Effects of SR-BI rs5888 and rs4238001 variations on hypertension

Introduction

Hypertension, preventable causes of death worldwide, was equivalent to 31.1% of the world’s adult population in 2010 [1]. The prevalence of hypertension was determined as 33.7% in Turkey. The frequency of hypertension increases with age and is seen more frequently in women than men in all age groups [2]. Hypertension is defined as an increase in blood pressure over 140/90 mmHg. The risk of morbidity and mortality due to diseases such as cardiovascular, cerebrovascular disease, heart failure and renal insufficiency increases with hypertension [3]. Therapeutics targeting the renin angiotensin system (RAS), the main mechanism in the regulation of blood pressure for the treatment of hypertension, regulate renin secretion by inhibiting the enzymatic activity of renin, the conversion of angiotensin I to angiotensin II, angiotensin II receptors or effects of aldosterone [4]. Angiotensin II, plays a role in this system, has been shown reduce the expression of scavenger receptor class B, type I (SR-BI) in vascular endothelial cells [5].

SR-BI is a 509-amino acid glycoprotein with a molecular weight of 82 kD on the cell surface [6], [7]. The gene symbol of SR-BI on chromosome 12 is SCARB1 and consists of 13 exons and gives two main transcripts, SR-BI and SR-BII [8], [9]. SR-BI contributes to the transformation of HDL₃ to HDL₂, which is the process of transporting cholesterol to the liver from peripheral tissues [10], [11]. SR-BI is also involved in the uptake of apo-B-containing lipoproteins (VLDL, LDL) into the cell. ApoB and ApoE are ligands of SR-BI affecting the recognition and cell-mediation of these lipoproteins [12], [13], [14].

The rs4238001 C/T variation in the exon 1 of the SR-BI gene has been reported to cause an amino acid change of glycine to serine. Another C/T variation observed in exon 8 of the SR-BI gene, a silent mutation (rs5888, A350A), is thought to affecting the level of expression of the SR-BI gene or changing the splice regions [15]. Ritsch et al. reported that exon 8 C/T exchange plays a role in the development of peripheral vascular diseases [16]. Because of these effects, it is aimed to investigate the effect of these variants on the lipid change and vascular effects on hypertension.

Materials and methods

Results

The mean age of the subjects who constituted the hypertension and control group was 64.98±16.37 and 56.07±3.96, respectively (p<0.001). The data of height, weight and fasting blood glucose were significantly different between the groups (p<0.01), while there was no significant difference in total cholesterol, triglyceride, high density lipoprotein (HDL) and low density lipoprotein (LDL) levels (Table 1). The mean systemic blood pressure was 152.47±15.7 and the mean diastolic blood pressure was 90.86±8.72 in the hypertension group.

When genotype and allele distributions between hypertension and control groups were analyzed according to Hardy Weinberg equilibrium; rs4238001 was in the equilibrium while rs5888 was not in Hardy Weinberg’s equilibrium (p=0.023) (Table 2). According to the genotype and allele distributions of rs4238001 and rs5888 variations shown in Table 3, there was no significant difference in rs4238001 between hypertension and control group (p>0.05). The TT genotype was found 35.6% and 35.8% in patients and controls and T allele was 50.68% and 53.73% in hypertension and control groups, respectively. When rs5888 variation was examined, the mutant TT genotype was found 50% and 35.58% in hypertension and control groups, respectively. It was found that normal homozygous CC and heterozygous CT carriers have an average of 2-fold less risk of hypertension (OR: 0.462, 95% CI: 0.236–0.901, p=0.023) than the TT genotype carriers (Table 3). When the correlation analysis between SR-BI rs4238001 and rs5888 genotypes and parameters was performed, no statistically significant correlation was observed (p>0.05).

Discussion

In our study, rs4238001 mutant TT genotype was determined as 35.6% and 35.8% in hypertension and control groups, respectively and there was no significant difference between the groups (p>0.05). When rs5888 variation was examined, the mutant TT genotype was found 50% and 35.58% in hypertension and control groups, respectively. Normal homozygous CC and heterozygous CT carriers were found have an average of 2-fold less risk of hypertension than TT genotype carriers (p=0.023).

Higher levels of plasma total cholesterol and non-high-density lipoprotein cholesterol were found associated with increased risk of hypertension in males [17]. Because of hypertension is found higher in familial lipid syndromes, lipid related genes may be involved in the development of hypertension [18]. Scavenger receptor class B type I (SR-BI) gene is the one of the lipoprotein associated genes and identified as an independent predictor of high-density lipoprotein cholesterol levels [19].

The rs4238001 C/T variant in the exon 1 of the SR-BI gene was found associated with high HDL and low LDL [20]. This variation of p.Gly2Ser leading to amino acid changes ranged from 10% to 19% [15], while we found this rate as 35–36%. This mutant genotype was found at similar ratios between control and hypertension groups and there was no relation between the disease and genotypes. Acton et al. found that male carriers of the rs4238001 risk T allele had significantly higher HDL-C levels [21], while Manichaikul et al. reported that no significant effects of the T allele on HDL-C levels in males [22]. Another study showed that body mass index (BMI) and rs4238001 were independent predictors of SR-BI protein levels [19]. However, we did not find any relation between the genotypes and alleles of rs4238001 and parameters of the samples.

It has been suggested that the minor allele frequency of c.1050 C>T (rs 5888) in the SR-BI gene is 40–49%, and the minor T allele has anti-atherogenic effect by causing high HDL and low LDL levels [15]. In our study, the minor T-allele was observed in 67% of the cases. In addition, we found that carriers of normal homozygous CC and heterozygous CT had an average of 2-fold less risk of hypertension than those carrying the TT genotype (OR: 0.462, 95% CI: 0.236–0.901, p=0.023). Rodríguez-Esparragón et al. reported that c.1050 C>T CC major allele increases coronary heart disease by 50% independent of serum lipid levels [23]. Ritsch et al. reported that this change has a role in the development of peripheral vascular diseases as well as in increasing the risk of developing cardiovascular disease by causing atherogenic lipid profile in female [16]. Another study found no significant effect of rs5888 on blood pressure, although smokers had significantly higher TT genotype and T allele compare to non-smokers [18]. It was found that SR-BI rs5888 TT genotype, increased pulse pressure and diastolic blood pressure was associated in overweight/obese subjects [17]. Diastolic blood pressure was also found correlated with rs5888 alleles and genotypes in males [24]. In another study showed that the rs5888 TT genotype increases systolic blood pressure and pulse rate at a significant level in the alcohol consumers [25]. However, our results show the protective effects of C allele from the hypertension, we did not find any relation between both of systolic and diastolic blood pressure, serum lipid levels and rs5888 variation. The reason why this relationship could not be shown may be due to the small number of samples in rs5888 genotypes or the poor functional value of this polymorphism. Furthermore, since SR-BI protein shows its effect on serum lipid levels, it may be effective in the absence of the correlation between the rs5888 variation and serum lipid levels or blood pressure because of there is no significant difference between serum lipid levels of patient and control group (p>0.05).

Conclusion

SR-BI gene has roles in transporting serum lipids and it may contribute to development of hypertension. Thus, we studied rs4238001 and rs5888 gene variations in hypertension disease. We did not find any difference in the groups for rs4238001. However, rs5888 variation TT genotype was found higher in hypertension group and increases the risk of hypertension disease. As a result, SR-BI rs5888 TT genotype may increase hypertension risk by reducing lipid transport to the liver from the vessel wall via decreased protein levels of SR-BI [26] and this result should be proven via mRNA and protein analysis. Our study limitations are the small number of sample and lack of the analysis of mRNA and protein. However, this is the first result shows that SR-BI gene variations on the Turkish patients with hypertension.