Jenni M Rimpelä1,2, Teemu Niiranen3,4, Antti Jula3, Ilkka H Pörsti5, Antti Tikkakoski6, Aki Havulinna7, Terho Lehtimäki8, Veikko Salomaa9, Kimmo K Kontula1,2, Timo P Hiltunen1,2. 1. a Research Program for Clinical and Molecular Metabolism, Faculty of Medicine , University of Helsinki. 2. b Department of Medicine , University of Helsinki and Helsinki University Hospital , Helsinki , Finland. 3. c Department of Public Health Solutions , National Institute for Health and Welfare, Helsinki, Finland. 4. d Department of Medicine , University of Turku and Turku University Hospital , Turku , Finland. 5. e Faculty of Medicine and Health Technology , University of Tampere and Tampere University Hospital , Tampere , Finland. 6. f Department of Clinical Physiology and Nuclear Medicine , Tampere University Hospital , Tampere , Finland. 7. g Institute for Molecular Medicine Finland , FIMM, University of Helsinki, and Department of Health, National Institute for Health and Welfare , Helsinki , Finland. 8. h Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology , University of Tampere , Tampere , Finland. 9. i Department of Health , National Institute for Health and Welfare , Helsinki , Finland.
Abstract
Background: White-coat effect (WCE) confounds diagnosis and treatment of hypertension. The prevalence of white-coat hypertension is higher in Europe and Asia compared to other continents suggesting that genetic factors could play a role. Methods: To study genetic variation affecting WCE, we conducted a two-stage genome-wide association study involving 1343 Finnish subjects. For the discovery stage, we used Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 206), providing the mean WCE values from up to four separate office/ambulatory recordings conducted on placebo. Associations with p values <1 × 10-5 were included in the replication step in three independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 182), Finn-Home study (n = 773) and Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 182). Results: No single nucleotide polymorphisms reached genome-wide significance for association with either systolic or diastolic WCE. However, two loci provided suggestive evidence for association. A known coronary artery disease risk locus rs2292954 in SPG7 associated with systolic WCE (discovery p value = 2.2 × 10-6, replication p value = 0.03 in Finn-Home, meta-analysis p value 2.6 × 10-4), and rs10033652 in RASGEF1B with diastolic WCE (discovery p value = 4.9 × 10-6, replication p value = 0.04 in DILGOM, meta-analysis p value = 5.0 × 10-3). Conclusion: This study provides evidence for two novel candidate genes, SPG7 and RASGEF1B, associating with WCE. Our results need to be validated in even larger studies carried out in other populations.
Background: White-coat effect (WCE) confounds diagnosis and treatment of hypertension. The prevalence of white-coat hypertension is higher in Europe and Asia compared to other continents suggesting that genetic factors could play a role. Methods: To study genetic variation affecting WCE, we conducted a two-stage genome-wide association study involving 1343 Finnish subjects. For the discovery stage, we used Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 206), providing the mean WCE values from up to four separate office/ambulatory recordings conducted on placebo. Associations with p values <1 × 10-5 were included in the replication step in three independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 182), Finn-Home study (n = 773) and Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 182). Results: No single nucleotide polymorphisms reached genome-wide significance for association with either systolic or diastolic WCE. However, two loci provided suggestive evidence for association. A known coronary artery disease risk locus rs2292954 in SPG7 associated with systolic WCE (discovery p value = 2.2 × 10-6, replication p value = 0.03 in Finn-Home, meta-analysis p value 2.6 × 10-4), and rs10033652 in RASGEF1B with diastolic WCE (discovery p value = 4.9 × 10-6, replication p value = 0.04 in DILGOM, meta-analysis p value = 5.0 × 10-3). Conclusion: This study provides evidence for two novel candidate genes, SPG7 and RASGEF1B, associating with WCE. Our results need to be validated in even larger studies carried out in other populations.