Lack of association between SLCO1B1 polymorphism and the lipid-lowering effects of atorvastatin and simvastatin in Chinese individuals

To investigate the SLCO1B1 388A>G and 521T>C polymorphisms in hyperlipidemia patients and evaluate the effect of the two polymorphisms on the lipid-lowering efficacy of pitavastatin. The functional polymorphisms of SLCO1B1 (388A>G and 521T>C) were genotyped in 140 Chinese patients with essential hyperlipidemia using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and one-step tetra-primers ARMS-PCR. Eighty-five patients were enrolled in the clinical trial and given 2 mg of pitavastatin daily for 8 weeks. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) serum levels were measured at baseline, after 4 weeks and after 8 weeks of treatment. The allele frequencies of SLCO1B1 388A>G and 521T>C in essential hyperlipidemia patients were 71.1% and 11.1%, respectively. The 4- and 8-week treatment with pitavastatin significantly reduced TC, TG, and LDL levels, but there was no statistical difference among patients with wild type, SLCO1B1 388A>G or SLCO1B1 521T>C in the lipid-lowering efficacy of pitavastatin. The present study found that the allele frequencies of SLCO1B1 388A>G and 521T>C in Chinese patients with essential hyperlipidemia are comparable to those in healthy Chinese population. SLCO1B1 388A>G and 521T>C do not affect the lipid-lowering efficacy of pitavastatin.

Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is widely used both in primary and secondary prevention of coronary heart disease (CHD). Pravastatin is not subject to metabolism by cytochrome P450s, but it is actively transported from blood into target tissues (e.g. hepatocytes in the liver) by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1. The aim of the present study was to evaluate the impact of SLCO1B1 521T-->C (Val174Ala) functional genetic polymorphism on the lipid-lowering efficacy of multiple-dose pravastatin in Chinese patients with CHD. Forty-five hospitalized patients with CHD prospectively received pravastatin as a single-agent therapy (20 mg day(-1) p.o.) for 30 days. Serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol concentrations were determined before and after pravastatin treatment. Pravastatin treatment significantly decreased plasma lipids in all patients (P < 0.001). Importantly, we showed an attenuated pravastatin pharmacodynamic effect on total cholesterol in patients with 521TC heterozygote genotype (from 5.52 +/- 0.51 mmol l(-1) to 4.70 +/- 0.35 mmol l(-1), % change -14.5 +/- 6.6%, N = 9) compared with 521TT homozygote genotype (from 5.47 +/- 1.15 mmol l(-1) to 4.21 +/- 0.89 mmol l(-1), % change -22.4 +/- 10.3%, N = 36) (mean +/- SD, P = 0.03, two-tailed test with alpha set at 5%). SLCO1B1 521T-->C functional polymorphism did not significantly influence pravastatin pharmacodynamics on other plasma lipids (P > 0.05). The 521T-->C polymorphism of SLCO1B1 appears to modulate significantly the total cholesterol-lowering efficacy of pravastatin in Chinese patients with CHD. Further studies are warranted to determine the extent to which SLCO1B1 genetic variation may contribute to resistance to pravastatin in Asian patients treated with standard doses of pravastatin.

Familial hypercholesterolemia (FH) is one of the most common genetic disorders characterized by a predominant elevation in plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentration and higher incidence of premature atherosclerotic cardiovascular disease (ASCVD). It has been reported that the long-term coronary artery disease (CAD) and ASCVD risk in the US adults with the FH phenotype are up to approximately five-fold higher than that in the general population.[1] It has also been estimated that there is an important long-term burden of ASCVD in phenotypic but undiagnosed FH patients in the US, with the acceleration of CAD risk by 20–30 years.[1] In recent years, the features of under-diagnosis and under-treatment of FH patients has attained an intensive attention worldwide.[2] This increased risk is age dependent, with the highest relative risk in younger index ages. Notably, several atherosclerosis-related international academic organizations or societies have issued statements or guidelines consequently, which call for the actions to improve the diagnosis and treatment of this unique, treatable disease globally.[3–6] In the Asia Pacific region, FH is estimated to affect at least 15 million people.[7] Among them, China alone may account for more than half of the FH patients as it is the world's most populous country. The general knowledge regarding FH is not very unfamiliar for medical professionals. Premature ASCVD is a great concern in FH patients due to the extremely high plasma LDL-C concentration. If homozygous FH (HoFH) is left untreated, tendon xanthomas may usually be detected.[2] Since the 1950s, FH patients have been divided into heterozygous FH (HeFH) and HoFH, and diagnosing HeFH and HoFH based on the phenotypic features of ASCVD or xanthomas has frequently been difficult without the DNA analysis of FH genes.[3] With the development of genetic testing technology, multiple studies revealed that a severe defect in the ability to bind and internalize LDL particles was caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR).[8] Recent genetic insights indicate that besides LDLR (approximately 75%–95%), mutations in alleles of other genes including apolipoprotein B (ApoB), proprotein convertase subtilin/kexin9 (PCSK9), and LDLR adapter protein 1 (LDLRAP1) may also be a cause in few FH patients, which can result in impaired LDL metabolism, leading to life-long elevations in LDL-C and increased risk for premature ASCVD.[8–10] Currently, it is estimated that this unique disease of abnormal cholesterol metabolism presents in all racial and ethnic groups affecting 1 of 200–500 individuals worldwide and is now increasingly recognized as a global health issue.[5,6] From the perspectives of theory and clinical practice, FH as a major global public health challenge is even more serious in China. First, China is the largest country in the world and accounts for nearly one-fifth (18.84%) of the total 6.7 billion of the world's population. A commonly cited estimation of the frequency of HeFH is 1/500 (0.2%), which was calculated from the FH frequency in survivors of myocardial infarction (MI), of <60 years of age in a single study with some assumptive frequencies, including the prevalence of CAD in the population of the US.[4] However, contemporary data have suggested a higher frequency, highlighting that the burden of the disease is increasing including in the Chinese population.[9,10] According to the recently published 2016 Chinese guidelines for the management of dyslipidemia in adults (2016 revised version), the prevalence of dyslipidemia in Chinese adults reaches as high as 40.4% and covered approximately 160 million individuals.[11] This implies that at least seven millions of Chinese individuals may be classified as HeFH according to the commonly cited overall frequency estimation. Furthermore, a Chinese FH patients’ study with a large sample size from Beijing Fuwai hospital has recently reported that 3.5% of the patients were identified with definite/probable FH phenotype (definite, 1.0% and probable, 2.5%).[9] This study enrolled 8,050 consecutive patients undergoing coronary angiography (CAG) due to angina-like chest pain, and FH was diagnosed made using Dutch Lipid Clinic Network (DLCN) criteria and target exome sequencing in LDLR, ApoB, and PCSK9 genes. Simultaneously, another study by the same researchers showed that in 1843 consecutive patients with myocardial infraction (MI), the prevalence of definite/probable FH was 3.9% (7.1% in patients with premature MI and 0.9% in those with non-premature MI).[10] The authors concluded that the prevalence of FH among Chinese patients with MI or undergoing CAG appeared to be common, particularly among those with premature MI. These data strongly emphasize that FH is not uncommon in China. Therefore, FH should be considered as a condition of high concern, and more efforts are needed for its management. Another challenge is the change in the pattern of lipids during the past several years in China. Although the serum LDL-C concentration and the frequency of CAD may be slightly lower in the Chinese population than those before. With rapid economic growth and lifestyle changes, Chinese populations are experiencing increased cardiovascular risk and cardiovascular disease has become the leading cause of death.[11] A national prospective cohort study performed between 1991 and 2000 reported that 43.8% of deaths in Chinese adults of ≥ 40 years of age were attributable to CAD and stroke.[12] A report from the China National Diabetes and Metabolic Disorders Study (CNDMDS) comprising 46,232 Chinese adults suggests an alarm that levels of total cholesterol (TC) and LDL-C are considerably higher than those previously reported in the general Chinese population.[13] Accordingly, the increasing cholesterol levels have changed the FH phenotype in China, which may be another challenge in its diagnosis. Moreover, early diagnosis as well as effective treatment strategies in affected children with FH are challenges among experts, especially in China due to the single-child policy.[14] Single-child policy which lasted for more than half of a century, resulted in many single-child families. This phenomenon has a high impact on the family in terms of economics burden, psychological stress, healthcare issues, and domestic happiness. Hence, earlier screening of FH individuals including parent-mediated early diagnosis and intervention is important for single-child families.[15] Hence, parent-mediated early diagnosis and treatment for young children are the best strategies for prevention of premature ASCVD and improvement of survival in FH, especially in HoFH patients in the single-child society setting. Furthermore, improving public and healthcare professionals’ awareness of FH is another way for early diagnosis of FH. It is worth emphasizing that Chinese medical professionals should be obliged to actively take part in a global call for FH management.[16] In China, many people are unaware of FH, even among medical professionals who are working in well-known hospitals located in the first line cities. To improve the awareness, knowledge, and perception of FH among practitioners and hospitalized patients, a FH survey was recently performed in multiple cardiovascular centers including Beijing, Shanghai, Guangzhou, Wuhan, and Changchun (unpublished data). Surprisingly, among 345 cardiologists and 1,083 hospitalized patients with CAD, <10% of doctors recognized that an individual with plasma LDL-C >6.5 mmol/L might be considered as a diagnosis of FH (probable), and 3% of them answered that a person whose plasma LDL-C levels are > 8.5 mmol/L should be diagnosed as FH. Although as high as 82% of hospitalized patients vaguely considered that lipid disorders could be genetically inherited, only 0.7% of them learned about FH through consultation of a health website before hospitalization. More importantly, <50% of the investigated patients did not recognize that consistent elevated plasma LDL-C level was a risk factor of CAD. Therefore, a program of FH course for professionals and more propaganda for the population are urgently needed to improve the management of FH in China. Besides early diagnosis, early intervention of FH is crucial for the prevention of CAD. FH represents a major gap in preventive medicine and is clearly a public health problem. Considering the public health challenges that FH poses, gaps in care are currently being addressed by clinicians and researchers worldwide. Treatment of elevated LDL-C concentration in FH involves dietary and lifestyle management and pharmacotherapy. Statins are the mainstay pharmacotherapy and are supported by new evidence. A proportion of patients may need additional therapy with ezetimibe or bile-acid sequestrants. Furthermore, PCSK9 inhibitors are also recommended to treat FH. Without treatment, approximately 50% of men and 30% of women experience an ASCVD-related event by age 50 and 60 years, respectively. Evidence has shown that young adults with 20 years of statin therapy started in childhood had lower rates of both ASCVD-related events (1%) and death (0%) than their affected parent at a comparable age (26% and 7%, respectively), who started statin therapy later in life. According to previous studies,[17,18] 750,000 cases of CAD onset and 10,500 CAD deaths could be prevented if early intervention be employed based on the estimated seven million HeFH patients in China. Hence, early and appropriate intervention is of high importance. In addition, although China has already developed its own diagnostic criteria for FH, which is simpler and more convenient for clinically early diagnosis, more efforts are needed for its popularization and application. During the past several decades, there were scarce studies focusing on FH in China, which were mainly presented as case reports.[19] More recently, a novel modified system of simplified Chinese criteria for FH has been developed.[20] In this criteria, definite FH could be diagnosed in patients who meet any two out of the three items: LDL-C > 4.8 mmol/L, tendon xanthomas, and DNA mutation, which has similar sensitivity and specificity with the Simon Broome (SB) criteria and the Dutch Lipid Clinic Network (DLCN) criteria demonstrated by a large Chinese cohort.[20] However, these novel criteria need to be generalized in Chinese population. Studies in Chinese general population are required to test and confirm these novel FH criteria. Finally, China needs more joint efforts to respond to FH-related global call to arms due to the basic features of developing countries and imbalance in economics. As well-known, there is a great difference of health insurance system and economic growth between urban and rural areas in China, which may influence the early-diagnosis of FH in children and adolescents.[16] Early detection of FH is difficult due to lack of conventional physical examination, especially in vast rural areas of rural China. Universal lipid screening is not conventionally used in some parts of rural area. More efforts are needed for FH screening, early diagnosis, and early treatment, such as establishing a special network and foundation, performing a registry study, and strengthening the publicity.[21] The professionals, society, and even government should pay attention to this issue. Universal lipid screening FH in children between the ages of 9 and 11 years and common genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies to improve the efficacy of early identification and management of FH in China.[1,2] China may bear a heavy health burden as the most populous country in the world.[22,23] Conclusion FH is a common genetic disease characterized by premature ASCVD, which is associated with higher cardiovascular events but is preventable and treatable. With one-sixth of the world's population of individuals who are living with FH residing in China, the time has come to action for FH individuals. The phenotype of FH in China and other Chinese populations is now comparable to that in Western countries and the prevalence of FH in the general population is also similar. However, only a very small proportion of cases has been identified and treated. Although intensive statin treatment or statin plus ezetimibe or PCSK9 inhibitor is recommended for Chinese FH patients, the LDL-C target is often not achieved. Despite a high progress in FH management in China during the last decade, more efforts are needed to improve the current situation of our patients with FH, including engaging healthcare professionals, developing public awareness campaigns, and establishing national FH alliances. Universal lipid screening in children and common or expanded genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies. Finally, optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of FH patients. In summary, although the progress in FH management has been made in China during the past years, greater efforts are still needed in the future. Funding This work was partially supported by the Capital Health Development Fund (201614035), and CAMS Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr Jianjun Li, MD, PhD. Conflict of interest statement The author has no conflict of interest with regard to the content of this manuscript.

Goals of non-high density lipoprotein cholesterol need to be adjusted in Chinese acute coronary syndrome patients: Findings from the CCC-ACS project

Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism

Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. Organic anion-transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 gene (solute carrier organic anion transporter family member 1B1) facilitates hepatic uptake of simvastatin and atorvastatin. SLCO1B1 polymorphisms are strongly associated with statin-induced myopathy whereas few studies have assessed their effect on statin differential response. In the present study, we analyzed the association of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms with response to atorvastatin and simvastatin in 386 adults (201 atorvastatin-treated and 185 simvastatin-treated) with primary hypercholesterolemia, all of Greek origin. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. Genetic polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A novel RFLP protocol was developed for the simultaneous identification of 388A>G and 411G>A polymorphisms. SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms were not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed on the effect of the analyzed SLCO1B1 polymorphisms in statin lipid lowering response in either statin-treated patient cohort. Further studies in different populations are required to draw firm conclusion on the potential association of SLCO1B1 polymorphisms with statin lipid-lowering response.

Objective To investigate the impacts of c. 388A>G polymorphism of the solute carrier organic anion transporter 1B1 (SLCO1B1) gene on lipid-lowering and anti-atherosclerosis effects of atorvastatin in Chinese patients with ischemic stroke. Methods The patients with ischemic stroke whose baseline low-density lipoprotein cholesterol (LDL-C) >1.8 mmol/L were enrolled prospectively. They received atorvastatin (20 mg/d) for 12 months. The lipid and bilateral carotid intima-media thickness (CIMT) were measured respectively before and after treatment. The CIMT differences between SLCO1B1 c. 388A>G genotype groups were compared. Results A total of 71 patients with ischemic stroke were enrolled, including 5 AA genotype, 31 AG genotype, and 35 GG genotype. The A allele frequency was 28.9% and the G allele frequency was 71.1%. After treatment, the total cholesterol (TC), triglyceride (TG), and LDL-C in all patients were significantly lower than those before treatment, and high-density lipoprotein cholesterol (HDL-C) was significantly increase (all P<0.001), but CIMT did not have significant change (P=0.475). The proportion of patients whose LDL-C<1.8 mmol/L or LDL-C decreased ≥50% in the GG genotype group was significantly higher than the AG+ AA genotypes group (74.29% vs. 44.44%; χ2=6.540, P=0.011). Conclusions SLCO1B1 gene c. 388A >G polymorphism could influence the lipid-lowering effect of atorvastatin, lipid-lowering effect in the GG genotype group was better than that in the AG+ AA genotype group. SLCO1B1 gene c. 388A >G polymorphism did not have effect on the anti-atherosclerosis effect of atorvastatin, but it might be associated with too short follow-up time. Key words: Stroke; Brain Ischemia; Atorvastatin Calcium; Organic Anion Transporters; Polymorphism, Genetic; Atherosclerosis; Carotid Intima-Media Thickness; Cholesterol, LDL; Treatment Outcome

IntroductionMycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.MethodsThis study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 −118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 −106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.ResultsSLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 −106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).ConclusionFor Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 −106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.

Lack of association between the ABCB1 G2677 W polymorphism and the lipid-lowering effects of atorvastatin in Tunisian patients

Organic anion-transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1) is an influx transporter expressed on the sinusoidal membrane of human hepatocytes, where it mediates the uptake of its substrates from blood into liver. In vitro, the SLCO1B1 c.521T>C (p.Val174Ala) single-nucleotide polymorphism (SNP) has been associated with reduced and the c.388A>G (p.Asn130Asp) SNP with both enhanced and reduced transport activity of OATP1B1. In vivo in humans, the c.521C allele (present in SLCO1B1*5 and *15 haplotypes) is associated with decreased hepatic uptake and increased plasma concentrations of several OATP1B1 substrates. The SLCO1B1*1B (c.388G-c.521T) haplotype is associated with enhanced hepatic uptake and decreased plasma concentrations of some OATP1B1 substrates. The SLCO1B1 c.521CC genotype has been associated with an about 60-190% increased, and the SLCO1B1*1B/*1B genotype with an about 30% decreased area under the plasma concentration-time curve of repaglinide. Moreover, SLCO1B1 polymorphism can affect the extent of interaction between OATP1B1 inhibitors and repaglinide. Accordingly, SLCO1B1 genotyping may help in choosing the optimal starting dose of repaglinide. In Chinese individuals, the SLCO1B1 c.521C allele has been associated with increased plasma concentrations of nateglinide, but the association could not be replicated in Caucasians. SLCO1B1 genotype has had no effect on the pharmacokinetics of rosiglitazone, pioglitazone or their metabolites. The hepatic uptake of metformin is mediated by organic cation transporters 1 and 3, and the liver is not important for the elimination or action of the dipeptidylpeptidase 4 inhibitors sitagliptin, vildagliptin and saxagliptin. Therefore, SLCO1B1 polymorphism unlikely affects the response to these antidiabetics. Possible effects of SLCO1B1 polymorphism on sulfonylureas remain to be investigated.

The Chinese population has a comparable prevalence of obstructive sleep apnea (OSA) compared to their Caucasian counterparts, but are notably less obese. Given this difference in body weight, Chinese patients could have a distinct OSA phenotype. We aimed to compare the characteristics of obstructive events in Chinese and Caucasian individuals matched for OSA severity. Chinese and Caucasian subjects with moderate-to-severe OSA (apnea–hypopnea index (AHI) ≥ 20events/h) were included in the study (n = 90) and matched for age, gender and AHI. Data were analysed to identify differences in event type, effect of sleep state and body position, degree of hypoxemia, and prevalence of metabolic risk factors. Data presented are Mean ± SEM or Median (IQR). Chinese subjects had a significantly lower body mass index (BMI) compared to AHI-matched Caucasian counterparts [27 (25–30) versus 34 (30–39) kg/m2, p < 0.001]. Chinese subjects had more apneas compared to Caucasian subjects [14.4 (5.8–31.8) versus 8.1 (2.2–20.7) events/h, p = 0.011]. Events were longer in the Chinese group (apnea: 25.1 ± 1.2 s versus 19.3 ± 1.3 s, p = 0.001; hypopnea 25.3 ± 1.0 s versus 22.9 ± 1.0 s, p = 0.03), but were associated with less hypoxemia (% time < 90%: 14.6 ± 2.5 versus 25.0 ± 3.7%, p = 0.01). Chinese individuals with moderate-to-severe OSA have a distinct phenotype characterised by longer and more frequent apneas, yet less hypoxemia, in the setting of a lower BMI, compared to Caucasians of equivalent disease severity. Postulated mechanisms include differing upper airway anatomy, control of breathing or lung reserve.

Su1765 Exome Sequencing Detect Potential Susceptibility Gene Mutations in Chinese Crohn's Disease Patient

Su1766 Phenotype of Peripheral T Lymphocyte Did Not Correlate With Genotype At rs7746082, a Confirmed Focal SNP on 6q21 for Crohn's Disease Susceptibility

Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants. At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms. Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons. With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.

Fexofenadine pharmacokinetics are associated with a polymorphism of the <i>SLCO1B1</i> gene (encoding OATP1B1)