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. 2016 Feb 15;8(2):1218–1227.

Prevalence of ABCB4 polymorphisms in gallstone disease in han-Chinese population

Lei Zhan 1, Yao-Zhen Pan 1, Ling Chen 1, Hao Zhang 1, Hong Zhang 1, Jian Song 1, Chi-Meng Tzeng 2, Cheng-Yi Sun 1
PMCID: PMC4846965  PMID: 27158408

Abstract

ATP Binding Cassette Transporter A4 (ABCB4) is a sterol export pump that regulates excretion of biliary cholesterol. We tested association between ABCB4 polymorphisms and gallstone disease using meta-analysis. In a cross-sectional study, 296 subjects were recruited from a hospital-based population. Total of 171 subjects were diagnosed as gallstone disease by abdominal ultrasonography from three cohort studies. We evaluated prevalence of ABCG8 rs11887534 (D19H) as a positive control, and the ABCB4 rs1202283 and rs2230028 polymorphisms on Chinese population were screened by meta-analysis and genotyped using TaqMan® SNP assay. Stata/SE 11.0 software and random-effects model were used in meta-analyzing 3 cohort between study heterogeneity. Four studies including three cohorts were used for final meta-analysis. In allelic model, minor alleles of ABCB4 rs1202283 (OR = 0.41, 95% CI: 0.25-0.67, P<0.001) and of ABCB4 rs2230028 (OR = 0.12, 95% CI: 0.06-0.22, P = 0.001) were associated with an increased risk for gallstone disease in Europeans. Funnel plot and Egger’s test suggested absence of publication bias. Concentration of total cholesterol, low-density lipoprotein cholesterol (LDLC) (P = 0.015) and high-density lipoprotein cholesterol (HDLC) (P = 0.028) were significantly higher in subjects with gallstones disease than controls. ABCB4 rs1202283 (heterozygote AG) (P<0.0001), rs2230028 (heterozygote CT) (P = 0.023) and ABCG8 rs11887534 (heterozygote CG) (P = 0.006) were significantly associated with gallstone disease in Chinese population. Genetic risk associated with ABCB4 rs2230028 (homozygote GG) polymorphism was dominated in asymptomatic gallstone disease (95% C.I.: 0.219-0.768; P = 0.005). In conclusion, carriers of ABCB4 rs1202283, rs2230028 are at an increased risk for gallstone disease, while ABCB4 rs2230028 is associated with asymptomatic gallstone disease.

Keywords: Gallstone disease, single nucleotide polymorphism, ATP binding cassette transporter A4

Introduction

Gallstone disease is common in Western countries [1]. In China, the prevalence of gallstone disease has increased to 10.8% in the general population compared to 5% five years ago. While an additional 2.97% gallstone disease subjects have a previous history of cholecystectomy. The majority of the gallstone disease is associated with high cholesterol. Recently, studies have suggested that genetic factors, in interaction with environmental factors, are the predisposition to gallstone disease [2]. Katsika et al. [3], suggested that genetic heredity contributes 25% of factors to gallstone formation after an elegant analysis of data from Swedish twins.

Since late 1980s’, studies have attempted to reveal susceptible genes associated with gallstone disease in different populations. The possible genes studies included apolipoprotein (Apo)-E [4-7], Apo-B, [5,6] and cholesterol alpha-hydroxylase [5,6]. In the last decade, the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter located in the hepatocyte canalicular membrane was identified as involving in the transport of phosphatidylcholine into bile. Mutation in the ABCB4 gene may lead to low levels of biliary phosphatidylcholine, resulting in enhanced cholesterol precipitation and formation of crystals and gallstones. The first evidence that human gallstone disease might be caused by a single gene defect came [8,9]. These studies showed that ABCB4 gene mutations represented a genetic risk factor in a symptomatic and recurring form of gallstone disease in young adults. Furthermore, gallstone formation is a consistent feature of ABCB4 knockout mice [10]. Accordingly, ABCB4 genotyping could be used to confirm the diagnosis of LPAC in young adults who present with symptomatic gallstone disease and allow familial screening [9]. With the understanding of ABCB4 as important in regulating biliary cholesterol content and cholesterol absorption, studies on association of ABCB4 polymorphisms and gallstone disease have been published [8,11-18]. The most studied loci are ABCB4 exon 6 (Rs1202283) and exon 16 (Rs2230028). Due to difference in allele frequency at each polymorphic locus between different ethnicities, the associations between these SNPs and gallstone disease have not been consistent. Furthermore, the functional roles of these polymorphic loci have not been fully clarified. Additionally, no study has ever determined whether any difference exists for these SNPs are associated with gallstone disease risk in Chinese people.

In this study, we evaluated the association between polymorphisms at ABCB4 Exon 6 (Rs1202283), Exon 16 (Rs2230028) and gallstone disease using meta-analysis. We evaluated two loci attaining a genome-wide significance level of a P value less than 0.01 in this meta-analysis of four studies including 529 gallstone patients and 461 controls. Then we screened a Chinese population with these two polymorphisms and examined the risk stratification and their interaction with age, sex, body mass index (BMI) status and symptoms in gallstone disease. According to the likely mode of inheritance extracted from the meta-analysis for each locus, we illustrated that these two loci are associated with the gallstone disease risk of Chinese people by TaqMan® SNP genotyping assay.

Materials and methods

Literature search

We searched public databases PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), Embase (http://www.embase.com), ISI Wed of Knowledge (http://isiknowledge.com), Wanfang (http://www.wanfangdata.com.cn) and China Biological Medicine (CBM) (http://cbm.imicams.ac.cn) with the last update as of May 2015. The keywords used for search were ‘gallstone disease’ and ‘ATP Binding Cassette Transporter A4 or ABCB4’ combined with ‘gene or variants or polymorphism or alleles’, all of which were MeSH terms (Medical Subject Headings in the US National Library of Medicine). Only studies published in English or Chinese were identified. Afterwards, the full texts of the retrieved articles were scrutinized to ensure that data of interest was included. If two or more studies shared the same studied populations, the study with the small size was excluded. If more than one geographical or ethnic population were included in one paper, each ethnical population was considered separately.

Study criteria

Inclusion criteria were listed as the followings: 1. evaluation of the association between ABCB4 polymorphism and gallstone disease; 2. case-control study using either hospital-based or population-based designs; 3. genotype/allele counts of ABCB4 polymorphisms between cases and controls for estimating binary variable. Gallstone disease was diagnosed by ultrasonography or operation. Studies were excluded if they were published in a non-English and non-Chinese language or published in conference abstract form only.

Extracted information

We abstracted the following information from qualified studies (Table 1), including first author’s last name, publication date, population ethnicity, methods of diagnosis of gallstone, study design, methods of genotyping and the genotype in cases and controls. Information such as cases and controls’ age, gender and BMI were also collected.

Table 1.

List of references

References Year Ethnicity SNPs Methods Number
Case Control
Oliver Rosmorduc et al. 2003 French Exon 4, 5, 6, 8, 16 PCR-RFLP 108 66
Karl Esten Nakken et al. 2008 Norwegian Exon 5, 6, 13, 14, 15, 16 AD 16 95
Bronsky et al. 2010 Czech Exon 6, 16 PCR-RFLP 35 150
Milan Jirsa et al. 2014 Czech Exon 6, 16 AD 370 150
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AD: allelic discrimination; PCR: polymerase chain reaction; RFLP: restricted fragment length polymorphism.

Subjects

For the validation study, all the cases and controls were recruited in the Department of Biliary-Hepatic Surgery at The Affiliated Hospital of Guizhou Medical University, the Gallstone Disease Biobank project. The study protocol was approved by Ethical Committee at The Affiliated Hospital of Guizhou Medical University and written informed consent was obtained from all participants. We examined a sub-cohort that consisted of 296 individuals who were randomly selected from the total cohort using a random selection algorithm. The whole blood samples were obtained from these individuals. Demographic characteristic were described in Table 2. Among these patients, whole blood sample was collected from 171 patients with gallstone disease and 125 gallstone-free patients. All samples were stored in -80°C until analysis. Patients with hepatic, renal or endocrine disorders were not included in the study.

Table 2.

Baseline data for 296 recruited subjects

IndexIndex Gallstones (n = 171) No stones (n = 125) P
Sex ratio (M:F) 72:99 51:74 0.905†
Age (years) 46.1±9.2 53.2±5.6 0.267
BMI (kg/m2) 24.9±3.1 24.6±2.9 0.889
AST (units/l) 34.07±17.8 30.5±20.4 0.668
ALT (units/l) 33.2±19.3 29.2±21.6 0.867
LDLC (mg/dl) 130.7±35.1 113.3±28.9 0.015*
HDLC (mg/dl) 46.8±10.5 51.8±12.0 0.028*
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Two-sample Student’s t test, except

†

Pearson χ2 test.

Values are presented as mean ± s.d. BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDLC: low-density lipoprotein cholesterol; HDLC: high-density lipoprotein cholesterol.

*

P represents the significant differences between the Gallstones group and No stones group. P value <0.05.

SNP genotyping assay

We used MagCore® Genomic DNA Whole Blood Kit (RBC Bioscience, Taipei, Taiwan) for purification of total DNA (including genomic and mitochondrial DNA) from whole blood by MagCore® auto-extraction instrument. Analysis was performed with the TaqMan® SNP genotyping assay (Applied Biosystems, Foster City, CA, USA). The assay was designed for human SNP genotyping studies with the precision of TaqMan® reagent-based chemistry, ABCG8 gene D19H (C_26135643_10 for rs11887534) as positive control in Chinese [19], and the ABCB4 gene Exon 6 (C_8317490_30 for rs1202283) and Exon 16 (C_25472183_30 for rs2230028) were evaluated. Detection of the above gene variants was performed according to the SNP genotyping reaction protocol, under the following conditions, 95°C for 10 min, then 40 cycles of 95°C for 15 s alternating with 60°C for 90 s. The Agilent Mx3000p™ sequence detection system (Agilent Technologies, Santa Clara, CA, USA) was used to detect gene variants using VIC® and FAM™ dyes.

Statistical analysis

The meta-analysis was performed in Stata/SE 11.0 software (StataCorp LP, College Station, USA). We used the random-effects model with the method of DerSimonian & Laird to pool effect-size estimates from the individual studies. Heterogeneity was estimated qualitatively using the Mantel-Haenszel method [20], and quantified using the I2 statistic, with the ranges of 0 to 100% (I2 = 0-25%, no heterogeneity; I2 = 25-50%, moderate heterogeneity; I2 = 50-75%, large heterogeneity; I2 = 75-100%, extreme heterogeneity) [21]. Publication bias was evaluated by using funnel plots and the Egger test [22].

The biochemical and gene expression data analysis were performed using SPSS® 13.0 for Windows® (SPSS, Chicago, Illinois, USA). The comparison among groups for categorical variables was performed with Pearson χ2 tests or Fisher’s exact tests. Continuous variables were compared by two-sample Student’s t tests. Allelic frequencies were estimated by direct gene counting. A χ2 test or a Fisher’s exact test was used for testing Hardy-Weinberg equilibrium and power calculations for the sample size of each genotype. Haploview was used for estimating haploblocks, and haplotype analysis used a Hap-clustering program [23]. Binary logistic regression gave odds ratios of having gallstones under the influence of genotypes ABCB4 rs1202283 and rs2230028. For the crude odds ratio, the presence or absence of gallstones was the dependent variable, and rs1202283 or rs2230028 was the independent variable. P<0.05 was considered significant with a two-tailed test.

Results

Association of rs1202283 and rs2230028 at ABCB4 with gallstone disease in European: meta-analysis

We identified 16 studies potentially relevant for our analysis. 12 papers were excluded, leaving four in the final analysis (Figure 1). The studies comprised of French, Norwegian and Czech cohorts. All studies had genotypic information for ABCB4 rs1202283, rs2230028. A summary of study population characteristics is presented in Table 1. In allelic model, minor alleles of rs1202283 (pooled OR = 0.41, 95% CI: 0.25-0.67, P<0.001, Figure 2A) and rs2230028 (pooled OR = 0.12, 95% CI: 0.06-0.22, P = 0.001, Figure 2B) were significantly associated with an increased risk of gallstone disease in Europeans.

Figure 1.

Figure 1

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Flow diagram of search strategy and study selection. Sixteen papers potentially relevant for our study. Twelve papers were excluded and four papers including three cohorts were included for the final analysis.

Figure 2.

Figure 2

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Pooled random-effect-based odds ratio of gallstone disease for ABCB4 polymorphism. A. Minor alleles of Exon 6 polymorphism (R = 0.41, 95% CI: 0.25-0.67, P<0.001) was related with an increased risk of gallstone disease in European. B. Exon 16 polymorphism (OR = 0.12, 95% CI: 0.06-0.22, P = 0.001) was also related with an increased risk of gallstone disease in Europeans.

Publication bias

We used Funnel plot and Egger’s test to assess for publication bias. The resultant symmetrical funnel plot was symmetrical, consistent with an absence of publication bias. This was consistent with results of the Egger test for Exon 6 (P = 0.461) and Exon 16 (P = 0.315), Figure 3A and 3B.

Figure 3.

Figure 3

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Begg’s funnel plot of the Egger’s test for publication bias of ABCB4 polymorphism and gallstone disease. The horizontal line in the funnel plot indicates the fixed-effects summary estimates, and the sloping lines indicate the expected 95% CI for a given standard error. A. rs1202283. B. rs2230028.

Association of rs1202283 and rs2230028 at ABCB4 with gallstone disease in Chinese

Allelic frequencies of ABCB4 rs1202283 and rs2230028 are shown in Table 3. The distributions of genotypes in the whole study group were in Hardy-Weinberg equilibrium. The allelic frequencies were different from those reported previously in the European-American population. The homozygote AA allele of rs1202283 was quite rare (2.3%). Compared with Caucasians, the dominant allele distribution heterozygote CT of rs2230028 was high (97.6%) and the homozygote CC genotype was absent in the study population. ABCG8 rs11887534 (D19H) allele as a positive control exhibited the same results as previously reported in Chinese Taiwan population [19]. The association between the genotypes of ABCB4 rs1202283 and rs2230028, and the presence of gallstones are shown in Table 4, with ABCG8 rs11887534 (P = 0.006) as a positive control. There was a significant correlation of gallstone disease with the genotype distribution of rs1202283 (P = 3.5E-8) and rs2230028 (P = 0.023) polymorphisms. The minor alleles of rs1202283 and rs2230028 increased in patients with gallstones compared with controls. For example, in the rs1202283 polymorphism, the frequency of the heterozygote AG genotype was 52.6% in the gallstone group compared with 83.2% in the control group. The frequency of the rs2230028 heterozygote CT variant was 95.3% in the gallstone group compared with 100% in the control group.

Table 3.

Allelic frequencies of the polymorphisms in ABCB4 rs1202283 and rs2230028 in 296 subjects

Gene Allele ratio NCBI SNP reference Frequency
ABCB4: Exon 6 AA, AG, GG Rs1202283 23:194:79
ABCB4: Exon 16 CC, CT, TT Rs2230028 0:288:8
ABCG8: D19H CC, CG, GG Rs11887534 0:286:10
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NCBI: National Center for Biotechnology Information; SNP: single nucleotide polymorphism.

Table 4.

Association of genotype frequency of ABCB4 rs1202283 and rs2230028 with gallstone development

Gallstones (n = 171) No stones (n = 125) P *
ABCB4: Exon 6
    Genotype
        AG 90 104 3.5E-8
        AA + GG 81 21
ABCB4: Exon 16
    Genotype
        CT 163 125 0.023
        TT 8 0
ABCG8: D19H
    Genotype
        CG 10 0 0.006
        GG 161 125
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*

Pearson χ2 test.

ABCB4 rs1202283 GG genotype as risk with asymptomatic gallstone disease

For further analysis of the odds ratios of minor genotypes with gallstone disease, carriers of homozygote AA, heterozygote AG and homozygote GG genotypes of Exon 6 and those of homozygote CC, heterozygote CT and homozygote TT genotypes of Exon 16 were combined. The risk stratification of these minor genotypes for gallstone disease was determined and adjusted by age, sex, BMI and symptoms, which were well established as independent risk factors for gallstone disease. The rs1202283 heterozygote AG and rs2230028 homozygote TT variant contributed a significant and independent risk of gallstone formation. Epidemiological surveys demonstrated that the risk of asymptomatic gallstone disease increased with rs1202283 homozygote GG genotype at ABCB4. The gallstone risk associated with rs1202283 and rs2230028 polymorphisms was further stratified into different symptoms groups. The result clearly demonstrated a significant risk of asymptomatic gallstone disease associated with rs1202283 homozygote GG genotype than homozygote AA, heterozygote AG genotype (95% C.I.: 0.219-0.768; P = 0.005) and a greater risk than rs2230028 (95% C.I.: 0.264-4.506; P = 0.906). On the basis of these two SNPs in ABCB4, a haplotype analysis study was conducted. There was no significant difference in the distribution of each haplotype between the gallstone disease and control groups (Figure 4).

Figure 4.

Figure 4

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Overview of the physical and genetic structure of the ABCB4. The physical position of the investigated SNPs and a schematic representation of the gene structures are shown above. Haplotype blocks derived from the HapMap genotypes from individuals of Han Chinese Beijing (HCB) are outlined in black. No significant difference in the distribution of each haplotype between the gallstone disease and stone free groups.

Discussion

In this study, we pooled data from 4 studies which comprised of French, Norwegian and Czech cohorts. The meta-analysis of samples were selected from 529 gallstone patients and 461 control samples, and the results showed that ABCB4 rs1202283 and rs2230028 mutations were associated with an increased risk of gallstone disease in Europeans. An obvious difference of gallstone prevalence between ethnicities was present.

Gallstone disease is highly prevalent in European, Pima, Hispanic populations, and is relatively lower in Asian, and lowest in African populations [1]. Gallstone disease is a common clinical entity, with a prevalence of 10-15% detected by ultrasonography in Western populations. The overall prevalence is lower in Asia, ranging from 3-15% [24-26]. This difference may relate to both dietary habits and genetic factors. The relationship between diet and gallstones is still controversial [27]. Cholesterol gallstones are responsible for 80-90% of all gallstones in Western countries [24,25,28]. As a result of westernization of dietary habits, the composition of gallstones has also altered: up to 77% in Chinese populations are now cholesterol gallstones [25]. Therefore, we divided the population into Asian and Western.

We evaluated the two loci associated with gallstone disease attaining genome-wide significance in our meta-analysis as predictors of gallstone risk in 296 recruited subjects including 171 gallstone samples and 125 no gallstone controls. We found a significant correlation between the distribution of rs1202283 (AG) and rs2230028 (CT) polymorphisms and gallstone disease in the Chinese population. These similar results were present between ABCB4 polymorphism in relation with gallstone disease in both populations. Furthermore, upon dividing the population into Chinese and non-Chinese, the association of rs1202283 and rs2230028 at ABCB4 polymorphisms with gallstone disease did not change. The risk associated with Exon 6 (GG) was strong in asymptomatic gallstone disease. Additionally as a positive control, all the clinical conditions of ABCG8 D19H were similar to the Chinese Taiwan population previously reported [19]. The study also found that serum levels of total cholesterol, LDLC were significantly lower and HDLC were higher in subjects with gallstones than in those without gallstones.

Gallstone formation results from a complex interaction between multiple predisposing genes and environmental factors. Genetic susceptibility for gallstone formation is influenced by well-known risk factors including age, sex, obesity, parity, and medication [24,25,28,29]. In this study population, polymorphisms of ABCB4 and age, sex, obesity, parity, and medication were not associated with gallstone disease in univariable analysis. However, we found GG allele of rs2230028 polymorphism at ABCB4 gene was a common allele predicting susceptibility to asymptomatic gallstone disease independent of ethnicities. Previous studies also showed that Mdr2 gene knockout mice, the murine homolog of ABCB4, may develop bile cholesterol crystals [30,31]. The study by Oliver Rosmorduc et al. strongly suggested that ABCB4 mutations may lead to cholesterol gallstone when residual ABCB4 activity and subsequent biliary phospholipid secretion decreases below a critical threshold, which may depend on the type of mutation and other host or environmental factors [9]. Consistent with previous studies [13], this finding supports the hypothesis that the Exon 6 at ABCB4 mutation may affect the transporter function resulting in gallstone formation in earlier life. These polymorphisms may alter the conformation of ABCB4 transporters to modulate the intestinal absorption efficiency or the biliary secretion of cholesterol.

Epidemiological studies have indicated an association between low plasma HDLC levels and gallstone prevalence [26]. Super-saturation of bile with excess cholesterol is an essential step in gallstone formation. Bile is the major route for the elimination of excess cholesterol from the liver. In human studies, most of the cholesterol secreted into bile comes from circulating plasma lipoproteins, the free cholesterol carried by HDL particles binding to the scavenger receptor class B type 1 (SRB1), the uptake of cholesterol by LDL receptors or LDL receptor related proteins, and the dietary cholesterol in the chylomicron remnants. Newly synthesized cholesterol contributes very little (5-20%) to biliary cholesterol secretion [24,26,28,32]. In cholesterol homeostasis, plasma HDLC plays a key role in reverse cholesterol transport to the liver. The biliary secretion of free cholesterol markedly increases in Srb1 transgenic mice and transport of cholesterol into bile is mediated mainly by SRB1 [33]. More interestingly, the present study demonstrated that serum levels of total cholesterol, LDLC, and HDLC were significantly associated with abdominal pain in pancreatitis and other digestive system diseases [34,35]. As previously reported, polymorphism in ABCB4 was strongly associated (P = 9E-14) with the plasma LDLC concentrations on the high-cholesterol, high-fat diet. They indicated that genetic variation in ABCB4, or closely linked genes, was responsible for the dramatic differences among opossums in their LDLC response to an atherogenic diet [36,37]. Polymorphisms of ABCB4 and ABCB4-related genes may alter the transporter function, modify the intrahepatic cholesterol content and regulate the reverse cholesterol transport in cholesterol homeostasis. It is possible that gallstone formation may be a by-product of excess cholesterol excretion into bile to keep serum levels of cholesterol-containing lipoproteins lower and significantly associated with the risk of gallstone disease without symptoms, such as abdominal pain.

In summary, our results strongly support the role of rs1202283 (AG) and rs2230028 (CT) at ABCB4, and rs11887534 (CG) at ABCG8 were associated with the risk of gallstone disease. More notable is that the risk associated with rs1202283 (GG) was strong in asymptomatic gallstone disease. In the near future, ABCB4 genotyping should be used to confirm the diagnosis of asymptomatic gallstone disease and allow familial screening. Depending on the results, long-term curative or prophylactic ursodeoxycholic acid therapy could be initiated early to prevent the occurrence or recurrence of this disease and its severe complications.

Acknowledgements

This study was granted by the Brainstorm Project on Social Development by Department of Science and Technology of Guizhou Province (Grant No. SY [2015] 3047).

Disclosure of conflict of interest

None.

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