血压对膳食补钾反应性的遗传关联研究及血压与心血管疾病的流行病学研究

【作者】 余大海；

【导师】 顾东风；

【作者基本信息】 中国协和医科大学 ， 遗传学， 2009， 博士

【摘要】 随着社会和经济发展,心血管病已成为国人首要死亡原因,在心血管病危险因素中高血压是重要的可防控危险因素。目前国内外已有很多针对高血压的研究,而作为高血压的“后备军”正常高值血压(SBP:120-139mmHg和(或)DBP:80-89mmHg)在中国成人中的患病率如何,相应危险因素是什么?与其他心血管危险因素是否存在关联等尚不清楚。在已知四种血压测量指标(收缩压、舒张压、脉压、平均动脉压)中哪种预测心血管病风险更好,血压值与心血管病发病风险的定量关联如何也不十分清楚。其次,在高血压防治和遗传流行病学领域,膳食补钾很重要,而不同个体的血压对补钾反应不同,究竟哪些遗传标志物与钾敏感存在关联?这些问题都有待于研究。本研究在3个代表性较好的全国样本(InterASIA,CHEFS,GenSalt)中探讨上述问题。研究结果显示在中国35-74岁成人中正常高值血压的患病率为21.9%(男性25.7%,女性18.0%)。在超重及肥胖(体重指数≥25kg/m~2)的男性和女性中患病率分别为38.4%和27.8%,在向心性肥胖(男性腰围≥90cM,女性腰围≥80cM)的男性和女性中患病率分别为37.8%和25.9%。经调整协变量后发现超重和肥胖,以及向心性肥胖是正常高值血压的独立危险因素(调整后的比值比和95%可信区间分别为:男性,超重及肥胖2.01(1.64,2.42),向心性肥胖1.66(1.32,2.10);女性,超重及肥胖2.02(1.65,2.48),向心性肥胖1.91(1.58,2.32))。研究还发现正常高值血压与多个心血管危险因素聚集呈显著关联,83.1%,46.5%和17.0%的中国成人有≥1,≥2,和≥3个心血管病危险因素,正常高值血压与≥1,≥2,和≥3个心血管病危险因素关联的比值比分别为1.41,1.45,1.96,正常高值血压所致≥1,≥2,和≥3个心血管危险因素聚集的人群归因危险度分别为16.7%,18.0%和31.9%。因此针对正常高值血压个体危险因素聚集的现状应采取全面的生活方式干预措施。另外本研究发现在四种血压测量指标中,无论哪种血压测量指标随着血压水平的升高心血管病发病率和发病风险均显著升高(p值均＜0.0001)。收缩压＞140mmHg、舒张压＞87mmHg、脉压＞59mmHg和平均动脉压＞104mmHg,心血管病的发病率分别为2919.6/10万人年,1853.8/10万人年,2205.8/10万人年和2140.2/10万人年;与收缩压＜108mmHg,舒张压＜67mmHg,脉压＜36mmHg,平均动脉压＜82mmHg相比,收缩压＞140mmHg,舒张压＞87mmHg,脉压＞59mmHg,平均动脉压＞104mmHg心血管病发病相对风险分别为2.74,2.26,2.24,2.54;人群归因危险度分别为25.7%,20.0%,20.5%,和24.1%。四种指标每增加1个标准差(收缩压22mmHg,舒张压12mmHg,脉压16mmHg,平均动脉压14mmHg)心血管病相对风险增加1.45,1.46,1.28,和1.49倍。此外相同的血压水平在超重者、重度吸烟和饮酒者中风险更高。本研究认为收缩压和平均动脉压都是心血管病风险较好的预测因子,一些降压的治疗和防控措施不仅仅要针对高血压患者还要针对正常高值血压个体,而且对于一些超重、重度吸烟和重度饮酒的高危个体应采用更严格的降压治疗和生活方式干预措施。关于个体对补钾干预敏感差异的问题,本研究发现“肾钠-钾交换的细胞内信号蛋白”通路上的内收蛋白α亚单位(ADD1)基因的中2个SNP位点rs17833172和rs12503220和血压对膳食补钾干预反应呈显著关联(调整后p值均＜0.0001)。在这两个位点上基因型为GG或GA的个体相对于基因型为AA的个体,血压对膳食补钾干预的反应更显著(rs17833172基因型为GG或GA的个体收缩压、舒张压和平均动脉压平均下降3.52、1.41和2.21mmHg,rs12503220基因型为GG或GA的个体收缩压、舒张压和平均动脉压平均下降3.44、1.36、2.07mmHg)。这个阳性关联具有医学和公共卫生方面潜在意义,还需更多的研究进一步验证上述关联。更多还原

【Abstract】 Cardiovascular disease(CVD) now has been the leading cause of death among Chinese adults.Among many CVD risk factors hypertension is the most important modifiable risk factor.Many preventive strategies focused on hypertension.However, few researches on prehypertension defined as systolic blood pressure(SBP) of 120 to 139 mmHg or diastolic BP(DBP) of 80 to 89 mmHg were reported among Chinese adults.And the prevalence and risk factors of prehypertension among Chinese adults are unclear.Whether prehypertension is associated with clustering of CVD risk factors is not understood.Secondly,which is the best predictor among four BP measures,SBP,DBP, pulse pressure(PP),or mean arterial pressure(MAP)? How about the quantitative association between BP levels and risk of CVD? Thirdly,although dietary potassium-supplementation intervention is an important intervention for hypertension, the response to potassium-supplementation varies among individuals based on different genetic background.However the association between genetic markers and potassium sensitivity is not well established.This current study is designed to solve the above issues based on three national representative samples(InterASIA,CHEFS,GenSalt).It’s indicated that the prevalence of prehypertension is 21.9%(25.7%for men and 18.0%for women).The prevalence is 22.1%,21.9%,24.9%,and 20.0%for urban residents,rural residents,northern residents, and southern residents,respectively.Moreover the prevalence for overweight or obese (body mass index,BMI≥25kg/m~2) men and women is 38.4%and 27.8%,respectively. And the prevalence for central obese(waist circumference,WC≥90cM for men and WC≥80cM for women) men and women is 37.8%and 25.9%,respectively.Adjusted odds ratio(95%confidence interval) for prehypertension is 2.01(1.64,2.42) for overweight or obese men,1.66(1.32,2.10) for central obese men,2.02(1.65,2.48) for overweight or obese women,1.91(1.58,2.32) for central obese women,respectively.It’s also found that prehypertension is significantly associated with clustering of CVD risk factors.83.1%, 46.5%,and 17.0%of Chinese adults have≥1,≥2 and≥3 CVD risk factors,respectively. Adjusted odds ratio for the association between prehypertension is 1.41,1.45 and 1.96 for having≥1,≥2 and≥3 CVD risk factors,respectively.And population attributable risk (PAR) for clustering of CVD risk factors attributable to prehypertension is 16.7%,18.0%, and 31.9%for having≥1,≥2 and≥3 CVD risk factors,respectively.It’s recommended by this current study that it would be more helpful for prehypertensive individuals to accept global lifestyle modification than anti-hypertension pharmacological treatment for its clustering of CVD risk factors.It’s also found in this study that despite of BP measures the risk of CVD increases with the increase of BP(all p for trend＜0.0001).The incidence of CVD is 2919.6/100, 000 person-years,1853.8/100,000 person-years,2205.8/100,000 person-years,and 2140.2/100,000 person-years for SBP＞140mmHg,DBP＞87mmHg,PP＞59mmHg, MAP＞104mmHg,respectively.Compared with SBP＜10mmHg,DBP＜67mmHg, PP＜36mmHg,MAP＜82mmHg,the relative risk(RR) of CVD is 2.74,2.26,2.24 and 2.54 for SBP＞140 mmHg,DBP＞87mmHg,PP＞59mmHg,MAP＞104mmHg,respectively. Compared with SBP＜10mmHg,DBP＜67mmHg,PP＜36mmHg,MAP＜82mmHg,the PAR of CVD is 25.7%,20.0%,20.5%and 24.1%for SBP＞140 mmHg,DBP＞87mmHg, PP＞59mmHg,MAP＞104mmHg,respectively.Moreover 1 standard deviation increase of 4 BP measures(22 mmHg for SBP,12 mmHg for DBP,16 mmHg for PP,and 14 mmHg for MAP) leads to the increase of risk for CVD as 1.45 fold,1.46 fold,1.28 fold and 1.49 fold,respectively.Furthermore higher risks are common among overweight adults,heavy smokers and heavy drinkers.SBP is an important predictor for CVD as well as MAP. Anti-hypertension treatment and preventive strategies such as strict lifestyle modifications should target not only on hypertension patients but also on prehypertensive individuals,especially those with overweight or unhealthy lifestyle like heavy drinking or heavy smoking.Two single nucleotide polymorphism(SNP) rs17833172 and rs12503220 on adducin 1 alpha(ADD1) gene which influencing renal sodium-potassium exchanging is significantly associated with BR response to dietary potassium-supplementation intervention(all adjusted p＜0.0001).For these two loci,BP levels of the allele G carriers are more sensitive to dietary potassium-supplementation intervention compared with those of allele A carriers.Responses to the potassium-supplement intervention for those carrying G allele of rs 17833172 were -3.52 mmHg for SBP,- 1.41 mmHg for DBP, and -2.12 mmHg for MAP.Responses to the potassium-supplement intervention for those carrying G allele of rs12503220 were -3.44 mmHg for SBP,-1.36 mmHg for DBP,and -2.07 mmHg for MAP.The positive findings reported here could have potential clinical and public health implications and warrant the need for further investigation of these variants.更多还原