NOS1AP is a genetic modifier of the long-QT syndrome.
BACKGROUND
In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population.


RESULTS
We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P=0.03; rs16847548, P=0.03).


CONCLUSIONS
These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations.
Crotti
Lia
L
Department of Lung, Blood, and Heart, University of Pavia, Pavia, Italy.
Monti
Maria Cristina
MC
Insolia
Roberto
R
Peljto
Anna
A
Goosen
Althea
A
Brink
Paul A
PA
Greenberg
David A
DA
Schwartz
Peter J
PJ
George
Alfred L
AL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000235:genetics; D003645:Death, Sudden; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; C488081:NOS1AP protein, human