Polymorphisms in genes of respiratory control and sudden infant death syndrome

Abstract

Sudden infant death syndrome (SIDS) is a multifactorial syndrome and assumingly, among other mechanisms, a deficit in respiratory control leads to a failure of arousal and autoresuscitation when the child is challenged by a stressful homeostatic event, e.g., hypoxia. We hypothesize that genetic polymorphisms involved in respiratory control mediated in the medulla oblongata contribute to SIDS. Therefore, a total of 366 SIDS cases and 421 controls were genotyped for 48 SNPs in 41 candidate genes. Genotyping was performed using Fluidigm nanofluidic technology. Results were obtained for 356 SIDS and 406 controls and 38 SNPs. After correction for multiple testing, one SNP retained a nominally significant association with seasonal SIDS: rs1801030 in the phenol sulfotransferase 1A1 gene (subgroup: death occurring during summer). A borderline association could be also observed for rs563649 in the opioid receptor μ1 gene in a recessive model (subgroup: death occurring during autumn). As a conclusion, although these data suggest two SNPs to be associated with different subgroups of SIDS cases, none of them can fully explain the SIDS condition, consistent with its multifactorial etiology. Given the great complexity of respiratory control and our initial findings reported here, we believe it is worthwhile to further investigate genes involved in the respiratory system.

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

“…While no confirmed SIDS biomarkers exist [e.g., Ref. (16, 17)] nor it is possible to differentiate accidental asphyxia from SIDS (18), a number of modifiable risk factors have been associated with SIDS, including prone sleep position, parental smoking during and after pregnancy, alcohol consumption by caregivers, overheating, preterm infants, infant head covering by soft bedding, bed sharing, and upper respiratory tract infection (19–21). Decreasing in these risk factors was effective in reducing the mortality rates over the past two decades (22), though not necessarily SIDS, which remains distinct from known mortalities and its main characteristics – male predominance (60:40 male:female USA ratio), significantly lower SIDS rates in USA Hispanics compared with whites, infants aged 2–4 months being at greatest risk of SIDS with most SIDS-related deaths occurring by 6 months, and seasonal variation with most cases occurring during winter (8, 23) – remain largely unexplained.…”

Noncardiac genetic predisposition in sudden infant death syndrome

“…Our current study now examines the potential contribution of "non-cardiac" genes in the pathogenesis of SIDS using a similar approach to examine 61 published non-cardiac genes previously implicated in SIDS 8,[17][18][19][20][21] . The majority had been identified as potential "SIDS-susceptibility" genes following both common and rare variant association studies, typically involving promoter region variants.…”

“…8 Based on our own literature search of articles from 2014 to 2018, 6 additional SIDS-susceptibility genes were included for a total list of 61 non-cardiac, candidate genes (see Online Supplement eTable 1). [17][18][19][20][21] Following exome sequencing, single nucleotide variants (SNVs) and insertion/deletions (INDELs) were filtered to identify variants which followed either a dominant or recessive inheritance pattern using Ingenuity Variant Software (Qiagen, Redwood City, CA). All variants within the 61 non-cardiac SIDS-susceptibility genes were first filtered for a call quality score ≥ 20 and a read depth ≥ 10.…”

Next-generation sequencing of human opioid receptor genes based on a custom AmpliSeq™ library and ion torrent personal genome machine

“…Single opioid receptor variants have been causally involved in reduced responses to analgesic treatment [44], hyperalgesic responses to opioid analgesics [45], protection against opioid induced side effects [46], [47], the individual sensitivity to painful stimuli [48], [49], the risk for drug addiction [50], [51], the individual response to stress [12], the success of naloxone treatment of alcoholism [52], or even the susceptibility to breast cancer [53] or the incidence of sudden infant death syndrome [54]. At the molecular level, in particular μ-opioid receptor variants have been shown to reduce opioid receptor expression [16], [17], receptor signaling [17], [18], [19] up to an almost complete functional loss [18], [20], and alternative splicing with the appearance of a six-transmembrane segment μ-opioid receptor [45] that triggers excitatory effects [43].…”