GENETIC AND ENVIRONMENTAL RISK FACTORS OF ESSENTIAL HYPERTENSION IN A PAKISTANI POPULATION

ABSTRACT

Aims: To study the prevalence of essential hypertension gene Serine Threonine Kinase 39 (STK39) single nucleotide polymorphisms (SNPs) rs35929607; and their effects in predisposing individuals to developing essential hypertension on exposure of environmental risk factors.

Setting: A population based cross sectional study on 563 subjects from Tharparkar desert, Sindh, Pakistan.  

Methods: A population based, random, cross sectional study was done on 563 subjects (295 males and 268 females) from 2002 to 2008 in Tharparkar Sindh, Pakistan after approval from the Ethics Review Committee of The Aga Khan University. The demographic, anthropometric data, blood pressure, comorbids and environmental factors were entered in a proforma. Non-hypertensive individuals were used as controls. Genetic analyses were carried out by tetra-primer ARMS-PCR method. Lipid profile, Microalbuminuria, C-reactive protein (CRP) and ECG were also done. Data was analyzed both descriptively and statistically by SPSS version 10 to calculate crude and adjusted odds ratios with 95% confidence intervals by simple, linear and multiple logistic regression analyses. Data was also analyzed by splitting population into two subethnicities i.e. SE1 with prevalence and SE2 without prevalence of essential hypertension to look at whether they are genetically different. In consanguineous and non-consanguineous members of SE1, pedigree analysis for inheritance pattern of essential hypertension was also done.

Results: Prevalence of essential hypertension was 14.3% with mean age of 52.1 years (± 15.9 SD). Prevalence of STK39 SNPs frequencies were 36.2% for AA, 61.0% for AG and 2.8% for GG genotypes. Frequency of reference allele (A) was 66.7% and of rare allele (G) was 33.3% (Chi square 73.1 and p-value > 1.21). Prevalence of variant allele-G was less in hypertensive subjects and those with raised systolic or diastolic BP, individual values being 35%, 39%, 34% respectively as compared to reference allele-A i.e. 64%, 60%, 65% respectively. The findings suggested that STK39 gene is not strongly associated with essential hypertension. Entire population was homogenous without stratification as it was found to fall in concordance with HWE. Parameters not falling within HWE and showing stratification in this population were essential hypertension, Systolic BP >140mmHg, Diastolic BP> 90mmHg and existence of asthma.  

In subjects with essential hypertension environmental risk factors like, increased age, raised BMI, diabetes, decreased physical activity, blood pressure in both parents and urinary infections showed significant association. Factors which failed to show any association with essential hypertension included male gender, consanguinity, isolated parental essential hypertension, extra salt usage, tobacco, saturated fat, alcohol, tea and coffee, non-vegetarian diet, stress, raised LDL cholesterol, TG cholesterol, low HDL cholesterol, C-reactive proteins, and raised microalbuminuria.  

Analyses for effects of genetic factors as compared to effects of risk factors clustering showed effect of risk factors more pronounced and significant to raise systolic and diastolic BP than the genetic factors operating alone. SE1 members (n=366) showed prevalence of GG, AA and AG genotypes as 2%, 34% and 64% as compared to 4%, 39% and 55%, respectively, for SE2 (n=197). SE1 subjects did not fall in concordance with Hardy-Weinberg Equilibrium (HWE; p 0.03) as opposed to SE2 which were within HWE (p 0.2). As compared to SE2, SE1 subjects had significantly different genotypes (SE1: χ² = 4.3, p = 0.03; and SE2: χ² = 1.08, p = 0.2). Similarly, SE1 and SE2 members also had dramatic differences in their allele frequencies (χ² = 4.48, OR 1.38 (1.02, 1.87), p = 0.03). The data suggests that with respect to STK39 gene polymorphisms, SE1 and SE2 indeed represent genetically different subethnicities. Pedigree analysis of SE1 showed dominant pattern of inheritance for EHTN in non-consanguineous and recessive in the consanguineous families.  

Conclusion: Prevalence of variant allele-G was less in hypertensive subjects as compared to reference allele-A, showing negligible effect of this gene on essential hypertension in this study. Single nucleotide polymorphisms in the STK39 gene when combined with various environmental risk factors enhance predisposition of individuals to developing essential hypertension.  

Key words: Essential hypertension, environmental risk factors, STK 39 gene, single nucleotide polymorphism, consanguinity, subethnicity, systolic blood pressure, diastolic blood pressure, BMI, body fat content and lipid profile.