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.     

Sudden infant death syndrome: association with a promoter polymorphism of the serotonin transporter gene

Serotonergic receptor binding in the arcuate nucleus, n. raphé obscurus, and other medullary regions is decreased in sudden infant death syndrome (SIDS) cases. Further, a variable tandem repeat sequence polymorphism in the promoter region of the serotonin transporter protein (5-HTT) gene has recently been associated with risk of SIDS in a Japanese cohort. 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). We therefore investigated the 5-HTT promoter polymorphism in a cohort of 87 SIDS cases (43 African American and 44 Caucasian) and gender/ethnicity-matched controls. Significant positive associations were found between SIDS and the 5-HTT genotype distribution (P = 0.022), specifically with the L/L genotype (P = 0.048), and between SIDS and the 5-HTT L allele (P = 0.005). There was also a significant negative association between SIDS and the S/S genotype (P = 0.011). The comparisons were repeated in the African American and Caucasian subgroups. The data patterns were consistent in the subgroups, i.e., the L/L genotype and L allele were increased in the cases, but not all subgroup comparisons were statistically significant. These results indicate a relationship between SIDS and the L allele of the 5-HTT gene in African Americans and Caucasians, and if confirmed, will provide an important tool for identifying at-risk individuals and estimating the risk of recurrence.     

Dopaminergic candidate genes in Tourette syndrome: association between tic severity and 3' UTR polymorphism of the dopamine transporter gene.

Multiple evidence suggests an involvement of the dopamine neurotransmitter system in Tourette syndrome (TS). Therefore, dopaminergic candidate genes are in the center of genetic association analyses of TS. In this study, 103 TS patients and their parents have been characterized for different dopamine-related polymorphisms including the 48 bp variable number of tandem repeats (VNTR) of the dopamine D4 receptor (DRD4) gene, the 40 bp VNTR of the dopamine transporter (DAT1, SLC6A3) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. In addition, the 120 bp duplication and three single nucleotide polymorphisms (SNPs) were assessed in the promoter region of the DRD4 gene. The -616G allele and the 2-G-A-C haplotype (i.e., the 2-repeat form of the 120 bp sequence approximately -616G approximately -615A approximately -521C combination) were preferentially transmitted, however, these results did not remain significant after correction for multiple testing. Case-control analyses have also been carried out, resulting in negative findings. On the other hand, using a dimensional approach, the DAT1 40 bp VNTR showed an association with the peak tic-severity as measured by the Yale Global Tic Severity Scale. Patients with at least one copy of the 9-repeat allele had significantly more severe symptoms than individuals with the homozygous 10/10 genotype (P = 0.002). In summary, allele frequencies did not differ between cases and controls, but DAT1 genotype accounted for variations of tic severity within the TS group.     

Medullary serotonin defects and respiratory dysfunction in sudden infant death syndrome

Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an infant less than 12 months of age that occurs during sleep and remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. It is the leading cause of postneonatal mortality in the developed world. The cause of SIDS is unknown, but is postulated to involve impairment of brainstem-mediated homeostatic control. Extensive evidence from animal studies indicates that serotonin (5-HT) neurons in the medulla oblongata play a role in the regulation of multiple aspects of respiratory and autonomic function. A subset of SIDS infants have several abnormalities in medullary markers of 5-HT function and genetic polymorphisms impacting the 5-HT system, informing the hypothesis that SIDS results from a defect in 5-HT brainstem-mediated control of respiratory (and autonomic) regulation. Here we review the evidence from postmortem human studies and animal studies to support this hypothesis and discuss how the pathogenesis of SIDS is likely to originate in utero during fetal development.     

Myocarditis and sudden infant death syndrome

This is a retrospective survey of findings of myocarditis in 437 infants under the age of 1 year who died suddenly and unexpectedly between 1982 and 1999, and were investigated at the Department of Forensic Medicine in Stockholm, Sweden. Myocarditis was diagnosed in 69/410 infants who died naturally (16.8%) and in 2/27 violent deaths (7.4%). In 43/410 natural deaths (10.5%) the myocarditis was an isolated finding and the only explanation for cause of death and in 26 (6.3%) there were additional possible causes of death. The myocarditis was acute in 45/69 and chronic in 24/69 natural deaths, and was found to occur as early as at a few weeks of age. No specific risk factors were found when reviewing critical time of year, age, gender, previous symptoms, sleeping position, aspiration of gastric contents and environmental factors in infant deaths with finding of myocarditis compared to 313 deaths due to sudden infant death syndrome. Myocarditis was found in 13 of 37 deaths where cultures for cytomegalovirus were positive. More than 50% of the foci of the isolated myocarditis were located in the upper part of the interventricular septum and the adjacent part of the right atrium, areas including parts of the conduction system. This localisation is significant for the cause of death when comparing deaths with myocarditis as an isolated finding to deaths with other possible causes.     

Intrauterine hypoxia and sudden infant death syndrome

Sudden infant death syndrome (SIDS) or crib or cot death are synonyms for the sudden, unexpected and unexplained death of an infant. The incidence of SIDS has been estimated to be from 1-2% to 3%. Protracted intrauterine hypoxia or recurrent hypoxic insults during fetal life undoubtedly influence the development of the central nervous structures as a tissue most susceptible to hypoxia, although well developed mechanisms of defense against hypoxia exist during the fetal life. The mechanisms underlying SIDS include neurologically compromised infants who are deprived of compensatory mechanisms during sleep, sustaining a hypoxic insult with alterations in neurotransmitter receptors within the regions involved in chemoreception and cardiovascular control. Changes in the brain result from perinatal prolonged hypoxia (persistent reticular pathways in the pons and medulla, astroglia in the brainstem, gliosis of brain nerve nuclei, defects in neurotransmitter receptors, neuronal apoptosis, microthrombosis, and hypoxic ischemic lesion). Hypoxic perinatal risk factors for SIDS included passive and active exposure to cigarette smoking in pregnancy, abuse of drugs, alcohol, coffee and medication in pregnancy, intrauterine growth retardation, perinatal hypoxia with or without resuscitation, preeclampsia, anemia in pregnancy, prematurity, multiparity, multiple pregnancy, pregnant women aged < 20 years and > 35 years, cardiocirculatory, pulmonary and endocrine diseases in pregnancy, and short time interval between two pregnancies. As cigarette smoking has been demonstrated to lead to fetoplacental insufficiency, which result in fetal hypoxia, it is concluded that hypoxia is a precondition for the occurrence of SIDS. Prenatal exposure to cigarette smoke decreases maternal red blood cell count, and concentrations of tyrosine and selenium, reduces fetal and neonatal cerebral blood flow, and increases maternal MCV, leukocytosis, especially neutrophils, monocytes and lymphocytes, maternal and fetal heart rate, systolic and diastolic blood pressure, resistance index in umbilical artery, fetal hemoglobin, cytokine, serotonine, dopamine, catecholamine, hypoxanthine, endorphin and interleukin-6. Pregnancy at a risk of hypoxia, especially in heavy smokers, is a major risk factor for SIDS, and such pregnancy requires close and intensive antenatal monitoring.     

Allergy and the risk of sudden infant death syndrome

Background and Objective There are several sources that suggest that there is a link between allergy and sudden infant death syndrome. We endevavoured to look for evidence of an association between allergic disease and the risk of sudden infant death syndrome (SIDS). Methods A nationwide case-control study covering a region with 78% of all births in New Zealand during 1987–90. Interviews were completed with the parents of 393 (81.0% of total) infants who died from the sudden infant death syndrome (SIDS), and 1592 (88.4% of total) control families who were a representative sample of all hospital births in the study region. Results Eczema was reported in 13.9% control infants compared with only 8.0% of the SIDS infants, univariate odds ratio for this in terms of risk for SIDS was 0.56 (95% confidence interval 0.37, 0.84) for infants with eczema compared with those without. This lesser risk for SIDS was unchanged when adjusted for potential confounding factors. The risk of SIDS was not associated with reported cow's milk reactions or a family history of allergic symptoms once adjustments were made for possible confounding factors. Conclusion Infants with skin disorders identified by their parents as eczema had a low risk for SIDS. Families can be reassured that atopy is not a risk factor for SIDS.     

The IL6 -174G/C polymorphism and sudden infant death syndrome

The interleukin-6 genotype (IL6 -174GG) has been proposed to be associated with sudden infant death syndrome (SIDS). The aim of this study was to investigate the -174G/C polymorphism in 175 Norwegian SIDS cases and 71 controls. There were no differences in genotype distribution between these two groups (p = 1.0). This confirms the findings in a combined SIDS group compared with European Caucasian controls, but not findings in smaller cohorts of SIDS cases from Australia and England. The discrepancy may result from bias introduced when investigating only a few SIDS cases, differences in diagnostic criteria when diagnosing the cause of death as SIDS, and differences in the distribution of the -174G/C polymorphism in different ethnic groups. Findings of an activated immune system in SIDS indicate that genes involved in the immune response are of importance. However, because there are several polymorphisms in the IL6 gene promoter that could potentially regulate the expression of the gene, more than one polymorphism should be investigated to assess the involvement of the IL-6 gene in SIDS.     

Staphylococcal toxins and sudden infant death syndrome.

AIMS: To investigate the hypothesis that commonly occurring bacterial toxins cause sudden infant death syndrome (SIDS) by (1), determining in which tissues bacterial toxins are concentrated after intravenous injection in rats; and (2), seeing if the same tissues contain detectable toxins in cases of SIDS. METHODS: The tissue distribution of intravenously injected staphylococcal enterotoxin A (SEA), enterotoxin B (SEB), enterotoxin C (SEC), enterotoxin D (SED), toxic shock syndrome toxin (TSST-1), and alpha-haemolysin was studied in rats using immunohistology and polyacrylamide gel electrophoresis with immunoblotting. Immunostaining was also carried out on formalin fixed kidneys from cases of SIDS and a comparison series of necropsy cases using anti-SEA, anti-SEB, anti-SEC2 and anti-SED. RESULTS: Immunohistology showed that SEB, SEC, SED and TSST-1 were all concentrated in the proximal convoluted tubular cells of the kidney. The presence of these toxins was confirmed in kidney homogenates using electrophoresis and immunoblotting. There was positive granular staining in the proximal convoluted tubular cells of the kidney in 36% of SIDS cases and 12% of the comparison series with anti SEC2 (chi 2 = 6; p < 0.025). CONCLUSION: SEC, or a bacterial toxin with epitopes in common, could have a pathogenic role in SIDS.     

Genetic investigation of the TSPYL1 gene in sudden infant death syndrome.

BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.     

Peripheral arterial chemoreceptors and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is the major cause of death in infants between 1 month and 1 year of age. Two particular concerns are that (1) premature or low birth weight (<2500-g) infants have a 2- to 40-fold greater risk of dying of SIDS (depending on the sleep position) than infants born at term and of normal birth weight, and that (2) the proportion of premature infants dying of SIDS has increased from 12 to 34% between 1988 and 2003. Hypo- and hypersensitivity of peripheral arterial chemoreceptors (PACs) may be one biological mechanism that could help to explain the epidemiological association between the increased incidence of SIDS in formerly premature infants. Because premature infants are often exposed to the extremes of oxygen stress during early postnatal development, they are more likely to have a maladaptive response of PACs later in their lives. As the first line of defense that mediates an increase in ventilation to a hypoxic challenge during wakefulness and sleep, PACs also mediate arousal responses during sleep in response to an asphyxial event that is often associated with upper airway obstruction. In most mammalian species, PACs are not fully developed at birth and thus are vulnerable to plasticity-induced changes mediated by environmental exposures such as the extremes of oxygen tension. Hypoxic or hyperoxic exposure during early postnatal development can lead to hyposensitive or hypersensitive PAC responses later in life. Although baseline chemoreceptor activity may not be the cause of an initial hypoxic or asphyxial event, the level of peripheral chemoreceptor drive does modulate the (1) time to arousal, (2) resumption of airflow during airway obstruction, (3) escape behaviors during rebreathing, and (4) cardiorespiratory responses that result from activation of the laryngeal chemoreflex. The laryngeal chemoreflex can be stimulated by reflux of gastric contents above the upper esophageal sphincter, or an increase in nasopharyngeal secretions from upper respiratory tract infections--events that contribute to some cases of SIDS. In this review, evidence is presented that both hypo- and hypersensitivity of PACs may be disadvantageous to the premature infant who is placed in an at risk environment for the occurrence of hypoxemia/asphyxia event thereby predisposing the infant to SIDS.     

Association of sudden infant death syndrome with VEGF and IL-6 gene polymorphisms

In the UK, Sudden Infant Death Syndrome (SIDS) is a major cause of postperinatal mortality up to the end of the first year of life. Several studies have found an association between cytokine IL-10 genotypes and SIDS. The aim of the present work was to test the hypothesis that SIDS is associated with high producer gene polymorphisms for certain proinflammatory cytokines and with low producer gene polymorphisms of certain antiinflammatory cytokines. DNA polymorphisms were investigated using sequence-specific primer (SSP)-polymerase chain reaction (PCR). Results demonstrated that SIDS and controls did not differ significantly with respect to genotype distributions for IL-4 -590 (chi(2) test, p = 0.164), IFN- gamma +874 (p = 0.050), or TGF-beta1 +869 (p = 0.322). However, significant associations with SIDS were seen for genotypes of VEGF -1154 (p = 0.005) and IL-6 -174 (p = 0.018). Comparison of allele frequencies for these cytokine genes between SIDS and control groups reflected the genotype data. Allele frequencies that did not demonstrate significant differences between test groups were IL-4 -590*T (chi2, p = 0.104), IFN- gamma +874*A (p = 0.052), and TGF-beta1 +869*C (p = 0.468). Those demonstrating significant differences between SIDS and control groups were VEGF -1154*A (p= 0.002, OR = 2.94, CI 1.46-6.02) and IL-6 -174*G (p= 0.034, OR = 2.18 CI 1.05-4.56). Thus, there are associations between SIDS and particular polymorphisms of VEGF and IL-6 cytokine genes in addition to those previously found in Manchester with another cohort of samples for the antiinflammatory cytokine IL-10. Moreover, these gene polymorphism associations suggest that the causation of SIDS is related to both fetal lung development and a child's innate ability to mount an inflammatory response to infection.     

Hypovitaminosis A: A model for sudden infant death syndrome

The cause of sudden infant death syndrome (SIDS) is unknown. It is the leading cause of death from age one month to one year in North America. The purpose of this essay is to generate some testable hypotheses as to the cause of SIDS by drawing attention to distinct epidemiological parallels between SIDS and a newly recognized form of enamel hypoplasia, termed localized hypoplasia of the primary canine tooth (LHPC), which has been attributed to vitamin A deficiency. LHPC and SIDS share a common epidemiological profile: winter seasonality, occurrence at 3–5 months, and affecting apparently healthy children, but with increased incidence in socio economically disadvantaged families particularly racial/ethnic minorities (except Hispanics who show a reduced incidence), previously compromised infant health, less prenatal counselling, and less breastfeeding. Vitamin A has pervasive functions throughout the body including bone growth and maintenance of epithelial membranes. It is proposed that SIDS is due in part to hypovitaminosis A through one of several mechanisms: imbalanced basicranial growth producing mechanical constriction on the respiratory nerves passing through the jugular foramen; or through compromised myelination and/or maturation of the brain stem and cranial nerves involved in respiration; or through pharyngeal collapse due to mandibular undergrowth; or dysfunction of hypoxia-sensitive epithelial cells in the trachea. It is recommended that assay of hypoxia-sensitive epithelial cells in the trachea. It is recommended that assay of the retinyl ester content of the liver of SIDS victims be included in autopsy protocol. © 1995 Wiley-Liss, Inc.     

Congenital central hypoventilation syndrome: Inheritance and relation to sudden infant death syndrome

We evaluated the families of 50 children with idiopathic congenital cental hypoventilation syndrome (CCHS) to (1) test genetic hypotheses, (2) explore the relationship to Hirschsprung disease (HD), and (3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIRI, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the result of HIR1 and HIR2, or between CON1 and Con2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely <5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demand further investigation. © 1993 Wiley-Liss, Inc.