and biliary cancer in the general population is currently unknown. Login to comment
22 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:22:183
status: VERIFIED
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This question is clinically important because (1) genetic variants identified in case-control studies often overestimate risk compared to studies of the general population10,11 ; (2) D19H has the potential to become the first lithogenic genetic variant included in presymptomatic genetic screening for gallstone disease and/or biliary cancer in the general population; and (3) the identification of specific genetic variants predisposing to gallstones and biliary cancer might also lead to new nonsurgical interventions that extend our current limited strategies for the prevention of these diseases. Login to comment
23 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:23:37
status: VERIFIED
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We tested the clinical impact of the D19H genotype in 62,279 individuals from the Danish general population followed from January 1976 through May 2009, of whom 3124 developed symptomatic gallstone disease and 30 developed biliary cancer. Login to comment
25 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:25:29
status: VERIFIED
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First, we determined whether D19H predicted risk of symptomatic gallstone disease and/or biliary cancer in the general population; on the basis of these results, we calculated the population-attributable risk. Login to comment
26 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:26:104
status: VERIFIED
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Subsequently, we determined the absolute 10-year risk of symptomatic gallstone disease as a function of D19H genotype stratified by sex, age, and body mass index (BMI). Login to comment
27 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:27:34
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:27:169
status: VERIFIED
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Finally, to explore the effect of D19H genotype on liver and pancreas damage, and on the putative effects on cholesterol excretion, we determined the association of the D19H genotype with plasma liver biochemistry and with plasma lipid and lipoprotein levels. Login to comment
53 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:53:123
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:53:124
status: NEW
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An ABI-Prism 7900HT Sequence Detection System (Applied Biosystems) and a TaqMan-based assay was used to genotype for ABCG8 D19H (rs11887534). Login to comment
64 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:64:55
status: VERIFIED
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For trend tests, subjects were classified according to D19H genotype and coded as 0 for noncarriers, 1 for heterozygotes and 2 for homozygotes. Login to comment
66 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:66:157
status: VERIFIED
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Kaplan-Meier curves and log-rank tests evaluated the cumulative incidence of symptomatic gallstone disease and biliary cancer as a function of age and ABCG8 D19H genotype. Login to comment
75 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:75:15
status: VERIFIED
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Interaction of D19H genotype with other risk factors for gallstones (age, sex, BMI, physical activity, parity, hormone replacement therapy, and alcohol intake) were evaluated by including two-factor interaction terms between genotype and other risk factors, one at a time, in the Cox regression model. Login to comment
76 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:76:137
status: VERIFIED
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Population-attributable risk was calculated as previously described.18 Absolute 10-year risks for symptomatic gallstone disease by ABCG8 D19H genotype, age (<40 years, 40-60 years, >60 years), and BMI (<25 kg/m2 [normal], 25-30 kg/m2 [overweight], >30 kg/m2 [obese]) were estimated with the use of the regression coefficients from a Poisson regression model for women and men separately, and presented as estimated incidence rates (number of events per 10 years) in percent.19,20 Results Clinical Characteristics. Login to comment
82 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:82:65
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:82:134
status: VERIFIED
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Risk factors for symptomatic gallstone disease did not differ by D19H genotype, and were thus unlikely to confound any association of D19H with risk of symptomatic gallstone disease (compare Table 1 with Table 2). Login to comment
84 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:84:101
status: VERIFIED
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The cumulative incidence of symptomatic gallstone disease as a function of age increased stepwise by D19H genotype, with HH homozygotes having the highest risk and DH heterozygotes an intermediate risk compared with noncarriers (Fig. 1; P for trend <0.001). Login to comment
87 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:87:55
status: VERIFIED
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HRs for symptomatic gallstone disease as a function of D19H genotype in the general population adjusted for age and sex were 1.9 (95% confidence interval [CI], 1.7-2.1) for DH heterozygotes and 3.3 (95% CI, 2.34.6) for HH homozygotes compared with noncarriers (Fig. 1). Login to comment
89 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:89:47
status: VERIFIED
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There were no significant interactions between D19H genotype and any of the abovementioned risk factors on risk of symptomatic gallstone disease. Login to comment
91 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:91:44
status: VERIFIED
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The HR for cholecystectomy as a function of D19H genotype in the general population adjusted for age and sex was 2.0 (95% CI, 1.8-2.3) for DH heterozygotes and 3.3 (95% CI, 2.2-4.9) for HH homozygotes Table 1. Characteristics of Individuals in the General Population* by Disease Status Characteristic No event Gallstone Disease Biliary Cancer Number of individuals (%) 59,155 (95) 3124 (5) 30 (0.05) Age (years) 57 (46-66) 60 (50-70)‡ 66 (61-72)‡ Women (%) 54 72‡ 57 BMI (kg/m2 ) 25 (23-28) 27 (24-30)‡ 27 (25-29)§ Physical activity (%) 46 36‡ 27§ Mean parity (number of births)† 1.8 2.0‡ 1.4 Hormone replacement therapy (%)† 13 20‡ 18 Alcohol consumption (%) 49 40‡ 50 Lipid-lowering therapy (%) 8 11‡ 0 Values are median (interquartile range) or percentage. Physical activity was 4 hours or more per week of light physical activity in leisure time. Alcohol consumption was at least twice weekly. P values as calculated by Mann-Whitney U test or Pearson`s chi-square test. Login to comment
96 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:96:90
status: VERIFIED
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Table 2. Characteristics of Individuals in the General Population* as a Function of ABCG8 D19H Genotype Characteristic DD Noncarriers DH Heterozygotes HH Homozygotes P Value Number of individuals (%) 54,526 (87.5) 7,506 (12.1) 247 (0.4) NA Age (years) 57 (46-67) 57 (47-67) 57 (45-68) 0.57 Women (%) 55 55 53 0.36 BMI (kg/m2 ) 26 (23-29) 26 (23-28) 26 (23-28) 0.83 Physical activity (%) 46 45 43 0.37 Mean parity (number of births)† 1.8 1.8 1.7 0.54 Hormone replacement therapy (%)† 14 13 11 0.71 Alcohol consumption (%) 48 49 48 0.72 Values are median (interquartile range) or percentage. Physical activity was 4 hours or more per week of light physical activity in leisure time. Alcohol consumption was at least twice weekly. P values as calculated by Kruskal-Wallis analysis of variance or Pearson`s chi-square test. Login to comment
100 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:100:0
status: VERIFIED
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D19H genotype did not associate with overall mortality. Login to comment
101 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:101:26
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:101:172
status: VERIFIED
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Based on the frequency of D19H and the observed HRs for symptomatic gallstone disease as a function of genotype, the fraction of all gallstones that could be attributed to D19H was 11%. Login to comment
102 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:102:128
status: VERIFIED
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Absolute 10-year risk of symptomatic gallstone disease increased from men to women, with increasing age, increasing BMI, and by D19H genotype (Fig. 2). Login to comment
106 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:106:77
status: VERIFIED
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The cumulative incidence of biliary cancer as a function of age increased by D19H genotype (Fig. 3; P < 0.001). Login to comment
107 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:107:43
status: VERIFIED
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The HR for biliary cancer as a function of D19H genotype adjusted for age and sex was 4.0 (95% CI, 1.9-8.4) for DH heterozygotes and HH homozygotes combined compared with noncarriers (Fig. 3) (3.8 [95% CI, 1.8-8.1] in DH heterozygotes and 10.3 [95% CI, 1.4-77.5] in HH homozygotes). Login to comment
110 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:110:50
status: VERIFIED
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The fraction of all biliary cancers attributed to D19H was 27% (for clinical characteristics of patients, see Table 3). Login to comment
112 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:112:0
status: VERIFIED
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D19H associated with stepwise increases in plasma levels of gamma glutamyltransferase and alanine aminotransferase of, respectively, 3% and 2% for heterozygotes, and 25% and 14% for homozygotes compared with noncarriers (Fig. 4; P for trend <0.001). Login to comment
113 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:113:59
status: VERIFIED
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Alcohol intake was equally distributed among the different D19H genotypes and therefore did not confound these associations (Table 2). Login to comment
116 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:116:0
status: VERIFIED
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D19H genotype associated with modest stepwise reductions in plasma levels of total cholesterol and LDL cholesterol of 1.6% and 2.4%, respectively, in DH heterozygotes, and of 3.5% and 4.5%, respectively, in homozygotes compared with noncarriers (Fig. 4; P for trend <0.001). Login to comment
120 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:120:132
status: VERIFIED
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Cumulative incidence of symptomatic gallstone disease (graph at top) and mean age at onset (table at bottom) as a function of ABCG8 D19H genotype in the general population. Login to comment
124 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:124:77
status: VERIFIED
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Absolute 10-year risk of developing gallstone disease as a function of ABCG8 D19H genotype, by sex, age (<40 years, 40-60 years, >60 years), and body mass index (<25 kg/m2 , normal weight; 25-30 kg/m2 , overweight; >30 kg/m2 , obese). Login to comment
127 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:127:28
status: VERIFIED
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There was no association of D19H with HDL cholesterol or triglycerides. Login to comment
128 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:128:201
status: VERIFIED
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Discussion The principal findings of this study of 62,279 individuals from the general population, of which 3124 developed symptomatic gallstone disease and 30 developed biliary cancer, are: (1) ABCG8 D19H genotype associated with an approximate 2-fold to 3.5-fold increase in risk of symptomatic gallstone disease in more than 12% of the general population. Login to comment
129 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:129:4
status: VERIFIED
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(2) D19H genotype associated with stepwise reductions in mean age at onset of symptomatic gallstone disease of up to 4 years in homozygotes. Login to comment
130 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:130:94
status: VERIFIED
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(3) A total of 11% of symptomatic gallstones in the general population could be attributed to D19H genotype. Login to comment
131 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:131:45
status: VERIFIED
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(4) Heterozygous and homozygous carriers for D19H had a four-fold Fig. 3. Login to comment
132 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:132:88
status: VERIFIED
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Cumulative incidence of biliary cancer in the general population as a function of ABCG8 D19H genotype. Login to comment
135 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:135:83
status: VERIFIED
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Table 3. Characteristics of the 30 Participants With Biliary Cancer Subject Number D19H Genotype Sex (F/M) BMI (kg/m2) Age at Baseline Examination Age at Diagnosis of Gallstone Disease Age at Cholecystectomy Age at Diagnosis of Biliary Cancer ICD-10 Code Age at Death 1 HH F 28 62 77 77 C24.9 77 2 DH F 24 52 57 57 C24.0 58 3 DH F 24 62 59 74 C24.0 75 4 DH F 33 67 71 C24.9 71 5 DH M 31 68 81 C23.9 81 6 DH F 27 71 82 82 83 C24.8 83 7 DH M 29 72 79 C24.0 80 8 DH F 29 73 76 76 77 C24.1 77 9 DH F 30 78 79 79 79 C24.9 81 10 DH F 22 85 87 C23.9 87 11 DH M 28 87 91 C23.9 91 12 DD M 27 45 48 C24.0 51 13 DD F 38 45 61 C24.0 14 DD M 28 46 48 58 C24.0 58 15 DD F 31 50 51 51 C24.0 51 16 DD M 25 50 66 C24.9 17 DD M 25 54 69 70 C23.9 71 18 DD M 27 61 68 C24.0 68 19 DD F 30 61 67 67 C23.9 68 20 DD F 20 62 75 C24.9 77 21 DD M 26 63 79 C24.9 22 DD F 25 63 66 C23.9 66 23 DD F 26 64 72 72 C24.0 72 24 DD F 26 67 77 C23.9 78 25 DD F 26 69 80 C24.0 82 26 DD M 28 72 74 C22.1 74 27 DD F 38 72 78 C24.9 79 28 DD M 29 78 80 80 C24.1 80 29 DD M 24 81 82 C24.1 86 30 DD M 28 82 89 C23.9 90 BMI is in kg/m2 . Login to comment
140 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:140:61
status: VERIFIED
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(5) A total of 27% of biliary cancers could be attributed to D19H. Login to comment
141 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:141:4
status: VERIFIED
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(6) D19H genotype associated with stepwise increases in plasma alanine aminotransferase and gamma glutamyltransferase, and with a modest stepwise decrease in total and LDL cholesterol levels. Login to comment
143 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:143:88
status: VERIFIED
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The incidence of symptomatic gallstone disease and biliary cancer, and the frequency of D19H, in our study are comparable to previous studies in Western countries.6,21,22 The incidence rates of mainly biliary cancer were lower in the CGPS compared to the CCHS. Login to comment
147 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:147:193
status: VERIFIED
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Possible explanations for this include a higher background risk of biliary cancer in India than in Western countries,9,21 a different etiology (bacterial infection of bile), and a frequency of D19H among controls of 23%, which is twice that reported in Western populations. Login to comment
148 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:148:14
status: VERIFIED
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We found that D19H associates with reductions in plasma total and LDL cholesterol levels. Login to comment
149 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:149:213
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:149:279
status: VERIFIED
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ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:149:528
status: VERIFIED
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In hepatocytes, ABCG8 forms half of a transmembrane sterol transporter that effluxes sterols into bile.27 Because biliary supersaturation with cholesterol is a pivotal event in cholesterol gallstone formation and D19H is associated with gallstones, it has been hypothesized that D19H constitutes a gain-of-function variant that increases biliary cholesterol efflux.6-8 Overexpression of ABCG8 in mice leads to reduced levels of plasma sterols.28 By analogy, a stepwise reduction in levels of plasma cholesterol as a function of D19H genotype in humans would support the gain-of-function hypothesis. Login to comment
151 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:151:127
status: VERIFIED
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We detected a modest but statistically highly significant stepwise reduction in plasma LDL cholesterol levels as a function of D19H genotype. Login to comment
154 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:154:87
status: VERIFIED
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We found a modest stepwise reduction in use of lipid-lowering therapy as a function of D19H genotype. Login to comment
155 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:155:262
status: VERIFIED
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Regardless of whether we restricted the follow-up period to the period 1976-1990 (i.e., prior to the advent of statins) or excluded all participants on lipid-lowering therapy during the study, the hazard ratios for symptomatic gallstone disease as a function of D19H genotype were largely unchanged. Login to comment
156 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:156:114
status: VERIFIED
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Together, these results indicate that the increased risk of symptomatic gallstone disease observed in carriers of D19H could not be explained by their lower use of lipid-lowering therapy. Login to comment
158 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:158:121
status: VERIFIED
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Baseline liver parameters, plasma lipid and lipoprotein levels, and use of lipid-lowering therapy as a function of ABCG8 D19H genotype. Login to comment
165 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:165:53
status: VERIFIED
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Although functional studies aimed at testing whether D19H constitutes a gain-of-function variant that increases biliary cholesterol efflux are clearly warranted, a clinically interesting question is whether the putative increase in biliary cholesterol efflux can be counteracted medically. Login to comment
166 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:166:151
status: VERIFIED
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An affirmative answer to this question could resurrect the widely abandoned concept of nonsurgical treatment for gallstones, at least in the subset of D19H-positive patients. Login to comment
170 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:170:21
status: VERIFIED
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In conclusion, ABCG8 D19H is the first genetic variant to predict risk of symptomatic gallstone disease and biliary cancer in the general population. Login to comment
171 ABCG8 p.Asp19His
X
ABCG8 p.Asp19His 21274884:171:153
status: VERIFIED
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The clinical impact appears to be substantial in that 11% of all symptomatic gallstones and 27% of all biliary cancers in our study can be attributed to D19H genotype. Login to comment