title: Association of the serotonin transporter gene with sudden infant death syndrome: a haplotype analysis.
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.
authors.affiliation: Department of Pediatrics, Rush Children's Hospital at Rush-Presbyterian-St. Luke's Medical Center, Rush University, 1653 West Congress Parkway, Chicago, IL 60612, USA. dweese@rush.edu
authors.forename: Debra E
authors.initials: DE
authors.lastname: Weese-Mayer
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Berry-Kravis
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.forename: Jean M
authors.initials: JM
authors.lastname: Silvestri
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
mesh_terms: D001741:Black or African American / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D018598:Minisatellite Repeats / Q000235:genetics; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins; D013398:Sudden Infant Death / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins