Serotonin gene variants are unlikely to play a significant role in the pathogenesis of the sudden infant death syndrome

Abstract

Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an infant less than 12 months of age that is related to a sleep period and remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. The cause of SIDS is unknown, but a major subset of SIDS is proposed to result from abnormalities in serotonin (5-HT) and related neurotransmitters in regions of the lower brainstem that result in failure of protective homeostatic responses to life-threatening challenges during sleep. Multiple studies have implicated gene variants that affect different elements of 5-HT neurotransmission in the pathogenesis of these abnormalities in SIDS. In this review I discuss the data from these studies together with some new data correlating genotype with brainstem 5-HT neurochemistry in the same SIDS cases and conclude that these gene variants are unlikely to play a major role in the pathogenesis of the medullary 5-HT abnormalities observed in SIDS.

Figure 1. Triple Risk Model for SIDS Demonstrating Genetic-Environmental Interactions

The Triple Risk Model for SIDS proposes that death occurs when three factors simultaneously impinge upon the infant: 1) an underlying vulnerability in the infant; 2) a critical developmental period, i.e., the first year of life; and 3) an exogenous stressor, e.g., prone sleep. According to this model, normal infants do not die of SIDS, but rather, only infants with an underlying disease process. Gene variants are thought to contribute to SIDS risk either by directly causing or contributing to the failure of homoestatic mechanisms or by rendering the infant less resilient to environmental stressors.

Figure 2. Model of 5-HT neurotransmission

Schematic of 5-HT synthesis, release, and metabolism in a pre-synaptic neuron showing 5-HT pathway genes analyzed in SIDS. 1) FEV, Fifth Ewing Variant gene-transcription factor critical in differentiation of the 5-HT neuronal phenotype. Promotes the expression of TPH2, 5-HTT and 5-HT receptor genes in 5-HT neurons. 2) TPH2, tryptophan hydroxylase-2 gene-rate limiting enzyme in biosynthesis of 5-HT, catalyses the formation of 5-hydoxytryptophan from tryptophan (Tryp), which is then converted to 5-HT by aromatic acid decarboxylase (not shown). 3) 5-HT_1A and 5-HT_2A receptor genes-mediate the downstream effects of 5-HT. 4) 5-HTT, serotonin transporter gene-transports 5-HT released into the synapse back into the neuron for re-packing in vesicles for future release or degradation by MAO-A. 5) MAO-A, mononamine oxidase A-mitochondrial enzyme primarily responsible for the degradation of 5-HT into 5-hydoxy-indole-acetaldehyde (not shown) that is then converted into 5-hydroxy-indole-acetic acid (5-HIAA) by aldehyde dehydrogenase (not shown).

Figure 3. Serotonin gene variants studied in SIDS

Schematic of the 5-HTT gene (SLC6A4) and the location of the 5-HTTLPR, Intron 2 and 3′ UTR polymorphisms and their putative effects on gene transcription.

Figure 4. 5-HTTLPR allele frequencies in Caucasians

Graphs comparing the S and L allele frequencies in Caucasian control populations in different studies. Note that the S allele is the major allele (i.e., allele present in highest frequency) in the populations analyzed by Weese-Mayer et al., (2003a) and Nonnis-Marzano et al., (2008), the reverse of the other study populations and the expected allele frequency for this polymorphism in Caucasians. This suggests that sample bias may influence the observations in these studies. Names under each data group refer to the first author of the study from which the data is extracted with the exceptions of “San Diego” and “Coriell” that refer to the San Diego SIDS Dataset and the HD100CAU human variation DNA panel from the Coriell Institute Cell Repository (Camden, NJ) from Paterson et al., (2010).

Figure 5. Intron 2 allele frequencies in San Diego and Coriell Caucasians

Graph comparing the intron 2 genotype frequencies in Caucasian San Diego SIDS cases, Controls and Coriell controls. The frequency of the 1212 genotype is significantly higher in the San Diego Control population compared to the SIDS cases and Coriel Controls. χ2 =12.23 df=2 p=0.002 for San Diego Controls vs. Coriell and χ2 =8.17 df=2 p=0.017 for San Diego Controls vs. San Diego SIDS.

Figure 6. MAO-A gene promoter polymorphism

Schematic of the MAO-A and the location of the promoter VNTR and its putative effects on gene transcription.

Figure 7. Medullary 5-HTT binding density correlated with 5-HTTLPR genotype in SIDS cases

Medullary 5-HTT binding density is significantly lower in SIDS cases with the SL genotype in the gigantocellularis (GC) (*p<0.001), paragigantocellularlis lateralis (PGCL) (*p=0.02), and intermediate reticular (IRN) (*p=0.04) nucleus by genotype (ANCOVA).

Figure 8. Medullary 5-HTT binding and 5-HT_1A receptor binding density correlated with Intron 2 genotype in SIDS cases

A. Medullary 5-HTT binding density in SIDS cases in the intermediate reticular nucleus (IRN) and nucleus of the solitary tract (NTS); binding density is significantly lower in SIDS cases with the 1010 genotype in the NTS (*p=0.05, ANCOVA) and shows a trend to be lower in the IRZ (p=0.06 ANCOVA). B. Medullary 5-HT_1A receptor binding density in SIDS cases in the gigantocellularis (GC) nucleus; receptor binding density is significantly lower in SIDS cases with the 1010 genotype (*p=0.05, ANCOVA).

Figure 9. 5-HT_1A receptor binding density and 5-HT tissue level correlated with MAO-A genotype in SIDS cases

A. Medullary 5-HT_1A binding density in the raphe obscurus (ROB) is significantly lower in male SIDS cases with the 3 allele compared to SIDS cases with the 4 allele nuclei. *p=0.02, ANCOVA. B. Medullary 5-HT tissue level in the raphe obscurus (ROB) is significantly lower in female SIDS cases with the 33 genotype compared to SIDS cases with the 34 or 44 genotypes. *p=0.01, ANCOVA.