TY - JOUR
T1 - Genotype-Phenotype Aspects of Type 2 Long QT Syndrome
AU - Shimizu, Wataru
AU - Moss, Arthur J.
AU - Wilde, Arthur A.M.
AU - Towbin, Jeffrey A.
AU - Ackerman, Michael J.
AU - January, Craig T.
AU - Tester, David J.
AU - Zareba, Wojciech
AU - Robinson, Jennifer L.
AU - Qi, Ming
AU - Vincent, G. Michael
AU - Kaufman, Elizabeth S.
AU - Hofman, Nynke
AU - Noda, Takashi
AU - Kamakura, Shiro
AU - Miyamoto, Yoshihiro
AU - Shah, Samit
AU - Amin, Vinit
AU - Goldenberg, Ilan
AU - Andrews, Mark L.
AU - McNitt, Scott
N1 - Funding Information:
Dr. Ackerman has a consulting relationship and license agreement/royalty arrangement with PGxHealth (FAMILION). This work was supported in part by a Health Sciences Research Grant (H18-Research on Human Genome-002) and a Research Grant for the Cardiovascular Diseases (21C-8) from the Ministry of Health, Labour and Welfare, Japan (to Dr. Shimizu); research grants HL-33843 and HL-51618 (to Dr. Moss) and HL-60723 (to Dr. January) from the National Institutes of Health, Bethesda, Maryland; and grant 2000.059 from the Nederlandse Hartstichting, Amsterdam, the Netherlands (to Dr. Wilde). Dr. Ackerman has received support from Medtronic, PGxHealth, and Pfizer. Dr. January has received support from Cellular Dynamics International. Dr. Tester receives modest royalties from PGxHealth. Dr. Kaufman receives research support from CardioDx and St. Jude Medical. Drs. Shimizu, Moss, Wilde, Towbin, Ackerman, and January contributed equally to the original concept of this investigation.
PY - 2009/11/24
Y1 - 2009/11/24
N2 - Objectives: The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS). Background: Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology. Methods: Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events. Results: For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in α-helical domains than in subjects with mutations in β-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent β-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001). Conclusions: The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.
AB - Objectives: The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS). Background: Previous studies were limited by population size in their ability to examine phenotypic effect of location, type, and topology. Methods: Study subjects included 858 type 2 LQTS patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contributions of clinical and genetic factors to the first cardiac events. Results: For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (hazard ratio [HR]: 2.87 and 1.86, respectively), but the transmembrane nonpore (S1-S4) region was not (HR: 1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane nonpore regions (HR: 1.54 and 2.42, respectively). However, for nonmissense mutations, these other regions were no longer riskier than the C-terminus (HR: 1.13, 0.77, and 0.46, respectively). Likewise, subjects with nonmissense mutations were at significantly higher risk than were subjects with missense mutations in the C-terminus region (HR: 2.00), but that was not the case in other regions. This mutation location-type interaction was significant (p = 0.008). A significantly higher risk was found in subjects with mutations located in α-helical domains than in subjects with mutations in β-sheet domains or other locations (HR: 1.74 and 1.33, respectively). Time-dependent β-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p < 0.001). Conclusions: The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.
KW - arrhythmia
KW - electrocardiography
KW - genetics
KW - long QT syndrome
KW - syncope
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U2 - 10.1016/j.jacc.2009.08.028
DO - 10.1016/j.jacc.2009.08.028
M3 - Article
C2 - 19926013
AN - SCOPUS:71849098104
SN - 0735-1097
VL - 54
SP - 2052
EP - 2062
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -