INTRODUCTION search for common variants associated with complex traits.
Owing to the small size of existing SCD collections, the stat-
Sudden cardiac death (SCD) is one of the major causes of car- istical power to study this trait through GWA studies is
diovascular mortality in developed countries and mostly limited. The focus has been on intermediate quantitative
occurs in individuals unrecognized to be at risk (1). Familial measurespredictiveofSCD.Oneofthequantitativepredictors
aggregation of SCD, independent of other risk factors, of arrhythmogenesis is the electrocardiographic (ECG) QT
suggests a genetic role in SCD risk (2–5). By the use of interval duration, a non-invasive measure of ventricular
genome-wide association studies (GWAS), it is possible to repolarization. Variation of the QT interval in the generalpopulation is35% heritable and prolonged QT intervals are population consisted of 5661 subjects from the Rotterdam
associated with increased cardiovascular morbidity and mor- study, all with available QT measurements and without a
tality, including SCD (6–8). Using GWAS, a common left or right bundle branch block, atrial fibrillation and a
variant (rs10494366) in the nitric oxide synthase-1 adaptor QRS duration ,120 ms, to minimize QT measurement
protein (NOS1AP) gene was identified and reproducibly errors. During a mean follow-up of 10.8 years, 154 cases of
associated with QT interval duration (9–13). Previously, we SCD were identified, 85 of which witnessed.
have reported a fine mapping effort for this association in
the Rotterdam study, which refined the signal of association
to rs12143842 (14). This SNP was consistently the strongest
NOS1AP variants association with SCD
associated variant in recent GWAS reports on QT interval
in the Rotterdam study本文来自优.文,论-文·网原文请找腾讯752018766
(15–17).
The proportional hazards assumption for a constant hazard
Recently, two SNPs with very low linkage disequilibrium
ratio (HR) over time was met. After adjustment for age and
(rs16847548 and rs12567209) at the NOS1AP locus were
sex, rs12143842, rs16847548 and rs12567209 variants
reported to be independently associated with SCD risk in a
showed non-significant trends for association with SCD
large US community-b
hindi sms http://www.hindisms-hindi.com/ ased population study of European
under an additive genetic model in the Rotterdam Study
ancestry (18), but to date no replication has been reported.
alone (Table 2). Since rs16847548 is in linkage disequilibrium
The rs12143842 common variant is in considerable linkage
2
2
with rs12143842 (HapMaP CEU r 1/4 0.82), the results are
disequilibrium with rs16847548 (HapMap CEU r 1/4 0.82)
2
very similar for these SNPs (Table 3). For simplicity in sub-
but not rs12567209 (HapMap CEU r 1/4 0.027). The goal of
sequent analyses, we show results for the genotyped
the present study was to test for association of rs12143842
rs12143842 SNP only. Upon inclusion of both rs12567209
oritsrecently reported proxy rs16847548and the second inde-
and rs12143842 in the same model, in addition to age and
pendentvariantrs12567209withSCDintheRotterdamStudy,
sex, the HR for rs12567209 changed from 0.85 [95% confi-
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