Association of the serotonin transporter gene with sudden infant death syndrome: a haplotype analysis

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.     

Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.

The neurotransmitter serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5-HT transporter protein (5-HTT) regulates 5-HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion-deletion polymorphism in the 5-HTT-linked promoter region (5-HTTLPR) have yielded inconsistent results. We conducted a meta-analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5-HTTLPR alleles and AD. The frequency of the short (S) allele at 5-HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03-1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co-morbid psychiatric condition or an early-onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11-1.63)]. Allelic variation at 5-HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co-occurring clinical feature.     

Evidence for an association with the serotonin transporter promoter region polymorphism and autism

We have examined three functional polymorphisms, serotonin transporter promoter region polymorphism (5-HTTLPR), dopamine D4 exon III repeat region (DRD4), and catechol-O-methyltransferase (COMT), in a small family-based design toward identifying candidate genes that confer risk for autism. A significant excess of the long/long 5-HTTLPR genotype was observed (likelihood ratio = 7.18; P = 0.027; 2 df; n = 33 families) as well as preferential transmission of the long allele of the 5-HTTLPR (TDT chi-square = 5.44; P<0.025; 1 df). No association was observed between the COMT and DRD4 polymorphisms and autism in this sample. Some previous studies have observed linkage between autism and the 5-HTTLPR polymorphism and the current results are similar to those first reported by Klauck et al. [1997: Hum Genet 100:224-229; 1997: Hum Mol Genet 6:2233-2238]. Additionally, elevated serotonin levels have been consistently found in 30%-50% of autistic patients and may represent a marker for familial autism. Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake, as free 5-HT levels are normal and the current report of an excess of the long/long 5-HTTLPR genotype in autism could provide a partial molecular explanation for high platelet serotonin content in autism.     

Temperamental fearfulness in childhood and the serotonin transporter promoter region polymorphism: a multimethod association study

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample.     

Sudden infant death syndrome: a cybernetic etiology

The brain's processes, by hypothesis, involve information processing by an extraordinarily complex, highly sophisticated, self-organizing cybernetic system embedded in the central nervous system. This cybernetic system generates itself in successive stages. Breathing is, by default, an autonomous function, but breath control is learned. If there is not a smooth transfer of function at the time when a successor system (one that enables autonomous breathing to be overridden by voluntary control) takes over, breathing may cease, without any overt cause being detectable, even with a thorough postmortem examination. If conditions are such that, at that point, the infant's body lacks the strength to resume breathing again under autonomic control, Sudden Infant Death Syndrome may result. The theory explains why infants are at greater risk if they sleep face down.     

The serotonin transporter promoter polymorphism and suicide

Serotonergic dysfunction has been implicated in mood disorders and in the pathophysiology of suicidality. A functional polymorphism (a 44-base pair insertion (L)/deletion (S)) in the promoter of the gene encoding the serotonin transporter (5-HTTLPR), associated with mood disorders, has been inconsistently associated with suicidality. To add to this debate, we designed a case-control study involving 62 suicide victims and 72 controls matched for age, gender and ethnicity. All subjects underwent forensic investigation. No association could be detected between the 5-HTTLPR polymorphism and suicide. This result is consistent with the proposal that different genes are involved in hopelessness and suicidal behavior or in depressive illness.     

Sudden infant death syndrome: the colon connection

The etiology of sudden infant death syndrome (SIDS) is not known. Various maternal and infant risk factors have been identified. Adoption of the non-prone position has reduced the incidence of SIDS but has not eliminated the problem. Some sulfate reducing bacteria in the colon produce hydrogen sulfide (H2S) which is as toxic as hydrogen cyanide. Normally, the colonic mechanism for metabolizing and detoxifying H2S is very effective and no H2S appears in the exhaled breath although small amounts are present in the flatus. We are putting forth the hypothesis that in some cases of SIDS colonocytic mechanism for detoxifying H2S may not have matured by the age of 3 months and H2S may be absorbed resulting in SIDS. The hypothesis can be tested by in vitro evaluation of colonic tissue from SIDS cases for its ability to detoxify H2S.     

Sudden infant death syndrome: oxidative stress

In studies of oxidative stress in sudden infant death syndrome (SIDS) there were two major findings: (1) During normal post-natal development, there was a gradual decline in the number of Cu/Zn superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) immunoreactive neurons in the hippocampus and parahippocampus gyrus in the brain; (2) The total number of immunoreactive neurons was elevated in SIDS victims compared to age-matched controls in infants 6 months of age and under (1). SOD and neuronal aging and degeneration in the hippocampus and neocortex were features of SIDS, Alzheimer's disease and Down's syndrome. In the SIDS study of infants from 3-6 months of age, the elevation of SOD in SIDS victims was significant, whereas no significant elevation of GSHPx was detected. An imbalance between SOD and GSHPx was said to be crucial in the prevention of toxicity of free radicals (1). Zinc-deficient cells cannot up-regulate gene expression of the scavenger enzymes SOD and GSHPx in cells exposed to high levels of superoxide and hydrogen peroxide (2). GSHPx coupled to reduced nicotine adenine diphosphate (NADPH) regenerating systems via glutathione reductase is virtually able to guarantee an effective protection of biological structures against oxidative attack (22). When the capacity of the cell to regenerate GSH is exceeded - primarily due to an insufficient supply of NADPH-oxidised glutathione (GSSG) is released from the cell and protein synthesis turns off (20). We hypothesize that the increased incidence of aging and neuronal death and increased incidence of SOD and GSHPx reactive neurons in early post-natal development indicates an increased up-regulation of gene expression of scavenger enzymes during high exposure to oxidative stress after birth. GSH-dependent peroxide metabolism is linked to the pentose phosphate shunt via NADPH-dependent glutathione reductase (GR). GSHPx is a selenium containing enzyme which together with catalase (CAT) SOD and vitamin E protects cells in the free radical chain. Zinc upregulates gene expression of these antioxidants.     

Sudden infant death syndrome: respiratory causes

Sudden infant death syndrome (SIDS) claims one in five hundred babies between 1 and 12 months of life. Since no cause of death is found at autopsy, SIDS has been and often remains a complete enigma for pediatricians, physiologists and forensic pathologists. However, there is growing evidence from careful epidemiologic, pathologic and physiologic studies that subtle changes occur in those babies for a variable period of time before death. Some of these data are reviewed and interpreted in the light of the sleep apnea-hypoventilation inducing chronic hypoxemia hypothesis. It appears that no single factor is characteristic of, or responsible for, SIDS; rather, a combination of different adverse circumstances occurring during a period of increased vulnerability may cause the fatal outcome in some infants. Some preventive aspects of SIDS in low birth weight babies, siblings of SIDS victims and near-miss SIDS are discussed.     

Sudden infant death syndrome associated with rotavirus infection

Rotavirus was detected in the stools of five children stricken with sudden infant death syndrome (SIDS) over a three-week period. While none of the children had acute gastroenteritis, four of the five had acute upper respiratory infections. Rotavirus was also identified in tracheal aspirates from two of the infants. Extensive investigations failed to reveal the presence of any other viruses or toxins in specimens obtained from the five children with SIDS. Rotavirus was not found in the stool specimens obtained from a control group of 36 infants including six who died of causes other than SIDS. Future attempts at the prevention of rotavirus infections should be directed at populations susceptible to sudden infant death syndrome.