Effects Of Coc Exposure, Ace/agt Genes Polymorphism On The Risk Of Hypertension In Chinese

Combined oral contraceptive (COC) is one of the most effective and worldwide used contraception methods. At present, approximately 150 million women use oral contraceptives for contraception. In European countries, COC use accounted for 30% of the total contraception methods, while in China, the method is under a lower usage rate nearly 2% of the total contraception methods. However, the absolute number of COC user is nearly 6 million in China. Hypertension is one of the most important risk factors for cardiovascular diseases, while hypertension is a complex disorder of the internal environment accounted for both genetic and environmental factors. Of the multiple risk factors, COC is an important factor for blood pressure elevation; however, the detailed mechanism of this pathogenesis has not been fully understood.COC-induced hypertension maybe caused by multiple mechanisms and under regulation by several paths. Recently, studies have found that renin-angiotensin system (RAS) is one of the most important pathways for intermediating estrogen of COC and blood pressure elevation. RAS not only influenced by COC, and the vital role of RAS was in regulation of blood pressure and homeostasis. Several studies had found that hypertension in pregnancy, history of hypertension ad family history of hypertension were all the crucial risk factors for COC user in developing hypertension, which indicated that genetic background would play an important role for those women in hypertension. Studies of the recent years had showed that angiotensinogen (AGT) and gene angiotensin-converting enzyme (ACE) gene would be the most important candidate genes for hypertension. At the same time, those studies found that estrogen of COC may significantly increase the serum level of AGT.Thus, our study focus on functional single nucleotide polymorphisms (SNPs) of RAS with case-control method to evaluate the SNPs on the risk of hypertension, meanwhile, to evaluate the relationship between COC exposure and RAS functional SNPs for hypertension risk. Those above works will be valuable for choosing safe contraception method and for the enacting of first level of prevention of adverse reactions for contraception. PartⅠCOC exposure, ACE gene functional SNPs with the susceptibility of hypertensionAngiotensin-converting enzyme (ACE) would catalyze angistensin I (AT I) into angiotensin II (AT II), which was effective in blood pressure control and homeostasis. Thus, ACE gene was crucial in blood pressure control and the pathogenesis of hypertension. The insert/delete polymorphism (rs1799752) and A3250G polymorphism (rs4343) were important in regulation of serum ACE level. Thus, we choose these two polymorphisms for exploring their contribution on hypertension risk. Meanwhile, we also explore the relationship between these two polymorphisms and COC use on the risk of hypertension.We used case-control method for this study based on established female hypertension surveillance in Taicang and Rudong counties, Jiangsu Province, from March to June in 2004. Female hypertensive subjects were enrolled in our study. At the same time, female normotensive subjects were also selected as controls, who were matched to the cases by age (±3 years) and residence. Subjects with systolic blood pressure (SBP)≥140mmHg or diastolic blood pressure (DBP)≥90mmHg were defined as hypertensive cases; those subjects had been diagnosed as hypertension and still receiving antihypertensive medicines were also considered as hypertensive cases. Subjects with SBP <140mmHg and DBP<90mmHg were enrolled as normal controls. The detailed information of COC use was obtained from the family planning clinics, including bands of COC and duration of COC use. Those subjects taking COC less than 3 month were considered as none-users; otherwise, those receiving COC more than 3 month were considered as COC users (including current users and past users). We adopted PCR-primer introduced restriction analysis for primers and enzymes designing. Two analyzers independently read the gel and randomly selected 10% of the samples for repeated assay, and the results were in accord by 100%.Our results indicated that allele distribution of ACE gene I/D polymorphism and A2350G polymorphism were equal among hypertensive cases and controls (P=0.253, P=0.738). Single and multivariate logistic regression model (with adjusting for residence, age, smoke and drink) showed that the two loci were not in relation of hypertension risk. After adjusting for age and residence, the duration of COC use when no less than 15 years significantly increased the risk of hypertension. In the analysis of I/D and A2350G polymorphisms with interacting COC use, we found that women carried ID/DD genotypes with duration of COC use for no less than 15 years significantly increased the risk of hypertension by 0.76 fold (OR=1.76, 95%CI: 1.19-2.58), after adjusting for area, age, BMI and dinking status. Meanwhile, we found that women carried AG/GG genotypes of A2350G polymorphism with duration of COC use for no less than 15 years also increased the risk of hypertension by 0.57 fold (OR=1.57, 95%CI: 1.06-2.31). Those results indicated that the D allele of I/D and G allele of A2350G of ACE gene would be potential risk alleles for hypertensive COC users. PARTⅡCOC exposure, single nucleotide polymorphism of AGT gene promoter region and the risk of hypertension in Chinese womenAngiotensinogen (AGT) was found mainly in liver, artery and kidney. AGT was regulated by estrogen in effect of several biological responses. COC would significantly increase the serum AGT level of renin-angiotensin system (RAS). The concentration of Angiotensin I was determined by both AGT and plasma renin levels. As AGT would influence agniotensin II level, and further to influence aldosterone release, vessel contraction and blood volume expansion. Studies had found the M235T polymorphism would affect the serum level of AGT, meanwhile, the A-6G loci of AGT gene promoter region was in absolute disequilibrium with M235T loci, which implied A-6G loci would in regulation of AGT gene expression and further to affect the serum level of AGT.This study selected this A-6G loci of AGT gene promoter region to evaluate the relationship between A-6G and hypertension risk, and also the relationship between COC and A-6G loci for hypertension risk. We adopted restriction fragment length polymorphism-PCR for the genotyping. The results indicated that the A-6G loci was no in relation with hypertension. After adjusted for age and residence, duration of COC use≥15 years significantly increased the risk of hypertension. The serum levels of TC, TG and LDL were significantly higher in hypertensive cases, compared with control subjects. Single and multivariate logistic regression analysis showed that (with adjusting for age, residence, BMI and drink) A-6G genotypes were not contributing in hypertension risk. The interaction between A-6G loci and duration of COC use for hypertension revealed that women with COC use for no less than 15 years significantly increased the risk of hypertension with any genotype of A-6G loci.