|Year : 2016 | Volume
| Issue : 4 | Page : 179-184
Meta-analysis of the Association between Serotonin Transporter Polymorphisms and Sudden Infant Death Syndrome
Haojie Qin, Guohui Xu, Xinmin Pan, Yaonan Mo
Laboratory of Forensic Pathology, School of Forensic Medicine, Henan University of Science and Technology, Luoyang 471003, China
|Date of Web Publication||9-Jan-2017|
School of Forensic Medicine, Henan University of Science and Technology, Luoyang 471003
Source of Support: None, Conflict of Interest: None
The serotonin transporter (5-HTT) gene has been considered one of the risk factors for sudden infant death syndrome (SIDS), but the association remains unconfirmed. This meta-analysis was performed to quantitatively summarize the evidence for such a relationship. PubMed, EMBASE, and China National Knowledge Infrastructure databases were searched for eligible studies within a range of published years from 1990 to December 2015. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the different associations. A total of 8 studies with 624 cases and 796 controls were included for 5-HTT promoter polymorphism, 5 studies with 418 cases and 542 controls for intron 2, and 3 studies with 253 cases and 334 controls for haplotype. The pooled examinations showed an overall increased SIDS risk for the 5-HTT promoter polymorphism (OR = 1.65, 95% CI = 1.03–2.63, P = 0.035 for LL vs. LS and SS; OR = 1.46, 95% CI = 1.04–2.04, P = 0.028 for L vs. S), but no association (OR = 1.00, 95% CI = 0.75–1.33, P = 0.994 for 10 + 9 carriers vs. 12/12; OR = 0.97, 95% CI = 0.79–1.19, P = 0.753 for 10 + 9 vs. 12) for intron 2 polymorphism, and an unreliable association (OR = 0.52, 95% CI = 0.31–0.87, P = 0.013) for S-9 and S-10 haplotypes. This meta-analysis suggests that the L allele or LL homozygote of 5-HTT promoter polymorphism has an increased risk for SIDS, while intron 2 polymorphism has no association with SIDS.
Keywords: Gene polymorphism, meta-analysis, serotonin transporter, sudden infant death syndrome
|How to cite this article:|
Qin H, Xu G, Pan X, Mo Y. Meta-analysis of the Association between Serotonin Transporter Polymorphisms and Sudden Infant Death Syndrome. J Forensic Sci Med 2016;2:179-84
|How to cite this URL:|
Qin H, Xu G, Pan X, Mo Y. Meta-analysis of the Association between Serotonin Transporter Polymorphisms and Sudden Infant Death Syndrome. J Forensic Sci Med [serial online] 2016 [cited 2019 Mar 25];2:179-84. Available from: http://www.jfsmonline.com/text.asp?2016/2/4/179/197932
| Introduction|| |
Sudden infant death syndrome (SIDS), defined as the sudden and unexpected death of an infant <1 year of age that remains unexplained after a thorough clinical history review, death scene investigation, and postmortem examination, is the leading cause of postneonatal infant mortality, accounting for approximately a quarter of all deaths from 1 month to 1 year of age  and 8% of total infant deaths., SIDS is a multifactorial disorder influenced by developmental, environmental, and biological risk factors. In addition to the well-known environmental risk factors, such as prone sleeping, smoking during pregnancy, overheating, and cosleeping,,, biological and genetic factors, especially medullary serotonergic network deficiency, which is postulated to play a key pathogenetic role in SIDS incidence, have also received increasing attention. The serotonin transporter (5-HTT) gene has been proposed as one of the candidate genes, based on the decreased serotonergic receptor binding observed in the brainstems of SIDS victims.,
The 5-HTT gene (SLC6A4) is located on chromosome 17q11.2. Two common polymorphisms, a variable number of tandem repeat region (VNTR) in the promoter region and a VNTR in the second intron, have been identified., In the promoter region, the long “L” allele is more efficient in modulating transcription than the short “S” allele,, and in the intron 2 VNTR region, the 12-repeat allele has stronger enhancer-like properties than the 9- and 10-repeat alleles., The higher 5-HTT expression results in more effective reuptake of serotonin from the extracellular space and thus a lower serotonin level in the synapses., Serotonin is involved in the regulation of a broad range of physiologic systems, including the respiratory and cardiovascular systems, as well as temperature regulation and the sleep-wake cycle. Thus, these variants may eventually contribute to a dysregulation of the serotonergic network and therefore predispose to SIDS.
Several studies explored the potential association between 5-HTT gene polymorphisms and susceptibility to SIDS, but the results were inconsistent.,,,,,, Hence, we conducted this meta-analysis to investigate the proposed correlation more thoroughly.
| Methods|| |
Literature search strategy
Electronic searches were conducted in PubMed, EMBASE, and China National Knowledge Infrastructure databases (updated to December 2015), using the terms “Sudden infant death syndrome,” “serotonin transporter,” and “polymorphism.” No restrictions were placed on language. Only published journal articles and academic dissertations were included. The reference lists of the research papers were also searched to identify other relevant publications.
Inclusion and exclusion criteria
All studies included in the meta-analysis were required to meet the following criteria: (i) case–control study; (ii) evaluation of the association of 5-HTT promoter and/or intron 2 polymorphisms with SIDS risk; and (iii) sufficient available data to assess odds ratios (ORs) and 95% confidence intervals (CIs). Studies with insufficient, duplicate, or faulty data were excluded. For overlapping and republished studies, the first study published or the one with the largest sample size (depending on the data) was included.
All data were extracted independently by the first two reviewers according to the prespecified selection criteria and were reviewed and checked by the third investigator. Different races were categorized as Caucasian and non-Caucasian. Disagreements about the inclusion of studies and interpretation of data were resolved by discussion.
Hardy–Weinberg equilibrium (HWE) was assessed in control groups using Fisher's exact test before statistical analysis, and the studies that were not in HWE were excluded. Dichotomous data were presented as ORs with 95% CIs. Statistical heterogeneity was measured using the Q-statistic and I 2 test (significance set at P < 0.10). A fixed-effects model was used to estimate the summary OR when there was no heterogeneity; otherwise, a random-effects model was used. To explore sources of heterogeneity across studies, logistic meta-regression analyses were conducted, and the following study characteristics were examined: publication year, ethnicity, control population component, quantities and frequencies of alleles and genotypes, and the sample size. Sensitivity analyses were performed to investigate the influence of individual studies on the summary effect estimates. The Begg's rank correlation method and Egger's weighted regression method were also used to assess the publication bias. The statistical analyses were performed using Stata software (version 12.0; StataCorp, College Station, TX, USA), and P < 0.05 was considered statistically significant.
| Results|| |
The search strategy retrieved 47 potentially relevant articles. Based on the inclusion and exclusion criteria, only 6 articles consisting of 8 studies (2 articles were separately considered to have 2 studies with different populations) were included in the meta-analysis. A total of 8 studies ,,,,, with 624 cases and 796 controls examined 5-HTT promoter polymorphism, 5 studies ,,, with 418 cases and 542 controls assessed intron 2 polymorphism, and only 3 studies , with 253 cases and 334 controls assessed haplotype. The corresponding characteristics of the included studies are shown in [Table 1],[Table 2],[Table 3].
|Table 1: Characteristics of included studies of serotonin transporter promoter polymorphism and sudden infant death syndrome risk|
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|Table 2: Characteristics of included studies of serotonin transporter intron 2 polymorphism and sudden infant death syndrome risk|
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|Table 3: Characteristics of included studies of serotonin transporter haplotype and sudden infant death syndrome risk|
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Meta-analysis of serotonin transporter promoter polymorphism
For control subjects, the L allele was the minor allele, with a frequency ranging from 0.136 to 0.705. Because the SS genotype was not included in one study, pooled examination was carried out on the recessive (LL vs. LS and SS) and additive (L vs. S) genetic models. The recessive model showed that LL genotype was associated with an overall increased risk of SIDS (OR = 1.65, 95% CI = 1.03–2.63, P = 0.035), and the heterogeneity was significant (χ2 = 20.30, P = 0.005, I2 = 65.5%). However, when stratified for ethnic origin, no significant association was found in either Caucasians (OR = 1.69, 95% CI = 0.89–3.19, P value for odds ratio [POR] = 0.107; χ2 =18.09, P value for heterogeneity [Phet] = 0.001, I2 = 77.9%) or non-Caucasians (OR = 1.53, 95% CI = 0.83–2.83, POR = 0.174; χ2 = 2.20, Phet = 0.333, I2 = 9.0%). The forest plot is shown in [Figure 1]a. When control subjects were divided into the living and deceased, LL genotype showed an increased risk in the live subgroup (OR = 2.51, 95% CI = 1.28–4.91, POR = 0.007; χ2 =11.77, Phet = 0.019, I2 = 66.0%) but no association in the deceased subgroup (OR = 0.97, 95% CI = 0.65–1.43, POR = 0.861; χ2 =1.35, Phet = 0.510, I2 = 0.0%) [Figure 1]b.
|Figure 1: Forest plots of the serotonin transporter promoter polymorphism with sudden infant death syndrome risk. Recessive model (LL vs. LS and SS) with stratification for (a) ethnic origin and (b) control component; Additive model (L vs. S) with stratification for (c) ethnic origin and (d) control component|
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In the additive model, the L allele revealed an overall increased risk for SIDS (OR = 1.46, 95% CI = 1.04–2.04, P = 0.028), with significant heterogeneity (χ2 = 23.94, P = 0.001, I 2 = 70.8%). No significant associations were found both in Caucasians (OR = 1.54, 95% CI = 0.99–2.40, POR = 0.056; χ2 = 18.70, Phet = 0.001, I2 = 78.6%) and non-Caucasians (OR = 1.34, 95% CI = 0.73–2.46, POR = 0.344; χ2 = 5.11, Phet = 0.078, I2 = 60.9%) [Figure 1]c. However, when stratified for control subjects, the L allele showed an increased risk in the live subgroup (OR = 2.03, 95% CI = 1.30–3.15, POR = 0.002; χ2 = 11.35, Phet = 0.023, I2 = 64.8%) but no association in the deceased subgroup (OR = 0.95, 95% CI = 0.72–1.24, POR = 0.699; χ2 = 2.21, Phet = 0.332, I2 = 9.3%) [Figure 1]d.
Evaluation of heterogeneity showed that the control subject component (P = 0.034, adjusted R2 = 90.86% for LL vs. LS and SS; P = 0.020, adjusted R2 = 100% for L vs. S), cases with SS genotype (P = 0.050, adjusted R2 = 70.49% for LL vs. LS and SS; P = 0.018, adjusted R2 = 83.45% for L vs. S), and cases with S allele (P = 0.050, adjusted R2 = 59.39% for LL vs. LS and SS; P = 0.034, adjusted R2 = 65.46% for L vs. S) could substantially influence the initial heterogeneity.
Sensitivity analyses showed that the studies with live control subjects each had a significant influence on the pooled estimation. No evidence of publication bias was found in the study (LL vs. LS and SS: P = 0.063 for Begg's test and P = 0.604 for Egger's test; L vs. S: P = 0.108 for Begg's test and P = 0.500 for Egger's test).
Meta-analysis of serotonin transporter intron 2 polymorphism
The 10/10 + 9/10 genotype was the minor genotype and ranged from 0.07 to 0.21 in controls. The pooled examination of intron 2 polymorphism using the dominant model ([10/10 + 9/10] and [10/12 + 9/12] vs. 12/12, as the 10/10 + 9/10 genotype was absent in some studies) showed no association with susceptibility to SIDS (OR = 1.00, 95% CI = 0.75–1.33, P = 0.994), and no observable heterogeneity among studies was found (χ2 = 7.61, P = 0.107, I2 = 47.5%) [Figure 2]a. The additive model ([10 + 9] vs. 12) also showed no association (OR = 0.97, 95% CI = 0.79-1.19, P = 0.753) and no heterogeneity (χ2 = 5.68, P = 0.224, I2 = 29.6%) [Figure 2]b.
|Figure 2: Forest plots of the serotonin transporter intron 2 polymorphism with sudden infant death syndrome risk. (a) Dominant model (10 + 9 carriers vs. 12/12); (b) Additive model (10 + 9 vs. 12)|
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Sensitivity analyses found no significant influence of any one study on the incidence of SIDS. No evidence of publication bias was found with the Begg's test (P = 1.000 for dominant model; P = 0.086 for additive model) and Egger's test (P = 0.883 for dominant model; P = 0.284 for additive model).
Meta-analysis of serotonin transporter haplotype
For control subjects, the S-9 and S-10 haplotypes were the minor haplotype, with a frequency ranging from 0.023 to 0.141. The pooled examination showed that the S-9 and S-10 haplotypes had a decreased risk for SIDS [Table 4]. However, the removal of the Caucasian study by Weese-Mayer et al. (2003) changed the result (OR = 0.62 with 95% CI = 0.34–1.11). The other haplotypes had no significant association with SIDS [Table 4], and omitting the study by Opdal et al. (2008) would yield a different result (OR = 2.16, 95% CI = 1.36–3.41) for L-12 haplotype. There were observable heterogeneities among studies in L-9 and 10 and L-12 examinations; however, no single factor mentioned above was able to adequately explain the heterogeneity (P > 0.10, separately). No evidence of publication bias was found with the Begg's test and Egger's test [Table 4].
|Table 4: Meta-analysis of the association between serotonin transporter haplotype and the risk of sudden infant death syndrome|
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| Discussion|| |
The present meta-analysis found that LL genotype or L allele of 5-HTT promoter polymorphism had an overall increased risk for SIDS and that there were no significant differences between Caucasians and non-Caucasians. However, when we divided the control population into two groups based on living or deceased status, we found that this increased risk was present in the living instead of the deceased subgroup. This suggests that ethnic origin is not a contributor to the susceptibility difference and that 5-HTT promoter polymorphism might also be a risk factor for infant (<1 year old) death other than SIDS. In addition, the statistically insignificant associations between the 5-HTT promoter polymorphism and SIDS in Caucasian and non-Caucasian subgroups are possibly due to the relatively small study numbers and sample sizes, which can lead to a much wider range in the CI. There were obvious heterogeneities among studies, and these were related to the control subject component, or the numbers of SS genotype or S allele cases.
The pooled examination of intron 2 polymorphism revealed no association with SIDS, and no heterogeneity was found. Sensitivity analyses indicated that our results for the 5-HTT promoter and intron 2 polymorphisms were statistically reliable. The meta-analysis for haplotype showed a deceased SIDS risk for S-9 and S-10 haplotypes with unreliable results and no significant association for the other haplotypes (the result for L-12 was unreliable).
It is thought that the genetic susceptibility of 5-HTT polymorphisms may be due to variant-mediated abnormal gene expression; however, not all of our results were in accordance with this concept. The risk for SIDS in individual infants is determined by complex interactions between genetic and environmental risk factors. As the polymorphic variants of the 5-HTT gene might respond differently to external environmental stimuli, and some environmental and temporal risk factors appear to additively weaken the excitatory function of serotonin, it is difficult to highlight the different roles of variants through a single-gene polymorphism study alone.
Inevitably, the data included in the present meta-analysis had some limitations. First, the numbers of included studies and sample sizes were small and probably led to poor power for the pooled examination; because there were few data, races were only divided into Caucasians and non-Caucasians. Second, two studies were not included in the meta-analysis for haplotype because of the presence of data errors. Finally, the small number of included studies might also result in an inaccurate estimate of publication bias, even though the relative statistical tests did not show this, because the sensitivities of both the Begg and Egger's tests were generally low in a meta-analysis based on less than 20 trials.
| Conclusion|| |
Overall, this meta-analysis suggests that L allele or LL homozygote of 5-HTT promoter polymorphism has an overall increased SIDS risk, with no significant differences between Caucasians and non-Caucasians, and there is no significant difference between SIDS and other infant deaths. Intron 2 polymorphism has no association with the susceptibility to SIDS. The relationship between the haplotypes and SIDS remains unclear due to unreliable results in the current data. Since many of the included studies were based on a limited sample size (<150), accurate and reliable results, especially in haplotype analysis, should be confirmed by well-designed studies with a larger sample size and suitable control collections. Furthermore, estimations of gene-gene and gene-environment interactions and relative functional studies should also be performed to enable better and more comprehensive understanding.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Willinger M, James LS, Catz C. Defining the Sudden infant death syndrome (SIDS): Deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 1991;11:677-84.
Hunt C, Hauck F. Sudden infant death syndrome: Gene-environment interactions. In: Brugada R, editor. Clinical Approach to Sudden Cardiac Death Syndromes. London: Springer; 2010. p. 7-21.
Mathews TJ, MacDorman MF. Infant mortality statistics from the 2003 period linked birth/infant death data set. Natl Vital Stat Rep 2006;54:1-29.
Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: Final data for 2005. Natl Vital Stat Rep 2008;56:1-120.
Opdal SH, Rognum TO. The Sudden infant death syndrome gene: Does it exist? Pediatrics 2004;114:e506-12.
De Jonge GA, Engelberts AC. Cot deaths and sleeping position. Lancet 1989;2:1149-50.
Zhang K, Wang X. Maternal smoking and increased risk of Sudden infant death syndrome: A meta-analysis. Leg Med (Tokyo) 2013;15:115-21.
Kinney HC, Filiano JJ, White WF. Medullary serotonergic network deficiency in the Sudden infant death syndrome: Review of a 15-year study of a single dataset. J Neuropathol Exp Neurol 2001;60:228-47.
Panigrahy A, Filiano J, Sleeper LA, Mandell F, Valdes-Dapena M, Krous HF, et al.
Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the Sudden infant death syndrome. J Neuropathol Exp Neurol 2000;59:377-84.
Ozawa Y, Okado N. Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders. Neuropediatrics 2002;33:142-9.
Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, et al.
Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994;95:157-62.
Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, et al.
Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66:2621-4.
Heinz A, Jones DW, Mazzanti C, Goldman D, Ragan P, Hommer D, et al.
A relationship between serotonin transporter genotype and in vivo
protein expression and alcohol neurotoxicity. Biol Psychiatry 2000;47:643-9.
Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, et al.
Multiple serotonergic brainstem abnormalities in Sudden infant death syndrome. JAMA 2006;296:2124-32.
MacKenzie A, Quinn J. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci U S A 1999;96:15251-5.
Weese-Mayer DE, Zhou L, Berry-Kravis EM, Maher BS, Silvestri JM, Marazita ML. Association of the serotonin transporter gene with Sudden infant death syndrome: A haplotype analysis. Am J Med Genet A 2003;122A:238-45.
Opdal SH, Vege A, Rognum TO. Serotonin transporter gene variation in Sudden infant death syndrome. Acta Paediatr 2008;97:861-5.
Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N. Serotonin transporter gene variation is a risk factor for Sudden infant death syndrome in the Japanese population. Pediatrics 2001;107:690-2.
Nonnis Marzano F, Maldini M, Filonzi L, Lavezzi AM, Parmigiani S, Magnani C, et al.
Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the Sudden infant death syndrome. Genomics 2008;91:485-91.
Haas C, Braun J, Bär W, Bartsch C. No association of serotonin transporter gene variation with Sudden infant death syndrome (SIDS) in Caucasians. Leg Med (Tokyo) 2009;11 Suppl 1:S210-2.
Paterson DS, Rivera KD, Broadbelt KG, Trachtenberg FL, Belliveau RA, Holm IA, et al.
Lack of association of the serotonin transporter polymorphism with the Sudden infant death syndrome in the San Diego dataset. Pediatr Res 2010;68:409-13.
Opdal SH, Vege Å, Rognum TO. Genetic variation in the monoamine oxidase A and serotonin transporter genes in Sudden infant death syndrome. Acta Paediatr 2014;103:393-7.
Casale V, Oneda R, Matturri L, Lavezzi AM. Investigation of 5-HTT expression using quantitative real-time PCR in the human brain in SIDS Italian cases. Exp Mol Pathol 2013;94:239-42.
Okado N, Narita M, Narita N. A serotonin malfunction hypothesis by finding clear mutual relationships between several risk factors and symptoms associated with Sudden infant death syndrome. Med Hypotheses 2002;58:232-6.
Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: Power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119-29.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]