Statin-induced myopathy SLCO1B1 521T > C is associated with prediabetes, high body mass index and normal lipid profile in Emirati population

Abstract

Background

Statin-induced myopathy has been linked to the C allele of a single nucleotide polymorphism (SNP) (rs4149056) of SLCO1B1 gene. This effect is more significant, but not restricted to simvastatin. Many studies have included European, American, African and Southeast Asian ancestries, but few were carried out on Middle Eastern population.

Aim

To detect the prevalence of SLCO1B1 rs4149056 (521T > C) in Emirati population.

Method

We recruited 282 Emiratis through the UAE National Diabetes and Lifestyle Project. Ethical approval was obtained before the study starts. Besides basic data collection, venous blood samples were collected. Fasting blood glucose, Lipid profile, and insulin levels were measured. Genotyping for rs4149056 (521T > C) was tested in triplicates through Real Time-PCR using TaqMan® Drug Metabolism Genotyping Assay. rs2306283 (388A > G) was analyzed for comparison. In addition, presence of minor alleles of both SNPs define stronger association with statin-induced myopathy.

Results

The study included 282 individuals, 52.8% were males with median age of 39.5 years. 10% had Diabetes Mellitus and 23% were hypertensive. Median of body mass index (BMI) was 27.68 kg/m² in males and 28.38 kg/m² in females. One-hundred ninety-seven (69.9%) showed abnormal lipid profile (either increased LDL-cholesterol or triglycerides or both). For rs4149056, C allele was present in 21.3% (2.8% homozygous C and 18.4% heterozygous CT). Although homozygous C genotype prevalence was low, compared with Caucasians (4%) and Africans (0%), C allele was associated with a trend of having higher BMI and abnormal lipid profile. C allele subjects were all pre-diabetics with mean glycated hemoglobin above 6%. Mean BMI in CC, CT, and TT genotypes was 30.91 ± 4.4, 29.48 ± 4.2, 27.96 ± 5.5 kg/m² respectively, with lack of such a trend observed with the different genotypes of the rs2306283 (used for comparison). Abnormal lipid profile was observed in 7/8(87.5%), 38/52(73.1%) and 152/222(70%) of the CC, CT, and TT genotypes respectively.

Conclusion

There is lower prevalence of statin-induced myopathy-linked C allele of rs4149056 in SLCO1B1 gene in Emirati population, compared to Caucasians and Africans. However, there is a trend of higher glycosylated hemoglobin and BMI associated with normal lipid profile in patients having this allele.

Introduction

Pharmacogenomics has been emerging to achieve the aim of personalized medicine. Drug response may significantly vary due to single nucleotide polymorphisms affecting hepatic influx and efflux transporters. The occurrence of particular SNPs could greatly affect the density and activity of the transporters. In particular, it will lead to changes in the rate the handling the drugs by hepatocytes with subsequent effect on the pharmacokinetic parameters [1].

Statins are one of the most commonly used drug classes, because of the pandemic of obesity, metabolic syndrome and coronary artery disease. The drug has been one of the greatest therapeutic successes in modern medicine; decreasing cardiovascular events by around 25% [2], [3].

A meta-analysis of 82 genome-wide association studies (GWAS) and 43 Metabochip studies in nearly 340,000 individuals identified 97 loci associated with BMI. These loci accounted for approximately 2.7 percent of the variation in BMI, and the authors estimated that as much as 21 percent of BMI variation can be accounted for by common genetic variation [4].

Moreover, 49 genetic loci have been associated with waist-to-hip ratios adjusted for BMI and show sexual dimorphism among these genes, which are often expressed in adipose tissue [5].

Liver transporter OAPT1B1 and statin pharmacogenetics (simvastatin & others): OAPT1B1 is a 12 transmembrane uptake transporter (691 amino acids) located on the basolateral membrane of hepatocytes. Functional polymorphisms of OAPT1B1 were first described in 2001 [6].

A total of 190 common single-nucleotide polymorphisms (SNPs) with minor allele frequency greater than 5% have been identified in the SLCO1B1 gene [7]. Among these, two commonly occurring non-synonymous SNPs (521T > C, Val174Ala, rs4149056 and 388A > G, Asn130Asp, rs2306283) have been showed to cause an alteration in the pharmacokinetics (PK) and pharmacodynamics (PD) of the OATP1B1 substrates in our previous studies [8], [9].

Both rs2306283 G allele, rs4149056 C alleles were thoroughly studied. Combination of both resulted in identifying three genotypes; SLCO1B1∗1b (388A > G; rs2306283), ∗5 (521T > C; rs 4149056) and ∗15 (∗1b+∗5), [6]. Studies investigated effect of SLCO1B1 SNPs on the efficacy of different statins showed controversial results [10], [11].

Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) polymorphisms affect the amino acid sequence of the SLCO1B1 gene product. The presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin in elderly [12]. However, no effect of the rs2306283 SNP on any of the variables was noted in the same study. The aim of the current study is to explore the prevalence of SLCO1B1 rs4149056 (521T > C) in Emirati population.