Effects Of Combined Oral Contraceptives Use, Dyslipidemia, Hereditary Susceptibility On The Risk Of Hypertension In Women

Oral contraception remains as one of the effective contraceptive methods most commonly used worldwide. At present, it is estimated that the percentage of combined oral contraceptives (COC) use of women around the world was 8.5% and was the second used in all of contraception. Although the prevalence rate of COC use in China is only 1.5%, compared with other countries, the absolute number of COC user is larger due to enormous general population. Since it was introduced in the 1960s, COC has been implicated in increasing cardiovascular risk following use. Hypertension is one of the most commonly side effects of COC.COC was composed by synthetic estrogen and progestin. Numerous epidemiologic studies demonstrated that estrogen was related with elevated blood pressure. The result from WHO multicentre study suggested that although the incidence of hypertension would be lower with lower estrogen dose, significant rise in blood pressure has also been verified. Dyslipidemia is a common metabolism abnormality in hypertensive person and a strong predictor of cardiovascular disease. Dyslipidemia and hypertension were observed to be combined and influenced with each other to increase the risk of cardiovascular diseases.Hypertension is considered as a complex trait disease resulting from interaction between genetic and environmental factors. It is well known age, family history of hypertension, body mass index (BMI), dyslipidemia or COC use strongly related with hypertension. COC use was one of the important factors increased the blood pressure, but the detailed mechanism of this pathogenesis remained to be elucidated. In the present, Renin-angiotensin System (RAS) is the most important pathways for regulating blood pressure. Estrogens contained in COC have well-documented effects on the level of angiotensinogen (AGT) in RAS, activated it and increased the risk of hypertension. A number of studies founded that there was a significant association between AGT gene polymorphism and hypertension, but the conclusions existed discrepancy in different population. Accordingly, the aim of the present study was to evaluate the effects of COC use, dyslipidemia, and hereditary susceptibility on the risk of hypertension in a case-control design in Chinese women and to provide suggestions for guiding safe use of COC and studying etiological factor of women with hypertension.PartⅠCOC use, dyslipidemia and their interaction on the risk of hypertension in womenHypertension is one of the most commonly side effects and has been acknowledged as a relative or absolute contraindication for COC use. The majority of studies documented the association between hypertension and COC involved 50μg or more of estrogen. Up to 5% normotensive women using COC with high dose estrogen may develop hypertension. Although it was suggested that the incidence of hypertension would be lower with lower estrogen doses, significant rise in blood pressure on women using COC with lower estrogen doses has also been verified. In addition, it was reported that COC users with hypertension family history were more likely to develop hypertension. A study has shown that there was an association between plasma lipids and COC use. Several studies have provided strong evidence for the important role of dyslipidemia on the risk of hypertension. Moreover, family constellation study showed there was a clustering phenomenon of dyslipidemia in hypertensive families. There is demonstrating that interaction between risk factors plays an important role in the studies of complex trait diseases. However, few data to date were available with regard to the interaction between dyslipidemia and COC use on the risk of hypertension. Thus, we hypothesized that COC use, dyslipidemia, and their interaction were associated with the risk of hypertension in Chinese women.[Objective] To assess the associations of COC use, dyslipidemia and their interaction with the risk of hypertension in Chinese women.[Methods] In 2003, all of the women resided in Rudong and Taicang counties were investigated for the intervention study of hypertension. Based on this, a case-control study was carried out from April to May in 2004. A total of 1330 female subjects were recruited, of whom 665 hypertensive women were enrolled, then 665 normotensives were matched on region and age (+3 years). Lipid levels were determined by enzymatical methods and immunoturbidimetric assay.[Results]1. Associations between COC use and hypertensionThe risk of hypertension gradually increased with the cumulative time of COC use in women (P=0.0043), especially significantly increased among those with cumulative time of COC use15~20 and≥20 years (adjusted OR=1.46, 95%CI: 1.00-2.15; OR=1.49, 95%CI: 1.06-2.11), but gradually decreased from stopping use of COC (P<0.0001).2. Associations between lipid levels and hypertensionHypertensive women had a higher prevalence of dyslipidemia and higher levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (Lp (a)) than normotensive ones (P<0.05).3. The risk factors of hypertensionThe stepwise multiple logistic regression model demonstrated that age, family history of hypertension, dyslipidemia and accumulative time of COC use≥15 years were the significant contributors to hypertension.4. Interaction analysisThe multiplicative interaction between dyslipidemia and accumulative time of COC use≥15 years, dyslipidemia and family history of hypertension, or family history of hypertension and accumulative time of COC use≥15 years was confirmed and the interaction analyses showed that they can significantly increased the risk of hypertension (adjusted OR=2.82, 95%CI: 1.59-3.27; OR=4.33, 95% CI: 3.10-6.06; OR=4.56, 95%CI: 3.07-6.77). The multiplicative interactions of above risk factors were also confirmed (P<0.05). [Conclusion] Accumulative time of COC use≥15 years, dyslipidemia and their interaction increased the risk of hypertension.PartⅡAssociation of COC use and hereditary susceptibility on the risk of hypertension in womenMajority of studies documented the association between COC use and hypertension in women. Although it was suggested that the incidence of hypertension would be lower with lower estrogen doses, significant rise in blood pressure has also been verified. In addition, it was reported that COC users with hypertension family history were more likely to develop hypertension, which suggested that genetic background played an important role in the development of hypertension in women who have used COC. AGT distributed generally in liver, artery and kidney. Estrogen, the mainly component of COC, could significantly increase the serum AGT level of RAS. The concentration of AGT could influence agniotensinⅡ(AngⅡ) level, and further influence aldosterone release, vessel contraction and blood volume expansion, increase blood pressure eventually. As one of the important candidate genes, the expression of AGT gene was also regulated by estrogen. Thus, we hypothesized that COC use, AGT gene polymorphism and there joint actions were associated with the risk of hypertension in Chinese women.[Objective] To explore the associations of COC exposure, AGT gene polymorphism and there joint actions with the risk of hypertension in Chinese women.[Methods] In 2003, all of the women resided in Rudong and Taicang counties were investigated for the intervention study of hypertension. Based on this, a case-control study was carried out from April to May in 2004. A total of 1242 female subjects were recruited, of whom 621 hypertensive women were enrolled, then 621 normotensives were matched on region and age (+3 years). Five polymorphisms of the AGT gene (C-532T (rs5046) in 5'near gene, A-20C (rs5050) and A-6G (rs5051) in the 5'-untranslated region, T174M (rs4762) in exon 2 and C11535A (rs7079) in the 3'-untranslated region) were selected. The genotyping for five polymorphisms of AGT gene were detected by Restriction fragment length polymorphism-PCR (RFLP-PCR).[Results]1. Associations between COC use and hypertensionThe risk of hypertension gradually increased with the cumulative time of COC use in women (P=0.0226). Compared with none users, the risk of hypertension significantly increased among those with cumulative time of COC use15~20 and≥20 years (adjusted OR=1.55, 95%CI: 1.02-2.36; OR=1.54, 95%CI: 1.04-2.29). The risk of hypertension gradually decreased from stopping use of COC (P<0.0001).2. Associations between AGT gene polymorphisms and hypertension The differences in genotypes distributions of five polymorphisms of the AGT gene between cases and controls were no significant.3. The joint action analysisCompared with none users, women with AC/CC genotypes of A-20C locus, AG/GG genotypes of A-6G locus, CC genotypes of T174M locus or CA/AA genotypes of C11535A locus using COC≥15 years significantly increased the risk of hypertension (adjusted OR=1.88, 95%CI: 1.02-3.46; OR=1.84, 95%CI: 1.11-3.06; OR=1.41, 95%CI: 1.02-1.97; OR=1.84, 95%CI: 1.04-3.27).[Conclusion] The risk of hypertension significantly increased among women using COC≥15 years. The joint action between women using COC≥15 years and AGT gene polymorphisms significantly increased the risk of hypertension.