Although SIDS has been known since ancient times, it is still the most common cause of infant death in developed countries after neonatal period. The pathogenesis of this syndrome is still obscure and a possible genetic component has been recently hypothesized. Among possible genes involved in SIDS, several studies have identified polymorphisms in the serotonin transporter (5-HTT) as a predisposing factor in infant death. In this work, additional genes involved in serotonin synthesis and metabolism were investigated in brainstem samples obtained from an Italian SIDS cohort. In particular, genotypes and allelic frequencies of TPH-2, 5-HTTLPR, 5-HTT intron 2 VNTR, and MAOA-u VNTR were determined in 20 “genuine” SIDS and compared with results obtained in 150 healthy controls. The investigation was carried out in relation to the functional role of the different polymorphisms in regulating serotonin synthesis (TPH-2), neuronal re-uptake (5-HTTLPR and 5-HTT intron 2) and catabolism (MAOA) in the brainstem. The single nucleotide polymorphism (SNP) G1463A responsible of 80% functionality loss of TPH-2 (tryptophane hydroxylase-2) was neither detected in SIDS infants nor in the controls. On the contrary, a strict relation was found between 5-HTTLPR genotypes and allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of promoter region of serotonin transporter were significantly associated (LR test, P<0.001) with the syndrome (L/L: 60% SIDS vs. 14.3% controls; L: 80% SIDS vs. 42.8% controls). Interestingly, no SIDS infant with S/S genotype was found among the 20 investigated cases. Polymorphisms of VNTR of intron 2 of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, P=0.068). With respect to previous works, this tendency seemed influenced by the limited number of African-Italian SIDS in our dataset. Considering linkage disequilibrium between the two 5-HTT regions, the haplotype analysis related to promoter + intron 2 demonstrated that the L-12 haplotype was almost two fold in SIDS (42.80%) with respect to matched controls (24.70%). Values were even higher considering genotype combination L/L-12/12 (20% SIDS vs. 2.80%). With respect to serotonin degradation, differences in the frequency of MAOA-u (monoamine oxydase) VNTR genotype 3R/3R between SIDS and controls were observed. The genotype frequency was twice in the healthy controls (25.71%) than in SIDS infants (13.33%). Considering the functional role of 3R allele in the transcription efficiency of the gene, an additional molecular contribution connected to serotonin metabolism besides 5-HTT could be hypothesized

Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome / F. Nonnis Marzano, M. Maldini, L. Filonzi, A. M. Lavezzi, S. Parmigiani, C. Magnani, G. Bevilacqua, L. Matturri. - In: GENOMICS. - ISSN 0888-7543. - 91:6(2008), pp. 485-491. [10.1016/j.ygeno.2008.01.010]

Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome

A.M. Lavezzi;L. Matturri
Ultimo
2008

Abstract

Although SIDS has been known since ancient times, it is still the most common cause of infant death in developed countries after neonatal period. The pathogenesis of this syndrome is still obscure and a possible genetic component has been recently hypothesized. Among possible genes involved in SIDS, several studies have identified polymorphisms in the serotonin transporter (5-HTT) as a predisposing factor in infant death. In this work, additional genes involved in serotonin synthesis and metabolism were investigated in brainstem samples obtained from an Italian SIDS cohort. In particular, genotypes and allelic frequencies of TPH-2, 5-HTTLPR, 5-HTT intron 2 VNTR, and MAOA-u VNTR were determined in 20 “genuine” SIDS and compared with results obtained in 150 healthy controls. The investigation was carried out in relation to the functional role of the different polymorphisms in regulating serotonin synthesis (TPH-2), neuronal re-uptake (5-HTTLPR and 5-HTT intron 2) and catabolism (MAOA) in the brainstem. The single nucleotide polymorphism (SNP) G1463A responsible of 80% functionality loss of TPH-2 (tryptophane hydroxylase-2) was neither detected in SIDS infants nor in the controls. On the contrary, a strict relation was found between 5-HTTLPR genotypes and allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of promoter region of serotonin transporter were significantly associated (LR test, P<0.001) with the syndrome (L/L: 60% SIDS vs. 14.3% controls; L: 80% SIDS vs. 42.8% controls). Interestingly, no SIDS infant with S/S genotype was found among the 20 investigated cases. Polymorphisms of VNTR of intron 2 of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, P=0.068). With respect to previous works, this tendency seemed influenced by the limited number of African-Italian SIDS in our dataset. Considering linkage disequilibrium between the two 5-HTT regions, the haplotype analysis related to promoter + intron 2 demonstrated that the L-12 haplotype was almost two fold in SIDS (42.80%) with respect to matched controls (24.70%). Values were even higher considering genotype combination L/L-12/12 (20% SIDS vs. 2.80%). With respect to serotonin degradation, differences in the frequency of MAOA-u (monoamine oxydase) VNTR genotype 3R/3R between SIDS and controls were observed. The genotype frequency was twice in the healthy controls (25.71%) than in SIDS infants (13.33%). Considering the functional role of 3R allele in the transcription efficiency of the gene, an additional molecular contribution connected to serotonin metabolism besides 5-HTT could be hypothesized
5-HTT; MAOA; Molecular polymorphisms; Neurotransmitter; SIDS; TPH2
Settore MED/08 - Anatomia Patologica
2008
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/59209
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