Key result
Japanese LQT1 patients had a higher unadjusted rate of cardiac events than Caucasians (67% vs 39%), but this difference was explained by a higher frequency of dominant-negative mutations (HR 1.05; P=0.89).
Why the study?
Does ethnicity independently affect the risk of first cardiac events in patients with matched LQT1 mutations?
Cohort (n=100)
Yes
Does ethnicity independently affect the risk of first cardiac events in patients with matched LQT1 mutations?
Ethnic differences in the clinical expression of LQT1 are primarily driven by the underlying biophysical function of the specific mutations rather than ethnicity itself.
Mutation type, not ethnicity, drives LQT1 event risk; hypothesis-generating for genotype-guided stratification in prospective cohorts.
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.
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Liu et al. (2008) conducted a cohort in Long QT type-1 (LQT1) (n=100). Japanese ethnicity vs. Caucasian ethnicity was evaluated on occurrence of a first cardiac event from birth through age 40 years (HR 1.05, p=0.89). Japanese LQT1 patients had a higher unadjusted rate of cardiac events than Caucasians (67% vs 39%), but this difference was explained by a higher frequency of dominant-negative mutations (HR 1.05; P=0.89).
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