title: Phenotypic variability in Caucasian and Japanese patients with matched LQT1 mutations.
abstract: BACKGROUND
  Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene.
  
  
  METHODS
  The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having six identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (> 50%) or haploinsufficiency (< or =50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years.
  
  
  RESULTS
  Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; P = 0.01). The respective frequencies of dominant negative mutations in the two ethnic groups were 63% and 28% (P < 0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (P = 0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR = 1.05; P = 0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR = 3.78; P < 0.001).
  
  
  CONCLUSIONS
  Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations.
authors: Cardiology Division of the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY14642, USA.
authors: Judy F
authors: JF
authors: Liu
authors: Ilan
authors: I
authors: Goldenberg
authors: Arthur J
authors: AJ
authors: Moss
authors: Wataru
authors: W
authors: Shimizu
authors: Arthur A
authors: AA
authors: Wilde
authors: Nynke
authors: N
authors: Hofman
authors: Scott
authors: S
authors: McNitt
authors: Wojciech
authors: W
authors: Zareba
authors: Yoshihiro
authors: Y
authors: Miyamato
authors: Jennifer L
authors: JL
authors: Robinson
authors: Mark L
authors: ML
authors: Andrews
mesh_terms: D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D016009:Chi-Square Distribution; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008133:Long QT Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012042:Registries; D018570:Risk Assessment; D016019:Survival Analysis; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data
chemical_list: D051657:KCNQ1 Potassium Channel