Sudden Infant Death Syndrome: Gene–Environment Interactions

Sequencing of the human genome has resulted in a rapidly expanding understanding of the molecular basis of many human diseases and the incredible complexity of genotype–phenotype relationships. Some genes are expressed only in healthy individuals or in disease conditions, only at specified ages, or in response to specific perturbations or states (e.g., sleep). Some genes, thus contribute to susceptibility to disease, but other genes and their polymorphisms contribute to protection against illness. Knowing the genotype even in single-gene disorders does not necessarily identify the phenotype. Phenotype is also influenced by gene–gene and gene– environment interactions. Most human disorders are not single-gene disorders, but rather are polygenic disorders associated with complex and quite variable phenotypes. Multiple genes interact with multiple environments to both increase and decrease the risk of clinical disease, and epigenetic processes resulting from environmental factors can lead to altered gene expression. Common examples of major disorders with polygenic inheritance, genetic heterogeneity, and multiple environmental exposures determining phenotypic expression include atherosclerosis and cardiovascular disease, asthma, diabetes, and cancer. For such complex disorders, the whole is not only greater but may be different than the sum of its parts. Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant less than 1 year of age that is unexpected by history and unexplained after a thorough postmortem examination, including a complete autopsy, investigation of the scene of death, and review of the medical history. There were 2230 SIDS deaths in the U.S. in 2005, equaling a rate of 0.54 per 1,000 live births. SIDS rates have declined over 50% since the introduction of national Back to Sleep campaigns in the past decade, which encouraged parents to place infants on their back for sleep. However, SIDS remains the leading cause of postneonatal infant mortality, accounting for approximately a quarter of all deaths between 1 month and 1 year of age. Additionally, there is evidence that the declining SIDS rate has reached a plateau. Changes in the classification of sudden unexpected deaths in infants by medical examiners, coroners, and other certifiers from SIDS to the categories of “asphyxia” or “unascertained” may be falsely lowering the rate of SIDS, while the overall rate of sudden, unexpected deaths in infancy (SUDI) remains the same. As prone sleeping among infants has become less common, other risk factors have emerged as being important in the causal pathway of SIDS (see later sections). This chapter reviews the evidence indicating that SIDS, like other clinical disorders, has important genetic and environmental risk factors, that in complex and not yet well-defined ways interact to yield phenotypes susceptible to SUDI. Sudden Infant Death Syndrome: Gene–Environment Interactions