Association of the serotonin transporter gene with sudden infant death syndrome: A haplotype analysis

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Abstract
Serotonergic receptor binding in the arcuate nucleus, n. raphé obscurus, and other medullary regions is decreased in sudden infant death syndrome (SIDS) cases. Further, an insertion/deletion polymorphism in the promoter region of the serotonin transporter protein (5‐HTT) gene has recently been associated with risk of SIDS. This polymorphism differentially regulates 5‐HTT expression, with the long allele (L), the SIDS‐associated allele, being a more effective promoter than the short allele (S). To further elucidate the role of the 5‐HTT gene in SIDS, we investigated the 5‐HTT intron 2 polymorphism, which also differentially regulates 5‐HTT expression with the 12 repeat allele being the more effective promoter. In a cohort of 90 SIDS cases (44 African‐American and 46 Caucasian) and gender/ethnicity‐matched controls, significant positive associations were found between SIDS and the intron 2 genotype distribution (P‐value = 0.041) among African‐American SIDS vs. African‐American controls, specifically with the 12/12 genotype (P‐value = 0.03), and with the 12 repeat allele (P‐value=0.018). The frequency of the 12/12 genotype and 12‐repeat allele was significantly different (P < 0.001) between the African‐American and Caucasian SIDS cases. Furthermore, the promoter and intron 2 loci were in significant linkage disequilibrium, and the L‐12 haplotype was significantly associated with SIDS in the African‐American (P = 0.002) but not Caucasian (P = 0.117) subgroups. These results indicate a relationship between SIDS and the 12‐repeat allele of the intron 2 variable number tandem repeat of the 5‐HTT gene in African‐Americans, and a significant role of the haplotype containing the 12‐repeat allele and the promoter L‐allele in defining SIDS risk in African‐Americans. These data, if confirmed in larger studies, may begin to explain the differences in SIDS incidence by ethnicity, suggest a role for levels of 5‐HTT expression in generation of SIDS susceptibility, and provide an important tool for identifying at‐risk individuals and estimating the risk of recurrence.