ß 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:930–933 (2008) Research Letter Genetic Variation in the HTR1A Gene and Sudden Infant Death Syndrome Megan E. Morley, 1 Casey M. Rand, 1 Elizabeth M. Berry-Kravis, 1,2,3 Lili Zhou, 1 Wenqing Fan, 2 and Debra E. Weese-Mayer 1 * 1 Department of Pediatrics, Rush Children’s Hospital at Rush University Medical Center, Chicago, Illinois 2 Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 3 Department of Biochemistry, Rush University Medical Center, Chicago, Illinois Received 21 April 2007; Accepted 8 September 2007 How to cite this article: Morley ME, Rand CM, Berry-Kravis EM, Zhou L, Fan W, Weese-Mayer DE. 2008. Genetic variation in the HTR1A gene and sudden infant death syndrome. Am J Med Genet Part A 146A:930 – 933. To the Editor: Despite the success of the Back to Sleep campaign in the United States, sudden infant death syndrome (SIDS) remains one of the most prevalent causes of infant mortality, with 2,162 reported cases of SIDS in 2003 in the U.S. alone [Hoyert et al., 2006]. Recent neuropathological studies have implicated the serotonin (5-HT) system in the etiology of SIDS. Panigrahy et al. [2000] demonstrated that SIDS infants displayed decreased 5-HT receptor bind- ing in areas of the medulla important for carbon dioxide chemoreception. Ozawa and Okado [2002] demonstrated reduced expression of 5-HT receptor 1A (HTR1A) in medullary regions responsible for cardiorespiratory control among SIDS cases relative to controls. Paterson et al. [2006] subsequently re- ported discrepancies between several 5-HT system components in SIDS cases versus controls, including an increased density and number of serotonergic neurons in the medulla of SIDS cases, specifically in areas important for homeostatic control. Another body of recent research has focused on determining the genetic profile of the infant at increased risk for SIDS. Japanese SIDS cases were shown to have higher incidence of the long (L) allele in the promoter region of the serotonin transporter gene (SLC6A4) compared to controls [Narita et al., 2001] and these results were confirmed in African- American and Caucasian SIDS cases [Weese-Mayer et al., 2003a]. Additional variations in genes involved in 5-HT function and development have been asso- ciated with SIDS, including a functional variable number tandem repeat polymorphism in intron 2 of SLC6A4 [Weese-Mayer et al., 2003b], single base pair polymorphisms in exons 2 and 3 of PHOX2B [Rand et al., 2006a], and an intron 2 deletion polymorphism in FEV [Rand et al., 2007]. These findings suggest a genetic link between dysfunction/dysregulation of the ANS, the serotonergic network, and the etiology of SIDS, and support the neuropathological evidence of 5-HT system involvement in the pathogenesis of SIDS. The HTR1A receptor is key to the autonomic response to homeostatic stress and is densely distri- buted in medullary regions pertinent to cardiorespir- atory regulation [Thor et al., 1992]. Stimulation of the HTR1A receptor in these regions has been found to: (1) reduce the ventilatory response to hypercarbia, (2) cause fragmented sleep characterized by a decrease in body temperature, heart rate, body movements, and rapid eye movements, and (3) diminish the normal cardiovascular response brought on by acute psycho- logical and inflammatory stress [Messier et al., 2004; Darnall et al., 2005; Nalivaiko et al., 2005; Taylor et al., 2005]. Correspondingly, decreased HTR1A and 2A immunoreactivity in various nuclei of the medulla oblongata has been observed in SIDS cases compared to controls [Ozawa and Okado, 2002]. More recently, HTR1A receptor binding density was found to be significantly reduced in multiple medullary nuclei of SIDS cases, especially in male infants [Paterson et al., 2006]. Based on these studies, the HTR1A gene seemed Grant sponsor: CJ Foundation for SIDS; Grant sponsor: Justin Carl Suth SIDS Research Fund; Grant sponsor: Joseph Tyler Gertler SIDS Research Fund; Grant sponsor: Scottish Cot Death Trust; Grant sponsor: Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation of the Illinois-Eastern Iowa District Kiwanis International. *Correspondence to: Debra E. Weese-Mayer, M.D., Professor of Pediatrics at Rush University, Director, Pediatric Respiratory Medicine at Rush Children’s Hospital, 1653 West Congress Parkway, Chicago, IL 60612. E-mail: debra_e_weese-mayer@rsh.net DOI 10.1002/ajmg.a.32112