Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome.
Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.
Nonnis Marzano
Francesco
F
Department of Evolutionary and Functional Biology, University of Parma, 43100 Parma, Italy. francesco.nonnismarzano@unipr.it
Maldini
Milena
M
Filonzi
Laura
L
Lavezzi
Anna Maria
AM
Parmigiani
Stefano
S
Magnani
Cinzia
C
Bevilacqua
Giulio
G
Matturri
Luigi
L
D001933:Brain Stem / Q000378:metabolism*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007558:Italy; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D013398:Sudden Infant Death / Q000235:genetics*; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000502:physiology*
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase; D008995:Monoamine Oxidase