OBJECTIVES: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes-enriched sample of European ancestry. RESEARCH DESIGN AND METHODS: Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications. RESULTS: In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 x 10(-5)); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 x 10(-6)). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 x 10(-5); 13.9-ms difference, P = 1.6 x 10(-6), respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans. CONCLUSIONS: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.
OBJECTIVES: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes-enriched sample of European ancestry. RESEARCH DESIGN AND METHODS: Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications. RESULTS: In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 x 10(-5)); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 x 10(-6)). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 x 10(-5); 13.9-ms difference, P = 1.6 x 10(-6), respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans. CONCLUSIONS: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.
Authors: Peter A Noseworthy; Aki S Havulinna; Kimmo Porthan; Annukka M Lahtinen; Antti Jula; Pekka J Karhunen; Markus Perola; Lasse Oikarinen; Kimmo K Kontula; Veikko Salomaa; Christopher Newton-Cheh Journal: Circ Cardiovasc Genet Date: 2011-04-21
Authors: W H Linda Kao; Dan E Arking; Wendy Post; Thomas D Rea; Nona Sotoodehnia; Ronald J Prineas; Bryan Bishe; Betty Q Doan; Eric Boerwinkle; Bruce M Psaty; Gordon F Tomaselli; Josef Coresh; David S Siscovick; Eduardo Marbán; Peter M Spooner; Gregory L Burke; Aravinda Chakravarti Journal: Circulation Date: 2009-02-09 Impact factor: 29.690
Authors: Jianding Cheng; David W Van Norstrand; Argelia Medeiros-Domingo; Carmen Valdivia; Bi-hua Tan; Bin Ye; Stacie Kroboth; Matteo Vatta; David J Tester; Craig T January; Jonathan C Makielski; Michael J Ackerman Journal: Circ Arrhythm Electrophysiol Date: 2009-12
Authors: C Hu; C Wang; R Zhang; M C Ng; Y Bao; C Wang; W Y So; R C Ma; X Ma; J C Chan; K Xiang; W Jia Journal: Diabetologia Date: 2009-11-24 Impact factor: 10.122
Authors: Christopher Newton-Cheh; Mark Eijgelsheim; Kenneth M Rice; Paul I W de Bakker; Xiaoyan Yin; Karol Estrada; Joshua C Bis; Kristin Marciante; Fernando Rivadeneira; Peter A Noseworthy; Nona Sotoodehnia; Nicholas L Smith; Jerome I Rotter; Jan A Kors; Jacqueline C M Witteman; Albert Hofman; Susan R Heckbert; Christopher J O'Donnell; André G Uitterlinden; Bruce M Psaty; Thomas Lumley; Martin G Larson; Bruno H Ch Stricker Journal: Nat Genet Date: 2009-03-22 Impact factor: 38.330
Authors: Ilja M Nolte; Chris Wallace; Stephen J Newhouse; Daryl Waggott; Jingyuan Fu; Nicole Soranzo; Rhian Gwilliam; Panos Deloukas; Irina Savelieva; Dongling Zheng; Chrysoula Dalageorgou; Martin Farrall; Nilesh J Samani; John Connell; Morris Brown; Anna Dominiczak; Mark Lathrop; Eleftheria Zeggini; Louise V Wain; Christopher Newton-Cheh; Mark Eijgelsheim; Kenneth Rice; Paul I W de Bakker; Arne Pfeufer; Serena Sanna; Dan E Arking; Folkert W Asselbergs; Tim D Spector; Nicholas D Carter; Steve Jeffery; Martin Tobin; Mark Caulfield; Harold Snieder; Andrew D Paterson; Patricia B Munroe; Yalda Jamshidi Journal: PLoS One Date: 2009-07-09 Impact factor: 3.240