Abstract 2788: Common Cardiac Channel Polymorphisms in Sudden Infant Death Syndrome
Background: Approximately 10% of sudden infant death syndrome (SIDS) stems from rare long QT syndrome (LQTS)- or catecholaminergic polymorphic ventricular tachycardia (CPVT)-causing mutations. Several common cardiac channel polymorphisms (R1047L-KCNH2, H558R- and S1103Y-SCN5A, and D85N-KCNE1) in LQTS-associated genes have been shown to be pro-arrhythmic polymorphisms and S1103Y-SCN5A may confer increased susceptibility for SIDS among African-Americans. Here, we sought to determine whether such polymorphisms were over-represented in SIDS.
Methods: Using PCR, DHPLC, and direct DNA sequencing, 92 population-based SIDS cases (50 male, 56 white, 36 black, average age = 3.0 ± 2.6 months) were genotyped for the presence of common (> 1%) non-synonymous (code changing) single nucleotide polymorphisms (cSNPs) in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and RyR2 (CPVT1). The genotype frequencies among cases were compared to genotype frequencies derived from up to 2750 ethnic-matched reference alleles.
Results: Overall, there was no difference in either the most common KCNH2 polymorphism (K897T), the loss-of-function associated SCN5A polymorphism (H558R), or the most common RyR2 polymorphism (Q2958R). Among the white SIDS cases, R1047L-KCNH2 was present in 5/56 (9%) decedents compared to 7/187 (3.7%) controls but this did not achieve statistical significance. Among the black decedents, there was significant over-representation of the Y1103-encoding minor allele in SCN5A. Nine of the 36 black cases (25%) were heterozygous for S1103Y compared to 158/1375 black controls (11.5%, p < 0.03). In addition, V648I-KCNQ1 was detected in 4/36 (11%) black SIDS cases compared to 7/305 (2%) black controls (p = 0.02).
Conclusions: Besides rare LQTS/CPVT-causing mutations that underlie 10% of SIDS, this population-based study of SIDS provides independent, confirmatory evidence that the acidosis-sensitive S1103Y-SCN5A common polymorphism may confer increased risk for SIDS among black infants. Since the functional sequelae of V648I-KCNQ1 are currently unknown, the contribution of this black-specific common polymorphism to sudden unexplained death during infancy requires further investigation.