Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Heritability analyses show visit-to-visit blood pressure variability reflects different pathological phenotypes in younger and older adults: evidence from UK twins Cristina Menni a , Massimo Mangino a , Feng Zhang a , Gail Clement a , Harold Snieder b , Sandosh Padmanabhan c , and Tim D. Spector a Background: Clinic and long-term average blood pressure (BP) are heritable traits with estimates of heritability ranging from 0.31 to 0.68. Long-term visit-to-visit BP variability (BPV) is emerging as a new cardiovascular risk predictor, though it is unclear if this is completely independent of BP. We hypothesize that BPV should demonstrate the same pattern of additive genetic, shared environmental and unique environmental variance as BP, if both are phenotypic surrogates. Method: We studied 2889 twin pairs not on any BP- lowering therapy from the Twins UK cohort, and estimated the additive genetic variance for baseline BP, long-term average BP, BP trajectory (rate of change of BP in mmHg/ year) and BPV (coefficient of variation and average real variability over an average of 3.2 visits). Heritability estimates were obtained by structural equation modelling adjusting for age, age 2 , sex and BMI. Results: The heritabilities for baseline SBP and DBP were 0.51 (95% confidence interval 0.49, 0.53) and 0.56 (0.54, 0.58); long-term average SBP and DBP were 0.56 (0.53, 0.59) and 0.61 (0.58, 0.64); and systolic and diastolic trajectories over 10 years were 0.49 (0.46, 0.52) and 0.29 (0.27, 0.32), respectively. Both overall systolic and diastolic BPV showed no additive genetic variance contributing to the phenotypic variation, but after stratification by age, the younger subgroup (<51 years) showed heritability estimates of 0.44 (0.38, 0.50) for coefficient of variation and 0.35 (0.29, 0.41) for average real variability. Conclusion: Age is a major factor that influences heritability estimation of BPV and it is likely that BPV in younger and older age groups may reflect different pathological phenotypes. Keywords: blood pressure variability, heritability, twins Abbreviations: A, additive genetic variance; AIC, Akaike information criterion; AVR, average real variability; BP, blood pressure; BPV, blood pressure variability; C, shared/ common environmental variance; CKD, chronic kidney disease; E, unique environmental variance; h 2 , heritability INTRODUCTION L ong-term visit-to-visit blood pressure variability (BPV) is emerging as an independent cardiovascular risk predictor from post-hoc analysis of large clinical trials and population cohorts [1 – 3]. It is well established that blood pressure (BP) is heritable with estimates of herit- ability ranging from 0.31 to 0.68 [4–8], and high BP is an independent predictor of early mortality [9]. It is unclear whether the predictive value of long-term BPV is independ- ent of clinic or ambulatory BP readings, though there is some evidence that the risk posed by BPV is independent of average BP [1,10]. As BPV correlates with clinic and long- term average BP [3,11], we hypothesize that it should also demonstrate the same pattern of additive genetic (A), shared environmental (C) and unique environmental (E) variance, if it is a phenotypic surrogate of BP. Recently, heritability analysis of short-term BPV from ambulatory BP data showed daytime BPV was not heritable, whereas night-time BPV was 0.33–0.36 heritable [12]. We analysed the heritabilities of BP, long-term average BP, BP trajectory and BPV in a cohort of adult twins to determine if BPV is independent of BP. METHODS Study population Study participants were twins enrolled in the Twins UK registry, a national register of adult twins recruited as volunteers by successive media campaigns without select- ing for particular diseases or traits [13]. The registry Journal of Hypertension 2013, 31:000–000 a Department of Twin Research & Genetic Epidemiology, King’s College London, London, UK, b Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands and c British Heart Foundation (BHF) Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK Correspondence to Dr Sandosh Padmanabhan, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK. E-mail: sandosh.padmanabhan@glasgow.ac.uk or Prof Tim D Spector, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London SE1 7EH, UK. Tel: +4420 7188 5555; fax: +44 20 7188 6761; e-mail: tim.spector@kcl.ac.uk Received 4 December 2012 Revised 21 May 2013 Accepted 16 July 2013 J Hypertens 31:000–000 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0b013e32836523c1 Journal of Hypertension www.jhypertension.com 1 Original Article