Positive association between ATP2B1 rs17249754 and essential hypertension: a case-control study in Burkina Faso, West Africa

Cardiovascular diseases are the leading cause of mortality in the world and represent 31% of global deaths [1]. The common risk factors for developing cardiovascular disorders are obesity, arterial hypertension, diabetes and dyslipidemia [2].

Hypertension is the main leading causes for morbidity and mortality of cardiovascular diseases and affects about one-third of adults worldwide each year [3, 4]. Hypertension was once considered rare in Africa, but currently it has become a public health concern. Several studies estimated at 16.2% the overall prevalence of hypertension in 74.4 millions of hypertensive individuals in sub-Saharan Africa and the number of affected individuals will increase by 68% (125.5 million) by 2025 [5]. The causes of EH which accounts for 95% of cases of hypertension remain largely unknown, however interplay among genetic and non genetic factors might contribute to its etiology [6]. An estimated 30–60% of blood pressure variation is explained by genetic factors [7]. Determinants also include life-style [8], obesity [9] and environment which can impact blood pressure or risk of hypertension through the influence on gene expression or through interaction with gene products [10].

Recently, with the enormous progress made in molecular Biology domain, Genome-wide association studies (GWAS) have identified news genes and their variants which are associated with blood pressure variations and the risk of hypertension such as STK39 rs3754777 [11], ATP2B1 rs2681472 and rs17249754 [12]. In addition, other reports confirmed these associations in Asian and European population [7, 13‐16], but not all.

In this work, we genotyped index variants from these 2 candidate loci identified by studies and examined for the first time the association between them and systolic blood pressure (SBP), diastolic blood pressure (DBP) and the risk of developing EH in Burkina Faso, West Africa and in a second time we characterized some cardiovascular risk markers in patients with EH. The results will be instrumental in the future for a better clinical management of cardiovascular diseases in the country.

Hypertensive patients often present metabolic disorders which impact their quality of life and could increase their risk of developing cardiovascular diseases. In our study we characterized known cardiovascular risk markers in subjects with EH (cases) and normotensive individuals (controls). The results showed that subjects with EH had significantly higher levels of blood sugar (p <  0.001), BMI (p <  0.001) and total cholesterol (p <  0.05) compared to controls. These findings suggest that subjects with EH tend to develop disorders associated with metabolic syndrome as described previously [21]. These markers were positively correlated to the augmentation of systolic and diastolic blood pressure in our study population, supporting those several independent studies conducted in different population which showed that risk of hypertension increased with age [22] and BMI [23], and that dyslipidemia [24] and hyperglycemia [25] were more frequent in hypertensive compared to normotensive individuals. Epidemiological studies have demonstrated that Obesity and overweight were associated with an increase of cardiovascular risk markers [26], in our study we also found that BMI was positively correlated to all other cardiovascular risk markers such us SBP, DBP, HDL-c, LDL-c, TC, triglycerides and blood sugar level. Regular physical activities have been shown to reduce the risk of high blood pressure and could also help lipids repartition in the organism [27], in our study we also found that obese and overweight patients who are usually less active were the main group at risk of developing cardiovascular disorders as previously described [28].

In the genetic level we investigated the effect of genetic loci recently identified by GWAS with BP and the risk of developing EH. Our first gene of interest ATP2B1 also named PMCA1 (Plasma Membrane Calcium ATPase type 1) is located in chromosome 12, position 12q21.q23 and belongs to the P-type pump family [29]. It encoded a protein responsible for the regulated transport between the intracellular and the extracellular milieu of Ca²⁺, an ion which contributes to contraction-relaxation of vascular smooth muscles [30]. Mechanism by which ATP2B1 gene influences blood pressure is not yet clear but, investigations showed its mRNA overexpression in hypertensive animal models compared to normotensive [31] and an excessive increase of blood pressure through vasoconstriction in ATP2B1 gene deleted rats [32]. These findings may explain among other things the mechanism by which changes in the ATP2B1 gene product levels are involved in BP regulation and risk of EH. In our study we observed that individuals carrying the AA+AG genotype of ATP2B1 rs17249754 had a low risk of developing EH than those carrying the GG genotype (OR = 0.48; 95% CI = 0.31–0.75; p = 0.001). Furthermore, the A allele frequency of ATP2B1 rs17249754 in the case group was significantly lower than that of the control group (allelic OR = 0.56; 95% CI = 0.38–0.82; allelic p = 0.003). The association of ATP2B1 rs17249754 with hypertension has been previously shown in Koreans [12]. Subsequently GWA studies conducted by the Global Blood Pressure Genetics and CHARGE consortiums confirmed this association [13]. Recently Daily and al. in Korean, showed that carriers of the major allele G of ATP2B1 rs17249754 were at greater risk of developing hypertension and that high Na intake and low Ca increased the risk more in major allele than among minor allele carrier, suggesting that people with the G allele can reduce risk of high blood pressure by having good calcium status [33]. Interaction of BMI, gender and ATP2B1 rs17249754 in susceptibility to hypertension has been also reported in Han Chinese Population [15]. In our study, we were unable to perform sub-group analysis given the limited number of participants. Concerning ATP2B1 rs2681472, it was found to be associated with hypertension firstly in 2009 by Levy and al. [7]. In our cohort, we didn’t find any significant association between it and essential hypertension, but we found that individuals carrying the AA genotype had high SBP than those carrying the GG + AG genotype. The association between rs17249754 and EHT demonstrate the potential role of ATP2B1 in the regulation of blood pressure and treatment of EHT. Indeed, Okuyama and al., showed that mice lacking ATP2B1 had a higher response to CCBs for blood pressure-lowering effects than other anti-hypertensive drugs [34], and previously Tabara and al. showed that it may be a reduction in the expression of ATP2B1 which leads to raised blood pressure in those with a ATP2B1 risk allele for hypertension [35]. These data may suggest that hypertensive patients with variant G of rs17249754 (risk allele for hypertension) may also have a reduction in the expression of ATP2B1 and therefore a better response to CCBs compared to other antihypertensive drugs. However, further studies are needed to confirm that.

Our second gene of interest STK39, encodes a serine-threonine kinase named STE20/SPS1-related proline/alanine-rich kinase (SPAK), which seems to impact blood pressure by its action on renal excretion of sodium through its interaction with the WNK kinase and co-transporters cation-chloride [36]. Experimental studies showed that rats in which SPAK and WNK interaction were blocked had a lower blood pressure [37]. In the present study, we didn’t find any significant association of STK39 rs3754777 with EH as reported previously in Amish, non Amish [11], Belgian population [16] and male Han Chinese [38]. However, certain studies before ours reached to the same conclusion and failed to prove any association such as studies in British Caucasian [39] and Chinese Children [40].

In view of our results and other results obtained in previous studies, we can note a strong interaction between genetic variants and environmental and/or epigenetic factors, so that certain genetic variants only have significant effect in specific populations.

In conclusion, our study confirmed the significant association between ATP2B1 rs17249754 and EH in Burkinabe, suggesting the potential role of ATP2B1 in the regulation of blood pressure. It also showed a significant increase of cardiovascular risk markers in individuals with EH compared to normotensive and once again invite clinicians to be looking at the level of BMI, WC and cholesterol in the management of EH. However, the present research has some limitations, particularly the small size of the study population. A large scale study will be necessary to fully comprehend the role of ATP2B1 rs17249754 in the development of EH and response to CCBs in Burkina Faso.