Abstract
目的
基于福建省南靖县土楼地区大家系,探索静息心率和常见慢性病(高血压、糖尿病、血脂异常)的单表型遗传度和双表型遗传度。
方法
研究对象来源于2015年8月至2017年12月福建省漳州市南靖县土楼地区塔下村、曲江村、南欧村募集的张姓居民及其亲属,以及草坂村、图美村、背岭村募集的陈姓居民及其亲属。研究共纳入了来自452个大家系的1 563名研究对象。家系关系确定依据为家系信息登记及家谱。采用方差组分模型估计连续性变量的单表型、双表型遗传度,采用易患性-阈值模型估计二分类变量的单表型、双表型遗传度。
结果
家系重建纳入了1个七代家系,2个五代家系,23个四代家系,186个三代家系和240个二代家系。研究对象的平均年龄为57.2岁,男性占39.4%。研究对象的高血压、糖尿病、血脂异常患病率分别为49.2%、10.0%、45.2%。单表型遗传度估计显示,静息心率遗传度为0.263(95%CI: 0.120~0.407),高血压遗传度为0.404(95%CI: 0.135~0.673), 血脂异常遗传度为0.799(95%CI: 0.590~1)。收缩压、舒张压、血糖、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白的遗传度分别为0.379、0.306、0.393、0.452、0.568、0.852、0.387。双表型遗传度分析显示,静息心率与高血压、糖尿病、舒张压、血糖、甘油三酯存在表型相关性。双表型遗传度显示,静息心率与血糖(遗传相关性0.485,95%CI: 0.120~1,P<0.05)和糖尿病(遗传相关性0.795,95%CI: 0.181~0.788,P<0.05)具有较强的遗传相关性。
结论
静息心率是一个可遗传性状,其与常见慢性病及其相关指标存在相关性。静息心率与糖尿病和血糖值具有较强的遗传相关性,提示静息心率与糖尿病和血糖之间可能存在共同的遗传基础。
Keywords: 遗传度, 家系研究, 静息心率, 高血压, 糖尿病
Abstract
Objective
To estimate the univariate heritability of resting heart rate and common chronic disease such as hypertension, diabetes, and dyslipidemia based on extended pedigrees in Fujian Tulou area and to explore bivariate heritability to test for the genetic correlation between resting heart rate and other relative phenotypes.
Methods
The study was conducted in Tulou area of Nanjing County, Fujian Province from August 2015 to December 2017. The participants were residents with Zhang surname and their relatives from Taxia Village, Qujiang Village, and Nanou Village or residents with Chen surname and their relatives from Caoban Village, Tumei Village, and Beiling Village. The baseline survey recruited 1 563 family members from 452 extended pedigrees. The pedigree reconstruction was based on the family information registration and the genealogy booklet. Univariate and bivariate heritability was estimated using variance component models for continuous variables, and susceptibility-threshold model for binary variables.
Results
The pedigree reconstruction identified 1 seven-generation pedigree, 2 five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees. The mean age of the participants was 57.2 years and the males accounted for 39.4%. The prevalence of hypertension, diabetes, dyslipidemia in this population was 49.2%, 10.0%, and 45.2%, respectively. The univariate heritability estimation of resting heart rate, hypertension, and dyslipidemia was 0.263 (95%CI: 0.120-0.407), 0.404 (95%CI: 0.135-0.673), and 0.799 (95%CI: 0.590-1), respectively. The heritability of systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was 0.379, 0.306, 0.393, 0.452, 0.568, 0.852, and 0.387, respectively. In bivariate analysis, there were phenotypic correlations between resting heart rate with hypertension, diabetes, diastolic blood pressure, fasting glucose, and triglyceride. After taking resting heart rate into account, there were strong genetic correlations between resting heart rate with fasting glucose (genetic correlation 0.485, 95%CI: 0.120-1, P<0.05) and diabetes (genetic correlation 0.795, 95%CI: 0.181-0.788, P<0.05).
Conclusion
Resting heart rate was a heritable trait and correlated with several common chronic diseases and related traits. There was strong genetic correlation between resting heart rate with fasting glucose and diabetes, suggesting that they may share common genetic risk factors.
Keywords: Heritability, Pedigree, Resting heart rate, Hypertension, Diabetes
静息心率是指个体在安静、无活动状态下心脏每分钟搏动的次数。静息心率不仅是心脏生理功能的重要指标,既往研究发现静息心率也是多种慢性非传染性疾病(如高血压、糖尿病、冠心病)的独立预测因素[1,2,3]。既往双生子研究与家系研究提示,静息心率与血压、血脂、血糖、体重指数(body mass index, BMI)等多种表型的关联基础可能受到相同的遗传因素作用[4,5]。一项欧洲人群的全基因组关联研究发现,17个与静息心率相关的单核苷酸多态性位点与心血管疾病、代谢性疾病和肾疾病有关[6]。以上研究结果提示,静息心率与多种慢性病可能存在共同的遗传基础。
遗传度是评价遗传因素对性状变异影响的指标,能够反映总体遗传效应决定性状的比例,双生子设计和家系设计则是估计遗传度的常用方法。由于家系设计基于人群抽样,其得到的遗传度估计往往更为保守。大家系设计则能够得到较为丰富的家系关系,使得遗传度估计更加稳健[7]。既往双生子研究发现,静息心率的遗传度为0.61[4],而家系设计得到的静息心率遗传度为0.11~0.31[8]。目前,我国人群中静息心率单表型、双表型遗传度相关研究较少见。因此,本研究基于福建省南靖县募集的大家系,利用基线调查横断面数据,探索了静息心率与常见慢性病的遗传相关性。
1. 资料与方法
1.1. 研究对象
本研究资料来源于“中国环境流行病学特殊人群队列研究”项目[9],研究现场为福建省漳州市南靖县土楼地区,包括2015年8月至2017年12月塔下村、曲江村、南欧村募集的张姓居民,草坂村、图美村、背岭村募集的陈姓居民。研究对象的纳入标准为:(1)所有张姓、陈姓氏族成员及其有血缘关系的亲属和配偶;(2)自愿参与并完成问卷调查、家系信息收集、生化检查、体格检查;(3)无重大躯体性、精神性疾病(如残疾、重度痴呆等), 可以配合调查。
研究开始前获得北京大学生物医学伦理委员会审查批准(IRB00001052-14021), 所有研究对象包括患者和健康人均签署了知情同意书。
1.2. 家系构建
家系构建的依据为研究对象提供的家系信息,搜寻其亲属中被调查的研究对象,同时依据南靖县张姓、陈姓族谱进行家系信息补充并排除仅有1名调查对象的家系。
1.3. 结局定义
基线调查包括问卷调查、体格检查和血生化检测。采用电子血压计测量血压和静息心率,采用皮尺测量身高、腰围、臀围,以上变量每名调查对象测量2次,若两次测量结果之差大于5个单位,则测量第3次并取后两次测量值的均值进入统计分析。
研究涉及结局的定义:(1)高血压:自报二级以上医院诊断高血压病史或两周内服用降血压药物或体检中收缩压≥140 mmHg和(或)舒张压≥90 mmHg[10];(2)糖尿病:自报二级以上医院诊断的糖尿病史或空腹血糖≥7.0 mmol/L[11];(3)血脂异常:自报二级以上医院诊断的高脂血症史或血生化检测总胆固醇≥6.2 mmol/L或甘油三酯≥2.3 mmol/L或高密度脂蛋白<1.0 mmol/L或低密度脂蛋白≥4.1 mmol/L[12]。
1.4. 统计学分析
对连续性变量采用Kolmogorov-Smirnov检验其正态性,若符合正态分布,以均数±标准差描述集中趋势和离散趋势。对不符合正态分布的变量,经逆正态变换后纳入分析。对分类变量采用频率描述变量的水平,描述性分析采用Stata 软件13.1版本。连续型变量的单表型、双表型遗传度分析采用最大似然估计的方差组分模型进行,分类变量的单表型、双表型遗传度分析采用易患性-阈值模型进行[13,14]。为避免年龄、性别及其交互作用可能对结果造成的偏倚,根据既往研究经验,所有分析中均调整性别、年龄、性别×年龄、年龄2、性别×年龄2作为协变量,遗传度估计会在扣除协变量效应之后进行。单表型遗传度定义为加性遗传组分占表型变异的比例,双表型遗传度定义为两表型加性遗传组分相关系数。数据分析使用SOLAR软件(版本 8.1.1),P<0.05认为差异有统计学意义。
2. 结果
2.1. 基本人口学特征
本研究共纳入研究对象1 563人(表1),平均年龄57.2岁,男性占39.4%,全部为汉族。研究对象的高血压患病率为 49.2%, 糖尿病患病率为10.0%,血脂异常的患病率为45.2%。男性各种慢性病患病率均高于女性。本研究构建的家系包括1个七代家系,2个五代家系,23个四代家系,186个三代家系,240个两代家系(表2)。
1.
研究对象基本人口学特征
Demographic characteristics of participants
| Characteristics | Male | Female | Total | P |
| BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure. | ||||
| Gender, n(%) | 681 (39.4) | 882 (60.6) | 1 563 (100) | |
| Age/years, x±s | 58.4 ±13.0 | 56.4±13.4 | 57.2±13.2 | <0.05 |
| Marriage status, n(%) | <0.05 | |||
| Married | 632 (92.8) | 768 (87.1) | 1400 (89.6) | |
| Divorce/Widowed | 29 (4.3) | 96 (10.9) | 125 (8.0) | |
| Unmarried | 20 (2.9) | 18 (2.0) | 38 (2.4) | |
| Education level, n(%) | <0.05 | |||
| Below primary | 115 (16.9) | 417 (47.3) | 532 (34.0) | |
| Primary | 221 (32.5) | 222 (25.2) | 443 (28.3) | |
| Junior high | 222 (32.6) | 149 (16.9) | 371 (23.7) | |
| Senior high | 101 (14.8) | 66 (7.5) | 167 (10.7) | |
| College or above | 22 (3.2) | 28 (3.2) | 50 (3.2) | |
| Occupation, n(%) | <0.05 | |||
| Farmer or worker | 371 (54.5) | 368 (41.7) | 739 (47.3) | |
| Administrator or professional | 30 (4.4) | 28 (3.2) | 58 (3.7) | |
| Retiree or student | 115 (16.9) | 51 (5.8) | 166 (10.6) | |
| Household | 120 (17.6) | 99 (11.2) | 219 (14.0) | |
| Other | 45 (6.6) | 336 (38.1) | 381 (24.4) | |
| Smoking status, n(%) | <0.05 | |||
| Current smoking | 283 (41.6) | 22 (2.5) | 305 (19.5) | |
| Ex-smoking | 94 (13.8) | 3 (0.3) | 97 (6.2) | |
| Never smoking | 304 (44.6) | 857 (97.2) | 1161 (74.3) | |
| Alcohol consumption, n(%) | <0.05 | |||
| Current drinking | 137 (20.1) | 29 (3.3) | 166 (10.6) | |
| Ex-drinking | 31 (4.6) | 6 (0.7) | 37 (2.4) | |
| Never drinking | 513 (75.3) | 847 (96.0) | 1360 (87.0) | |
| Hypertension, n(%) | 367 (53.9) | 402 (45.6) | 769 (49.2) | <0.05 |
| Diabetes, n(%) | 88 (12.9) | 69 (7.8) | 157 (10.0) | <0.05 |
| Dyslipidemia, n(%) | 347 (51.0) | 359 (40.7) | 706 (45.2) | <0.05 |
| BMI/(kg/m2), x±s | 23.4±3.5 | 23.3±3.2 | 23.4±3.3 | 0.56 |
| SBP/mmHg), x±s | 139.6±20.5 | 137.3±22.3 | 138.3±21.5 | <0.05 |
| DBP (mm Hg), x±s | 82.2±11.3 | 78.2±11.2 | 79.9±11.4 | <0.05 |
| Resting heart rate/ (/min), x±s | 78.3±11.2 | 77.9±10.2 | 78.1±10.6 | 0.47 |
2.
家系构建基本信息
Basic information of pedigree reconstruction
| Generation | Pedigrees | Total family members | Investigated members | Average investigated members per pedigree | Investigation ratio/% |
| 2 | 240 | 751 | 503 | 2.10 | 70.0 |
| 3 | 186 | 1 575 | 814 | 4.38 | 51.7 |
| 4 | 23 | 380 | 191 | 8.30 | 50.3 |
| 5 | 2 | 50 | 23 | 11.5 | 46.0 |
| 7 | 1 | 62 | 32 | 32 | 51.6 |
2.2. 单变量遗传度估计
基于本研究构建的大家系,估计得到静息心率遗传度为0.263(P<0.001),且协变量对其贡献较小。高血压遗传度为0.404(P=0.001),血脂异常遗传度为0.799(P<0.001),其余表型遗传度见表3。
3.
静息心率及常见慢性病单表型遗传度
Univariate heritability of resting heart rate and common chronic diseases
| Variables | Effect of covariatesa | Heritability (95%CI) | P |
| a, covariates include gender, age, age×gender, age2, gender×age2; b, inverse normal transformation was applied for the variables not following normal distribution. SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CI, confidence interval. | |||
| Resting heart rate | 0.022 | 0.263 (0.120-0.407) | <0.001 |
| Hypertension | - | 0.404 (0.135-0.673) | 0.001 |
| Diabetes | - | 0.272 (-0.164-0.708) | 0.11 |
| Dyslipidemia | - | 0.799 (0.590-1.000) | <0.001 |
| SBP | 0.187 | 0.379 (0.213-0.545) | <0.001 |
| DBP | 0.069 | 0.306 (0.155-0.458) | <0.001 |
| Fasting glucoseb | 0.054 | 0.393 (0.244-0.543) | <0.001 |
| Total cholesterolb | 0.034 | 0.452 (0.306-0.598) | <0.001 |
| Triglycerideb | 0.040 | 0.568 (0.429-0.707) | <0.001 |
| HDL-Cb | 0.037 | 0.852 (0.741-0.964) | <0.001 |
| LDL-C | 0.042 | 0.387 (0.236-0.538) | <0.001 |
2.3. 双变量遗传度估计
基于本研究构建的大家系,双表型遗传度分析显示,静息心率与高血压、糖尿病、舒张压、血糖、甘油三酯均存在表型相关性,其中静息心率与血糖的表型相关性最高,为0.203(P<0.05)。静息心率与血糖和糖尿病具有较强的遗传相关性,分别为0.485(P<0.05)和0.795(P<0.05)。
3. 讨论
慢性非传染性疾病是造成我国居民健康寿命年损失的主要因素。2002年至2017年,中国高血压患病率增长约2.5倍[15,16],达到44.7%,糖尿病的患病率也持续增长达到了 9.1%[17]。为深入探索常见慢性病的病因,本研究基于福建南靖县土楼地区大家系,分析发现静息心率与高血压、糖尿病、血脂相关指标均存在表型相关性,其中糖尿病患病状态和血糖值与静息心率存在较强的遗传相关性,提示血糖水平和静息心率可能受到共同的遗传因素影响,这为后续遗传致病因素的深入探索提供了重要依据,静息心率相关的遗传危险因素可能同时影响糖尿病的发病风险。
本研究单表型遗传度分析显示,静息心率的遗传度为0.263,接近既往家系研究的结果[8],但低于双生子研究得出的遗传度[4]。结果提示静息心率为可遗传性状,受到加性遗传变异的影响,但遗传因素对静息心率的决定程度较低。本研究结果显示高血压、收缩压、舒张压的遗传度分别为0.404、0.379和0.306,其中高血压和收缩压除受遗传因素决定外,受年龄性别影响也较大。既往双生子研究和家系研究显示,高血压遗传度为0.3~0.5[18],收缩压遗传度为0.34[19],舒张压遗传度为0.368[20],与本研究结果相近。本研究发现,血糖水平受到遗传因素的影响,而本分析中糖尿病的患者及家系样本有限,通过采用易患性-阈值模型,未发现糖尿病具有统计学意义的遗传度,需进一步扩大家系样本后验证和评估糖尿病的遗传度。本研究还发现血脂异常、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白受遗传因素影响较大,其遗传度分别为0.799、0.451、0.568、0.852、0.387,与既往遗传度研究结果一致[5]。本研究发现,血脂异常作为综合多项血脂水平的指标具有较高的遗传度,但具体血脂相关指标受到遗传因素影响的程度不一,推测影响不同血脂指标的遗传危险因素可能存在一定差异。
4.
静息心率及常见慢性病双表型遗传度
Bivariate heritability of resting heart rate and common chronic diseases
| Variables | Environmental correlation | Pa | Genetic correlation (95%CI) | Pb | Pc | Phenotypic correlation | Pd |
| a, testing the difference between the environmental correlation and 0; b, testing the difference between the genetic correlation and 0; c, testing the difference between the genetic correlation and 1 or -1; d, testing the difference between the phenotypic correlation and 0; e, inverse normal transformation was applied for the variables not following normal distribution. All variables were adjusted for gender, age, age×gender, age2, gender×age2. SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CI, confidence interval. | |||||||
| Hypertension | 0.163 | 0.13 | -0.086 (-0.515-0.343) | 0.70 | <0.05 | 0.080 | <0.05 |
| Diabetes | -0.108 | 0.41 | 0.795 (0.120-1.000) | <0.05 | 0.31 | 0.159 | <0.05 |
| Dyslipidemia | 0.297 | 0.08 | -0.170 (-0.467-0.128) | 0.25 | <0.05 | 0.034 | 0.29 |
| SBP | 0.126 | 0.13 | -0.188 (-0.486-0.110) | 0.30 | <0.05 | 0.026 | 0.32 |
| DBP | 0.344 | <0.05 | -0.214 (-0.625-0.197) | 0.27 | <0.05 | 0.187 | <0.05 |
| Fasting glucosee | 0.068 | 0.40 | 0.485 (0.181-0.788) | <0.05 | <0.05 | 0.203 | <0.05 |
| Total cholesterole | 0.100 | 0.23 | -0.151 (-0.463-0.161) | 0.34 | <0.05 | 0.011 | 0.68 |
| Triglyceridee | 0.185 | <0.05 | -0.129 (-0.413-0.156) | 0.37 | <0.05 | 0.054 | <0.05 |
| HDL-Ce | -0.015 | 0.91 | 0.022 (-0.204-0.249) | 0.85 | <0.05 | 0.005 | 0.83 |
| LDL-C | 0.051 | 0.52 | -0.171 (-0.505-0.162) | 0.32 | <0.05 | -0.021 | 0.41 |
双表型遗传度是共同遗传因素导致的相关性占两个表型总相关性的比例。双表型遗传度的估计是将两个性状的表型相关系数分解为遗传相关系数和环境相关系数,其中,表型相关系数即表型相关性,表示性状的总体相关性;遗传相关系数即遗传相关性,表示影响两个表型的遗传物质的相似程度;环境相关系数即环境相关性,表示影响两个表型的环境因素的相似程度。既往双表型遗传度研究显示,静息心率与舒张压和人体压力感受器敏感性具有相关性,但主要受到共同的环境因素影响[14]。本研究发现,静息心率与高血压、糖尿病、血脂水平存在表型相关性,其中静息心率与血糖水平相关性最高,并且,静息心率与糖尿病和血糖水平具有较强的遗传相关性,提示其可能受共同的遗传物质控制。既往多个国家和地区的前瞻性队列研究显示,高静息心率显著增加糖尿病的发生风险,即静息心率与糖尿病存在关联[21,22]。而全基因组关联研究和转录组学研究发现,静息心率与糖尿病存在共同的遗传位点,由多基因评分得到其遗传相关性为0.22[23,24],该结果小于本研究得到的遗传相关性,提示可能尚存在未被发现的同时影响静息心率和糖尿病的遗传危险因素。而静息心率与糖尿病相关的机制可能是:高静息心率时交感神经活性增加,胰岛素抵抗,从而增加2型糖尿病的发病风险[25]。同时,2型糖尿病会引发一系列代谢系统紊乱,如肥胖、血压变化等,导致静息心率升高[26]。
福建土楼家系队列研究是我国仅有的几项家系队列研究之一,由于该地区居民以氏族聚集性生活,极适宜于收集家系资料和开展遗传流行病学研究。本研究利用该大家系资料进行遗传度估计,亲属关系丰富,因此遗传度估计结果更为可靠。同时本研究纳入1 563名研究对象,是我国目前规模较大的多代大家系研究,使得本研究得到的遗传度估计较为稳健。
本研究同时存在一定的局限性,本研究已构建的家系包含2 818名研究对象,后续工作尚需纳入未参与研究的家系对象,扩充得到更完整的家系信息。
综上所述,本研究提示静息心率与常见慢性疾病存在相关性,并且静息心率与糖尿病具有遗传相关性,提示二者可能存在共同的遗传基础,后续可继续深入探索影响静息心率和糖尿病的遗传危险因素。
Funding Statement
公益性行业科研专项（201502006）; 福建省卫生系统中青年骨干人才培养项目（2014-ZQN-ZD-7）
Special Fund for Health Scientific Research of Public Welfare(201502006); Training Project for Young Backbone Talents in Fujian Health System(2014-ZQN-ZD-7)
References
- 1.Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26(10):967–974. doi: 10.1093/eurheartj/ehi190. [DOI] [PubMed] [Google Scholar]
- 2.Hansen CS, Færch K, Jϕrgensen ME, et al. Heart rate, autonomic function, and future changes in glucose metabolism in individuals without diabetes: the whitehall II cohort study. Diabetes care. 2019;42(5):867–874. doi: 10.2337/dc18-1838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Inoue T, Iseki K, Iseki C, et al. Higher heart rate predicts the risk of developing hypertension in a normotensive screened cohort. Circ J. 2007;71(11):1755–1760. doi: 10.1253/circj.71.1755. [DOI] [PubMed] [Google Scholar]
- 4.Wang B, Liao C, Zhou B, et al. Genetic contribution to the variance of blood pressure and heart rate: a systematic review and meta-regression of twin studies. Twin Res Hum Genet. 2015;18(2):158–170. doi: 10.1017/thg.2015.8. [DOI] [PubMed] [Google Scholar]
- 5.Pilia G, Chen WM, Scuteri A, et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2006;2(8):e132. doi: 10.1371/journal.pgen.0020132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Nolte IM, Munoz ML, Tragante V, et al. Genetic loci associated with heart rate variability and their effects on cardiac disease risk. Nat Commun. 2017;8:15805. doi: 10.1038/ncomms15805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hopper JL, Bishop DT, Easton DF. Population-based family studies in genetic epidemiology. Lancet. 2005;366(9494):1397–1406. doi: 10.1016/S0140-6736(05)67570-8. [DOI] [PubMed] [Google Scholar]
- 8.Muñoz ML, Jaju D, Voruganti S, et al. Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman family study. J Hypertens. 2018;36(7):1477–1485. doi: 10.1097/HJH.0000000000001715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.黄 辉, 叶 莺, 黄 春兰, et al. 福建土楼家系队列研究:研究方法及调查对象基线和家系特征. 中华流行病学杂志. 2018;39(10):1402–1407. [Google Scholar]
- 10.中国高血压防治指南修订委员会. 中国高血压防治指南2010. 中华心血管病杂志. 2011;39(7):579–616. [PubMed] [Google Scholar]
- 11.中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2013年版) 中华内分泌代谢杂志. 2014;30(10):893–942. [Google Scholar]
- 12.中国成人血脂异常防治指南修订联合委员会. 中国成人血脂异常防治指南(2016年修) 中华心血管病杂志. 2016;44(10):833–853. doi: 10.3760/cma.j.issn.0253-3758.2016.10.005. [DOI] [PubMed] [Google Scholar]
- 13.Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62(5):1198–1211. doi: 10.1086/301844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Man T, Riese H, Jaju D, et al. Heritability and genetic and environmental correlations of heart rate variability and baroreceptor reflex sensitivity with ambulatory and beat-to-beat blood pressure. Sci Rep. 2019;9(1):1664. doi: 10.1038/s41598-018-38324-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Lu J, Lu Y, Wang X, et al. Prevalence, awareness, treatment, and control of hypertension in China: data from 1.7 million adults in a population-based screening study (China PEACE Million Persons Project) Lancet. 2017;390(10112):2549–2558. doi: 10.1016/S0140-6736(17)32478-9. [DOI] [PubMed] [Google Scholar]
- 16.Wang J, Zhang L, Wang F, et al. Prevalence, awareness, treatment, and control of hypertension in China: results from a national survey. Am J Hypertens. 2014;27(11):1355–1361. doi: 10.1093/ajh/hpu053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yang L, Shao J, Bian Y, et al. Prevalence of type 2 diabetes mellitus among inland residents in China (2000-2014): a meta-analysis. J Diabetes Investig. 2016;7(6):845–852. doi: 10.1111/jdi.12514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Padmanabhan S, Caulfield M, Dominiczak AF. Genetic and molecular aspects of hypertension. Circ Res. 2015;116(6):937–959. doi: 10.1161/CIRCRESAHA.116.303647. [DOI] [PubMed] [Google Scholar]
- 19.Adeyemo AA, Omotade OO, Rotimi CN, et al. Heritability of blood pressure in Nigerian families. J Hypertens. 2002;20(5):859–863. doi: 10.1097/00004872-200205000-00019. [DOI] [PubMed] [Google Scholar]
- 20.潘 发明, 臧 桐华, 佳 桐倪. 血压的遗传度分析. 中国公共卫生. 2002;18(9):1030–1032. [Google Scholar]
- 21.Xu C, Zhong J, Zhu H, et al. Independent and interactive associations of heart rate and body mass index or blood pressure with type 2 diabetes mellitus incidence: a prospective cohort study. J Diabetes Investig. 2019;10(4):1068–1074. doi: 10.1111/jdi.12999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Grantham NM, Magliano DJ, Tanamas SK, et al. Higher heart rate increases risk of diabetes among men: the Australian diabetes obesity and lifestyle (AusDiab) study. Diabet Med. 2013;30(4):421–427. doi: 10.1111/dme.12045. [DOI] [PubMed] [Google Scholar]
- 23.Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47(11):1236–1241. doi: 10.1038/ng.3406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Guo Y, Chung W, Zhu Z, et al. Genome-wide assessment for resting heart rate and shared genetics with cardiometabolic traits and type 2 diabetes. J Am Coll Cardiol. 2019;74(17):2162–2174. doi: 10.1016/j.jacc.2019.08.1055. [DOI] [PubMed] [Google Scholar]
- 25.Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol. 2008;51(18):1725–1733. doi: 10.1016/j.jacc.2008.01.038. [DOI] [PubMed] [Google Scholar]
- 26.Zhao Y, Zhang M, Liu Y, et al. 6-year change in resting heart rate is associated with incident type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2019;29(3):236–243. doi: 10.1016/j.numecd.2018.12.003. [DOI] [PubMed] [Google Scholar]