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Keywords:

  • SLCO1B1;
  • association study;
  • essential hypertension;
  • polymorphism

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Solute carrier organic anion transporter family member 1B1 (SLCO1B1) is an important hepatic uptake transporter that can transport a wide variety of endogenous compounds, including thyroid hormones and prostaglandin E2. Dysregulation of thyroid hormones and prostaglandin E2 plays a role in the development of hypertension, suggesting that SLCO1B1 might contribute to the aetiology of essential hypertension (EH). In this study, we selected five single nucleotide polymorphisms (SNPs) at the SLCO1B1 gene promoter or coding regions and performed a case-control association study involving 731 unrelated Uyghur subjects, including 374 hypertensive and 357 normotensive individuals, to investigate the potential genetic contribution of SLCO1B1 to the aetiology of EH. Of the five polymorphisms, only one (i.e., rs4149014) showed correlation with EH. The minor allele of SNP rs4149014 at the SLCO1B1 promoter showed association with increased risk for EH (adjusted OR 1.88; 95% CI 1.36–2.60; P= 1.22 × 10−4). This study provides preliminary genetic evidence for the role of variant of SLCO1B1 in the susceptibility to human EH in Uyghurs.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Solute carrier organic anion transporter family member 1B1 (SLCO1B1) is expressed exclusively at the basolateral membrane of hepatocytes and is involved in the hepatic uptake of a broad array of endogenous compounds, such as leukotriene C4, prostaglandin E2 (PGE2), thyroid hormones, bilirubin, and its glucuronide conjugates (Abe et al., 1999; Cui et al., 2001). Among them, thyroid hormones and PGE2 are related to blood pressure (BP) regulation. Thyroid hormones cause vascular relaxation, decrease systemic vascular resistance, induce a rise in cardiac contractility and frequency, and ultimately affect BP. Hypothyroidism has been shown to increase the prevalence of hypertension (Fletcher & Weetman, 1998; Danzi & Klein, 2003). PGE2 plays an important role in regulating renal and systemic hemodynamics and sodium homeostasis, and in causing a decrease in systemic arterial pressure. Dysregulation of PGE2 synthesis has also been suggested to perform a function in the pathogenesis of hypertension (Nasjletti, 1998; Ye et al., 2006). Thus, we examined SLCO1B1 as a candidate gene for human hypertension.

In this study, we selected five polymorphisms at the promoter or coding regions of SLCO1B1 and conducted association analysis to assess their roles in essential hypertension (EH) in a Uyghur population, which is currently residing in Xinjiang, China.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Subjects

A total of 731 unrelated Uyghur farmers were studied. They were recruited from three villages of the rural area of Tulupan District of Xinjiang, China. All participants were invited to have a health examination in the morning after an overnight fast. Participants were asked to avoid alcohol, cigarette smoking, tea, and exercise for at least 1 h before the BP was measured. The BP was measured with a standard mercury sphygmomanometer after having been seated for 10 min and with at least 5 min between measurements. Four BP measurements were made by two cardiologists, each taking two measures. The first reading of each cardiologist was discarded, and the second readings of the two cardiologists were recorded and averaged. Hypertensive subjects were defined as having systolic BP (SBP) ≥140 mm Hg, diastolic BP (DBP) ≥90 mm Hg, or taking antihypertensive therapy. The normotensive subjects were those with both SBP and DBP below 140 mm Hg and 90 mm Hg, respectively, and without a history of hypertension. All participants completed a questionnaire on personal medical history. Secondary hypertension was excluded by medical history and physical examination. All hypertensives were older than 30 years of age. The younger normotensives may not be proper controls as they are indeed free of disease at study entry but may develop hypertension at a later stage. Thus, in this study an older control population (age ≥40 years) was selected. Finally, 374 hypertensive and 357 normotensive subjects were included. Fasting venous blood samples from the participants were taken for biochemical analysis. The protocol was approved by a local ethics committee, and informed consent was obtained from each participant.

Genotyping

In this study, five single nucleotide polymorphisms (SNPs) (rs4149013, rs17328763, rs4149014, rs2306283, and rs4149056) were genotyped using GenomeLab SNPstream Genotyping System (Beckman Coulter Inc. Fullerton, CA) at the Chinese National Human Genome Center, Shanghai. The PCR and single base extension primers for each polymorphism are listed in Table S1.

Statistical Analysis

A χ2 test was used to examine Hardy–Weinberg equilibrium (HWE) for each locus. Haplotypes were reconstructed using PHASE version 2.1.1 software. Based on the reconstructed haplotype data, we used HaploBlockFinder (Zhang & Jin, 2003) to calculate |D′| and r2 to measure linkage disequilibrium (LD). The Haploview program was adopted to yield similar |D′| and r2 compared with HaploBlockFinder.

The demographic details of the hypertensive and normotensive groups with continuous variables were compared by student unpaired t test and categorical variables by Pearson's χ2 test. Differences in allele and genotype frequencies between hypertensives and normotensives were compared using Pearson's χ2 test or Fisher's exact test. Binary logistic regression analysis was performed to compute unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Dominant and recessive genetic models were also examined for each polymorphism. All aforementioned analyses were performed with SPSS version 15.0 software (SPSS Inc, Chicago, IL, USA). A two-sided probability value of ≤0.05 was considered statistically significant. Statistical powers, the percentages of studies which would be expected to yield a significant effect and reject the null hypothesis that OR was 1.0, were estimated using the Power and Precision version 3 program (Biostat, Englewood, NJ, USA). Unbiased estimates of FST were calculated following Weir and Hill (2002).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Demographic Details of Study Subjects

The demographic details of the hypertensive and normotensive groups are given in Table 1. Age, gender distribution, and fasting glucose were comparable between hypertensive and normotensive groups. Serum triglycerides and waist-to-hip ratio (WHR) were slightly higher in hypertensives than in normotensives (P < 0.05 and <0.01, respectively). Body mass index (BMI), SBP, DBP, and total cholesterol were significantly greater in hypertensive subjects when compared to normotensive controls (all P < 0.001). The OR for EH for every five-unit increase in BMI was 1.62 (95% CI 1.37–1.91) (P= 9.80 × 10−9). BMI remained associated with EH after adjustment for age and gender (OR 1.63; 95% CI 1.39–1.95; P= 6.11 × 10−9).

Table 1.  Demographic characteristics of study participants
 HypertensiveNormotensiveP
  1. Values shown are mean ± SD. N.S. = nonsignificant, BMI = body mass index, WHR = waist-to-hip ratio, SBP = systolic blood pressure, DBP = diastolic blood pressure, TC = total cholesterol, TG = triglycerides, GLU = fasting glucose.

N374357 
Age, y54.3 ± 10.353.1 ± 9.4N.S.
Men,%34.540.6N.S.
BMI, kg/m227.9 ± 4.625.8 ± 4.2<0.001
WHR0.890 ± 0.0990.872 ± 0.070<0.01
SBP, mm Hg162.8 ± 23.1119.3 ± 12.3<0.001
DBP, mm Hg95.5 ± 13.374.4 ± 8.3<0.001
GLU, mmol/l5.76 ± 1.645.83 ± 2.43N.S.
TC, mmol/l4.68 ± 1.244.39 ± 1.00<0.001
TG, mmol/l1.89 ± 1.361.65 ± 1.25<0.05

LD between Polymorphisms

Five polymorphisms were genotyped in this study. Table 2 lists all polymorphism information. Three polymorphisms (rs4149013, rs17328763, and rs4149014) are in the SLCO1B1 promoter region and two (rs2306283 and rs4149056) are in the coding region of SLCO1B1. LDs between them are shown in Table 3. As shown, no polymorphic pairs within SLCO1B1 had a high r2 value (all r2 < 0.3).

Table 2.  Genotype and allele frequencies of SNPs in the hypertensive and normotensive groups
PolymorphismsFunctionGenotype/AlleleHypertensiveNormotensiveP
  1. Significant results (P≤ 0.05) are in bold.

  2. 1The positions of variations correspond to positions in the SLCO1B1 DNA sequence with the first base of the ATG first codon set to 1.

rs4149013Promoter region: −120991AA299(0.826)277(0.801)0.339
AG61(0.169)64(0.185) 
GG2(0.006)5(0.014) 
A659(0.910)618(0.893)0.278
G65(0.090)74(0.107) 
rs17328763Promoter region: −119391TT324(0.890)295(0.858)0.192
TC40(0.110)47(0.137) 
CC0(0)2(0.006) 
T688(0.945)637(0.926)0.141
C40(0.055)51(0.074) 
rs4149014Promoter region: −115561TT246(0.667)271(0.768)0.006
TG112(0.304)78(0.221) 
GG11(0.030)4(0.011) 
T604(0.818)620(0.878)0.002
G134(0.182)86(0.122) 
rs2306283Exon 5:Asp130AsnCC137(0.374)116(0.331)0.365
CT180(0.492)177(0.506) 
TT49(0.134)57(0.163) 
C454(0.620)409(0.584)0.164
T278(0.380)291(0.416) 
rs4149056Exon 6:Val174AlaTT300(0.809)267(0.756)0.234
TC66(0.178)80(0.227) 
CC5(0.013)6(0.017) 
T666(0.898)614(0.870)0.098
C76(0.102)92(0.130) 
Table 3.  Linkage disequilibrium test of SLCO1B1
 rs17328763rs4149014rs2306283rs4149056
|D′|
rs414901310.9070.6440.581
rs17328763 0.6350.6650.081
rs4149014  0.6190.489
rs2306283   0.489
r2
rs41490130.0070.0160.0290.280
rs17328763 0.0050.0190.003
rs4149014  0.0440.006
rs2306283   0.020

Polymorphisms and Hypertension Risk

Table 2 presents the genotype distributions and allele frequencies of SLCO1B1 polymorphisms in the hypertensive and normotensive groups. No deviation from HWE was observed in all polymorphisms in the two groups. As shown in Table 2, the genotype distributions and allele frequencies of SNP rs4149014 differed significantly between hypertensive and normotensive subjects while the other four (i.e., SNP rs4149013, rs17328763, rs2306283, and rs4149056) did not. The minor allele of SNP rs4149014 showed association with a higher risk of EH (OR 1.62; 95% CI 1.20–2.18; P= 0.002, Power = 90%) (Additive model). After adjusting for gender, age, BMI, WHR, fasting glucose, total cholesterol, and triglycerides, this association remained significant (OR 1.88; 95% CI 1.36–2.60; P= 1.22 × 10−4) (Table S2). When dominant and recessive models were assessed for each of those five polymorphisms, significant association was seen only in the dominant model of SNP rs4149014 (OR 1.69; 95% CI 1.20–2.38; P= 0.003). After adjusting for gender, age, BMI, WHR, fasting glucose, total cholesterol, and triglycerides, this association remained significant (OR 2.00; 95% CI 1.40–2.86; P= 1.31 × 10−4). The additive model provided stronger evidence of association for SNP rs4149014 when compared to the dominant model.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

This study focused on three polymorphisms in the promoter region (rs4149013, rs17328763, and rs4149014) and two in the coding region of SLCO1B1 (rs2306283 and rs4149056) and conducted association analysis to assess their roles in EH in the Uyghur population. Of the five polymorphisms, only one (i.e., rs4149014) showed correlation with EH. The findings provided preliminary evidence that the minor allele of SNP rs4149014 at the SLCO1B1 promoter was associated with increased risk for EH in Uyghurs. It is presently unknown whether rs4149014 is located in an important motif within the SLCO1B1 promoter, and further studies are required to link the rs4149014 polymorphism with functional changes in SLCO1B1 expression.

Recently reported data suggested that SNP rs2306283 (Asp130Asn) and rs4149056 (Val174Ala), two common nonsynonymous SNPs within SLCO1B1, are associated with altered pharmacokinetics of pravastatin (Nishizato et al., 2003; Mwinyi et al., 2004; Kivisto & Niemi, 2007). A genome-wide study also indicated that SNP rs4363657, which is in nearly complete linkage disequilibrium with SNP rs4149056, is strongly associated with myopathy in Europeans (Link et al., 2008). Iwai et al. (2004) showed that transport activity for 17-beta-estradiol 17-beta-d-glucuronide of SLCO1B1*15 (Asp130Ala174) was decreased compared with SLCO1B1*1a (Asn130Val174) and the transport activity of SLCO1B1*1b (Asp130Val174) and SLCO1B1*5 (Asn130Ala174) was similar to that of SLCO1B1*1a. Japanese subjects with the SLCO1B1*15 allele had higher serum bilirubin levels and lower pravastin clearance (Ieiri et al., 2004), indicating that the variants at rs2306283 and rs4149056 may alter certain functions of the SLCO1B1 protein. Our results showed that neither SNP rs2306283 nor rs4149056 was associated with hypertension. In addition, a haplotype analysis for rs2306283 and rs4149056 did not yield any significant association with hypertension (data not shown). The frequency of the SLCO1B1*15 allele in Uyghurs (10.0%) is similar to that in the Japanese population (15.0%) (Nishizato et al., 2003) and the Chinese population (11%) (Xiang et al., 2006). Therefore, the results of this study may suggest that the amino acids at codon 130 and 174 of SLCO1B1 may not be the binding site for thyroid hormones and prostaglandin E2 that are involved in BP regulation.

SNP rs4149013, rs17328763, rs4149014, rs2306283, and rs4149056 were included in two (Adeyemo et al., 2009; Zhang et al., 2009), four (Burton et al., 2007; Adeyemo et al., 2009; Cho et al., 2009; Org et al., 2009), five (Burton et al., 2007; Adeyemo et al., 2009; Cho et al., 2009; Org et al., 2009; Zhang et al., 2009), two (Sabatti et al., 2009; Zhang et al., 2009) and two (Adeyemo et al., 2009; Zhang et al., 2009) genome-wide association studies (GWAS) of hypertension and/or BP, respectively. However, all of them failed to detect these five SNPs as associated with hypertension and BP.

Of note, SNP rs4149014 is virtually monomorphic in Caucasians. Of the 11 HapMap populations, the minor allele frequency of rs4149014 is higher than 0.100 only in the Chinese and Japanese populations. Of five GWAS of hypertension and/or BP which included rs4149014, two were conducted in Caucasians (Burton et al., 2007; Org et al., 2009), one in African Americans (Adeyemo et al., 2009), one in Koreans (Cho et al., 2009) and one in Chinese Han (Zhang et al., 2009).

It is also noted that the GWAS of hypertension and/or BP have been conducted in Europeans (Burton et al., 2007; Levy et al., 2007; Levy et al., 2009; Newton-Cheh et al., 2009; Org et al., 2009; Wang et al., 2009), African Americans (Adeyemo et al., 2009), Finns (Sabatti et al., 2009), Koreans (Cho et al., 2009) and Han Chinese (Zhang et al., 2009) and the results were different between different ethnic populations. For example, Zhang et al. (2009) indicated that the top 20 loci at P < 6 × 10−5 for hypertension and/or BP in Chinese did not overlap with those 10 loci that attained genome-wide significance (P < 5 × 10−8) in Europeans of the CHARGE consortium (Levy et al., 2009) and not all association of hypertension and/or BP in Chinese population for those 10 loci in the CHARGE consortium were statistically significant. Adeyemo et al. (2009) also demonstrated that there were considerable ethnic differences in genome-wide association of hypertension and/or BP between African Americans, an admixed population with European and African ancestries, and European-derived populations, although African Americans shared some genetics of BP and hypertension with Europeans.

The Uyghur population, settled in Xinjiang, China, is an admixed population with 60% European ancestry and 40% East Asian ancestry (Xu et al., 2008). Admixture affects allele frequencies at many loci as well as affecting local LD patterns. As shown in Table S3, SNP rs17328763, rs4149014, and rs2306283 had much higher FST between East Asian (Han Chinese in Beijing (CHB) and Japanese in Tokyo (JPT)) and European American in Utah (CEU) populations than rs4149013 and rs4149056. Compared to CEU population, CHB and JPT populations are more likely to have lower frequency of rs17328763 C allele and rs2306283 T allele of SLCO1B1, and higher frequency of rs4149014 G allele. The frequencies of rs17328763 C allele, rs2306283 T allele, and rs4149014 G allele of SLCO1B1 in the Uyghur population were intermediate between East Asian (CHB and JPT) and CEU populations, reflecting to a certain extent that Uyghurs are the outcome of the genetic admixture of the Caucasians and East Asians. As the population we studied was a Uyghur population, an admixture population, and living in the Tulupan area that is arid and one of the hottest places in the world, genetic association studies of hypertension in this population may yield different insights. Therefore we believed that our preliminary finding of an association of SNP rs4149014 provided the first genetic evidence that SLCO1B1 played a role in the susceptibility to human EH in Uyghurs.

This study only analyzed three variants in the promoter region and two nonsynonymous variants of SLCO1B1. We recognize that there may be additional SLCO1B1 variants that may affect the susceptibility to EH. However, this study included most of the important variants in the SLCO1B1 promoter or coding regions, which is economical and efficient, as the first pass, for pinpointing functional genetic variants responsible for the effects on EH. Due to the low number of SLCO1B1 variants and experimental subjects, the findings are preliminary. Further confirmation studies are needed to examine more variants that can cover all common SNPs spanning the SLCO1B1 gene and include more subjects.

This study also showed that BMI was associated with hypertension, which was consistent with most previous studies (Colin Bell et al., 2002; Kawada, 2002; Nguyen et al., 2009). Several mechanisms have been suggested to play a potential role in the effect of BMI on hypertension. One may be related to increased insulin resistance. Body fat may lead to an increase in fatty acids in the portal blood vessels, promoting insulin resistance and leading to the development of hypertension and other metabolic complications (Lamarche, 1998; Barnard & Wen, 1994). Other mechanisms include increased renal sodium reabsorption, subclinical inflammation, and leptin resistance (Narkiewicz, 2006).

In summary, this study showed that SNP rs4149014 in SLCO1B1 is associated with EH in the Uyghur population. Considering the complex nature of EH and the preliminary nature of this study, further validation work is imperative including replication in more subjects and functional studies to elucidate the effect of the polymorphism on EH.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

This work was funded by the grants from the National Natural Science Foundation of China (30500291), the Science and Technology Commission of Shanghai Municipality (04dz14003), the National Outstanding Youth Science Foundation of China (30625016), National Science Foundation of China (30890034), and 863 Program (2007AA02Z312). Li Jin is also supported by the Center for Evolutionary Biology and Shanghai Leading Academic Discipline Project (B111).

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  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Table S1 PCR and single base extension primers used for SNP detection

Table S2 Logistic Regression Analysis: Association of SNP rs4149014 With Essential Hypertension in the Uyghur Population

Table S3 Allele Frequencies and FST of SLCO1B1 Polymorphisms in the Uyghur and HapMap Populations

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AHG_622_sm_TableS1-S3.doc97KSupporting info item

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