Influence of the Functional Polymorphisms in the OrganicAnion Transporting Polypeptide 1B1

in the Susceptibility to Colorectal Cancer

Gul Ozhan,1 Mehtap Kara,1 Fatih M. Sari,1 Hakan T. Yanar,2 and Buket Alpertunga1

Colorectal cancer is an important cause of death throughout the world, and its etiology involves the interactionof genetic and environmental factors. Transporter proteins are important in protecting organs from xenobioticsor toxins. Organic anion-transporting polypeptide 1B1 (OATP1B1) plays role in hepatic uptake and clearance ofalbumin-bound amphipathic organic compounds, including endogen substances, drugs, or xenobiotics. TheSLCO1B1 gene expressing OATP1B1 is highly polymorphic. Up to now, SLCO1BI variants were the focus ofseveral investigations on drug pharmacokinetics and cancer susceptibility. However, no information has beenavailable on association between SLCO1B1 and colorectal cancer risk. Therefore, the study aims to investigatethe relationship between colorectal cancer and the functional common variants of SLCO1B1 (388 A > G, - 11187G > A, 521 T > C) and to estimate the prevalence of these variants in the Turkish population. To that end, thedistributions of the variants were determined in 100 patients with colorectal cancer and 150 healthy volunteers.SLCO1B1 521 T > C was statistically significantly associated with colorectal cancer risk (odds ratio [OR] = 2.66;95% confidence interval [CI] = 1.31–5.41; p = 0.0057). In haplotype-based analysis, SLCO1B1 haplotypeG388-T11187-T521 might be associated with the development of colorectal cancer (OR = 4.26; 95% CI = 1.62–11.16;p = 0.002). We believe that the findings may be beneficial to the development of efficacious preventive strategiesand therapies for colorectal cancer.

Introduction

Colon and rectal cancer are two of the most frequentneoplasms and are the main reasons of the high mortality

ratio among all suffering from different types of cancer. Everyyear, there are *220,000 new cases of colorectal cancer di-agnosed and the number of deaths approaches 112,000 in theEuropean Union (Coleman et al., 2004). Genetic factors to-gether with influence of xenobiotics that are present in diet,cigarette smoke, drugs, bacterial toxins, and other biologicaland chemical factors may increase the risk of colorectal cancerdevelopment (Fan et al., 2007; Panczyk et al., 2009). However,the biological processes connecting lifestyle characteristicsand colorectal carcinogenesis remain unclear.

The organic anion-transporting polypeptide 1B1(OATP1B1, encoded by SLCO1B1) is one of the main hepaticuptake transporters and is expressed mainly at the basolateralside of hepatocytes. SLCO1BI mRNA has been also detected inother tissues, including small intestinal enterocytes (Kallio-koski and Niemi, 2009). It mediates the uptake not only ofdiverse endogenous substrates, such as bile acids, bilirubin,

and steroid hormone conjugates, but also of several drugs,such as statins, rifampicin, and the irinotecan metabolite SN-38 (Han et al., 2009; Johnson et al., 2009; Kalliokoski et al., 2010;Wen and Xiong, 2010; Brunham et al., 2011; Marciante et al.,2011; Rodrigues et al., 2011). In addition to the drugs, thisuptake transporter is important for the removal of a variety ofxenobiotics, such as microcystins, deoxycholic acid, andphalloidin (Tirona et al., 2001; Gerloff, 2004; Meier-Abt et al.,2004; Hagenbuch and Meier, 2004; Ilic et al., 2011; Zhang et al.,2011). Furthermore, in some studies, the expression ofOATP1B1 protein was observed in prostate, ovarian, breast,and liver cancers (Ilic et al., 2011; Pressler et al., 2011; Svobodaet al., 2011; Wlcek et al., 2011; Banerjee et al., 2012; Sprowl et al.,2012). However, up to now, no information has been availableon association between the SLCO1B1 uptake transporter geneand colorectal cancer risk.

Numerous genetic polymorphisms have been described inthe SLCO1B1 gene, and some of them have been linked toincreased or decreased transport activity of this uptaketransporter. Among them, the most prevalent and most rele-vant single-nucleotide polymorphisms (SNPs) are 388 A > G

1Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.2Department of General Surgery, Faculty of Medicine, Istanbul University, Istanbul, Turkey.

GENETIC TESTING AND MOLECULAR BIOMARKERSVolume 17, Number 3, 2013ª Mary Ann Liebert, Inc.Pp. 214–218DOI: 10.1089/gtmb.2012.0334

214

(*15, rs2306283), - 11187 G > A (*17, rs4149015), and 521 T > C(*5, rs4149056) (Oswald et al., 2008). It is suggested that the 388A > G variant is associated with increased OATP1B1 activity,and 521 T > C and - 11187 G > A variants are associated withreduced transport (Niemi et al., 2004; Sortica et al., 2012). Theallelic frequencies of these SLCO1B1 SNPs are highly variablebetween ethnicities (Pasanen et al., 2006; Xu et al., 2007;Mwinyi et al., 2008; Kalliokoski and Niemi, 2009; Tirona et al.,2001).

In this population-based case–control study, we estimatethe prevalence of them in the Turkish population and evaluatethe association between three functional SLCO1B1 SNPs (388A > G, - 11187 G > A, and 521 T > C) and colorectal cancer risk.

Materials and Methods

To examine association between the SLCO1B1 genotypesand susceptibility to colorectal cancer, we conducted a pop-ulation-based case-control study in the Turkish population.The study was approved by the ethics committee of IstanbulUniversity, and all participants provided written informedconsent. Blood samples were collected from 100 patients withcolorectal cancer and 150 healthy volunteers seen at theHospital of Istanbul University and Bagcilar Training andResearch Hospital during the same period. The criteria fordiagnosis of colorectal cancer were a clinical history consistentwith the disease, positive colonoscopic results, and routinelaboratory analysis parameters. The histopathological exam-inations were evaluated according to the established clinicalcriteria (Compton and Greene, 2004). Controls were hospitalpatients with various diagnoses (eye diseases, pulmonarydiseases, cardiovascular diseases, and neurological disorders,etc.) who never had cancer. For all subjects, we recorded thesmoking status in addition to gender, age, and body–massindex (BMI, kg/cm2). For smoking status, a person who hadsmoked at least once a day for > 1 year was regarded as asmoker. The smoking status was categorized into two groups:nonsmokers (never) and smokers (former and current). Therewas no significant difference regarding gender, age, and BMIbetween the case (48 women and 52 men; mean age 48.7 – 10.7years; mean BMI 25.6 – 3.2 kg/cm2) and control groups (74women and 76 men; mean age 58.4 – 10.2 years; mean BMI23.7 – 3.6 kg/cm2). Smokers constituted 65% of cases and 47%control subjects.

Venous blood was drawn from subjects, and genomic DNAwas extracted from whole blood using standard phenol–chloroform extraction protocols. The DNA purity and con-centration were tested spectrophotometrically. The sampleswere stored at - 20�C until analysis. Genotyping of SLCO1B1388 A > G, - 11187 G > A and 521 T > C variants was per-formed by polymerase chain reaction (PCR)–restriction frag-ment length polymorphism methods (Table 1). Thetemperature was controlled by a programmable heat block(Applied Biosystems Gene Amp PCR System 9700). Restric-tion enzymes were obtained from New England Biolabs andFermentas. All other molecular biology chemicals were ob-tained from Fermentas and Sigma-Aldrich. Genotyping wasdone blinded to case–control status. A 10% random samplewas genotyped twice for quality assurance, which yielded100% concordance.

The Hardy–Weinberg equilibrium was tested to comparethe observed and expected genotype frequencies among casesand controls by using v2. The genotype and allele frequencieswere determined by direct counting. For analyses of genotypefrequencies, the wild-type category (chosen either as the mostcommon wild-type frequency or arbitrarily if both allelesshowed similar frequencies) was the reference group. Oddsratios (ORs) and 95% confidence intervals (CIs) were esti-mated by conditional logistic regression analyses based on thecomparison of genotypes between patients with colorectalcancer and healthy controls, adjusting for the potential con-founders, age, gender, smoking, and BMI. Statistical analysiswas implemented in the Statistical Package for Social Sciencesprogram (version 13.0). Haplotype frequencies were esti-mated from genotype data by PHASE (version 2) (Stephensand Donnelly, 2003). The distribution of haplotypes in thecases and controls was compared by v2 test. A two-sidedp-value < 0.01 was considered to be statistically significant.

Results

We performed a genetic association study on three func-tional SNPs of SLCO1B1 388 A > G, - 11187 G > A and 521T > C with colorectal cancer in the Turkish population. In thestudy, there were no significant differences between patientswith the colorectal cancer and healthy volunteers for age andgender distribution, and this suggested that the matchingbased on these two variables was adequate. We investigated

Table 1. Details of Methodology Used in Genotyping

PCR conditions

SNP Primer sequenceDenature annealing

extensionRestriction

enzymeFragment

length (bp)

SLCO1B1 5¢-ATTATgTCTgAAgAgTCAAAT-3¢ 94�C 30 s BspDI388 A > G 56.8�C 30 s 337, 230, 107(rs2306283) 5¢-ATATTTCTCTgTATTTCTAggAA-3¢ 72�C 30 s

SLCO1B1 5¢-CAATAATTAACCAAgAATAg-3¢ 94�C 30 s AluI- 11187 G > A 51.4�C 30 s 191, 171, 20(rs4149015) 5¢-ACATATATACACACTTTTAg-3¢ 72�C 30 s

SLCO1B1 5¢-CAgCATAAgAATggACTAATACACC-3¢ 94�C 30 s HhaI521 T > C 60�C 30 s 237, 218, 19(rs4149056) 5¢-gAAgCATATTACCCATgAgC-3¢ 72�C 30 s

bp, base pair; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphisms.

OATP1B1 VARIANTS IN COLORECTAL CANCER 215

the associations between smoking status both colorectal can-cer risk and SLCO1B1 variants. There was no interaction be-tween the polymorphisms and smoking status in relation tocolorectal cancer risk (results not shown).

The genotype distributions did not significantly deviatefrom the Hardy–Weinberg equilibrium in cases and controlsfor any of the examined SNPs (Table 2). We then analyzed thedifferences between cases and controls in the distribution ofthe genotype. The SLCO1B1 388G and 521C recessive al-lele frequencies were 0.385 and 0.135 in cases comparedwith 0.411 and 0.299 in controls, respectively. For SLCO1B1- 11187 G > A variants, the genotype observed both in casesand controls was only GG. However, it might be investigatedmore samples for SLCO1B1 - 11187 G > A to be sure.

In the study, it was observed that SLCO1B1 521 T > C wasstatistically significantly associated with colorectal cancerrisk. The association was seen with SLCO1B1 521 T > C( p = 0.0057); specifically, patients carrying the C allele incomparison to patients carrying the T allele had a significantlyhigher risk of disease (OR = 2.66; 95% CI = 1.31–5.41) (Table 2).To confirm the genotyping results for these variants, whichhave association with colorectal cancer, the selected PCR-amplified DNA samples (n = 6, for each genotype in both casesand controls) were examined by DNA sequencing, and theresults were also 100% concordant. On the other hand,

genotype distribution of SLCO1B1 388 A > G and - 11187G > A in cases and controls did not significantly differ, andthus these polymorphisms were not associated with the risk ofcolorectal cancer (Table 2).

Next, we examined the association between SLCO1B1haplotypes and risk of colorectal cancer. The results of hap-lotype-based analysis are shown in Table 3. We observedsignificant haplotype effect for all haplotypes ( p = 0.01).Four haplotypes were found with the SLCO1B1 haplotypeG388-G11187-C521 being the most common. The SLCO1B1 haplo-type G388-T11187-T521 might be associated with the developmentof colorectal cancer (OR = 4.26; 95% CI = 1.62–11.16; p = 0.002).

Discussion

The main finding of the present study was to observe sig-nificant differences between the genotype and haplotypefrequencies of three functional SLCO1B1 (388 A > G, - 11187G > A and 521 T > C) variants associated with colorectal cancerrisk.

OATP1B1 mainly expressed on the sinusoidal membrane ofhuman hepatocytes. However, SLCO1BI mRNA has been alsodetected in other tissues, including small intestinal en-terocytes (Kalliokoski and Niemi, 2009). A large number ofSNPs and other sequence variations have been described inthe SLCO1B1 gene, and their allele frequencies vary markedlybetween different populations (Tirona et al., 2001; Pasanenet al., 2006). 388 A > G is quite common in all populations, withan allele frequency ranging from 40% in Europeans to 80% inSub-Saharan Africans and East Asians, whereas the 521 T > CSNP, relatively common in Europeans and Asians (allele fre-quency 10%–20%), is less frequent in Sub-Saharan Africans(2%) (Pasanen et al., 2006; Kalliokoski and Niemi, 2009). Thefrequency of the - 11187 G > A was 14% in Chinese, similar tothat in Japanese (15.8%), but greater than that of Caucasians(2.4%) and African Americans (0%) (Xu et al., 2007). There wasonly one study about the frequencies of SLCO1B1 in theTurkish population (Mwinyi et al., 2008). In that study, eightSLCO1B1 SNPs (388 A > G, 411 G > A, 463 C > A, 521 T > C, 571C > T, 597 C > T, 1463 G > C, and 1929 A > C) were genotyped in300 German, 94 Turkish, and 115 African samples. For thefrequencies of SLCO1B1 388 A > G and 521 > T > C0, genotypeswere 0.463 and 0.122, respectively, in the Turkish population.In addition, between the Caucasian and African samples,significant differences in sequence variability were observedleading to a different haplotype profile in these populations(Mwinyi et al., 2008). In the present study, the frequencies of388A and 521T alleles with low activity are 0.599 and 0.766,

Table 2. Allele Frequencies of SLCO1B1Polymorphisms in Patients with Colorectal

Cancer and Healthy Subjects

Frequency

Polymorphisms AlleleCases

(n = 100)Controls(n = 150)

OR(95% CI)

p-Value

SLCO1B1 A 0.615 0.589 G vs. A388 A > G 0.774(rs2306283) G 0.385 0.411 0.91

(0.52–1.59)

SLCO1B1 G 1 1 G vs. A- 11187 G > A 1.0(rs4149015) A — — —

SLCO1B1 T 0.865 0.701 C vs. T521 T > C 0.0057(rs4149056) C 0.135 0.299 2.66

(1.31–5.41)

OR, odds ratio; CI, 95% confidence interval; ORs were adjusted forage, sex, smoking status for logistic regression analysis.

Table 3. Haplotype Frequencies Constructed by PHASE Algorithm and the Association

with Colorectal Cancer Risk

Haplotype Frequency

SLCO1B1 388A > G (rs2306283)

SLCO1B1 - 11187G > A (rs4149015)

SLCO1B1 521T > C (rs4149056)

Cases(n = 100)

Control(n = 150)

OR(95% CI) p-Value

G C C 0.538 0.550 1 (reference)G T C 0.327 0.151 0.45 (0.22–0.91) 0.040G C T 0.077 0.039 0.49 (0.14–1.73) 0.260G T T 0.058 0.260 4.26 (1.628–11.16) 0.002

p-value for testing all of haplotypes: cases versus controls = 0.01.

216 OZHAN ET AL.

respectively (Table 2). Frequency of the 388A allele was higherin the present population than in the previously studiedpopulation.

Up to now, SLCO1BI variants, especially 388 A > G, - 11187G > A, and 521 T > C), were the focus of several investigationsinto drug transport, efficacy, and toxicity, although OATP1B1mediates the uptake of endogenous substrates, drugs, andother xenobiotics (Han et al., 2009; Johnson et al., 2009; Kal-liokoski et al., 2010; Wen and Xiong, 2010; Brunham et al.,2011; Marciante et al., 2011; Rodrigues et al., 2011). For ex-ample, these genetic variations in the SLCO1B1 gene werereported to be identified as significant for statin-associatedmyopathy risk and for alterations in the pharmacokinetics ofstatins (Han et al., 2009; Johnson et al., 2009; Wen and Xiong,2010; Brunham et al., 2011; Marciante et al., 2011; Rodrigueset al., 2011; Santos et al., 2011). Han et al. (2009) observed thatthe 521TC or 521CC genotypes were significantly associatedwith higher SN-38 area under the plasma concentration–timecurve (AUC) and independently predictive for grade 4 neu-tropenia. Similarly, Kalliokoski et al. (2010) reported that the521CC genotype had been associated with about a 60%–190%increased AUC of repaglinide, oral antidiabetic drug. In aprospective study carried out in colorectal cancer patients byThomas et al. (2011), thymidylate synthase (TYMS), methy-lenetetrahydrofolate reductase (MTHFR), dihydropyrimidinedehydrogenase (DPYD), uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1), multidrug resistance-associatedprotein 1 (ABCC1), and SLCO1B1 genes involved in thepathways of 5-fluorouracil and irinotecan were investigatedfor their potential association with clinical outcomes andtoxicities. They found that no association was observed be-tween genetic markers and drug response. Only MTHFR 1298A > C and MTHFR diplotypes (for 677 C > T and 1298 A > C)can potentially predict toxicity in patients treated with 5-fluorouracil as a single chemotherapeutic drug. When inves-tigated the pharmacogenomic profile of irinotecan-inducedgastrointestinal toxicity in colorectal cancer patients by a thenovel drug-metabolizing enzyme and transporter microarraygenotyping platform, a weak correlation was found of ir-inotecan toxicity and G/A heterozygous genotype in theSLCO1B1 388 A > G gene (Di Martino et al., 2011). Rhodes et al.(2007) demonstrated the combination of SLCO1B1 521T allele,p-glycoprotein (ABCB1) 1236C allele, and UGT1A1*28 vari-ant-7 repeat was associated with grade-3/4 toxicities in met-astatic colorectal cancer patients treated with first-lineirinotecan. In the other study related to irinotecan pharma-cokinetics and neutropenia in cancer patients, it was observedthat SLCO1B1 521 T > C was associated with increasedirinotecan AUC, and SLCO1B1 388 A > G was associated withincreased absolute neutrophil count nadir (Innocenti et al.,2009).

In addition, the expression of OATP1B1 protein andSLCO1B1 polymorphism were recently associated with can-cer (prostate, ovarian, breast, and liver) and some disorders.Huang et al. (2004) reported that the incidence of severeneonatal hyperbilirubinemia was higher in Asians than inWhites, and neonates with the 388 A > G variant were at highrisk to develop severe hyprbilirubinemia. OATP1B1 influxestrone-3-sulfate and thyroxine and these hormones play amajor role in ovarian and thyroid cancers, respectively(Pressler et al., 2011). Lee et al. (2008) observed OATP1B3overexpression in apoptotic resistance in colon cancer, while

low expression of OATP1B1 and OATP1A2 mRNA in bothtumor and normal colonic mucosa. However, no informationhas been available on association between the SLCO1B1 up-take transporter gene and colorectal cancer risk. We havecompared the frequencies of three functional SLCO1B1 vari-ants in patients with colorectal cancer and healthy volunteersto identify a possible association between individual geneticvariation and susceptibility to colorectal cancer in the presentstudy. We observed that SLCO1B1 521 T > C was statisticallysignificantly associated with risk of developing colorectalcancer (OR = 2.66; 95% CI = 1.31–5.41; p = 0.0057) while therewas no association between SLCO1B1 388 A > G and - 11187G > A and risk of colorectal cancer (Table 2). As haplotypeanalysis for three SNPS, SLCO1B1 haplotype G388-T11187-T521

might be associated with the development of colorectal cancer(OR = 4.26; 95% CI = 1.62–11.16; p = 0.002) while there wasobserved significant effect for all of haplotypes ( p = 0.01).

In conclusion, our study is the first study to evaluate SNP-and haplotype-based associations between SLCO1B1 andcolorectal cancer. SLCO1B1 seems to play a role in colorectalcancer, but inheritance is complex, and genetic factors interactwith environmental factors. We believe that the findings maybe beneficial to the development of efficacious preventivestrategies and therapies for colorectal cancer. Nevertheless,further larger studies to confirm these findings and to identifythe risk-conferring variations in the gene are required. Also,the results may be a basis for studies on the interindividualvariability in drug disposition and perhaps certain diseaseprocesses in the Turkish population.

Acknowledgment

Authors wish to thank all subjects who volunteered toparticipate.

Author Disclosure Statement

The study was approved by the ethics committee of theUniversity (2011/87-555) and all participants provided writ-ten informed consent. This work conducted in accordancewith the Declaration of Helsinki (1964) was supported by theResearch Fund of Istanbul University (10477/11122).

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Address correspondence to:Gul Ozhan, PhD

Department of Pharmaceutical ToxicologyFaculty of PharmacyIstanbul University

BeyazitIstanbul 34116

Turkey

E-mail: gulozhan@istanbul.edu.tr

218 OZHAN ET AL.