Association of maternal and infant variants inPNOCandCOMTgenes with neonatal abstinence syndrome severity

Abstract

Background and Objectives There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings. Methods For the replication cohort, full-term opioid-exposed newborns and their mothers (n=113 pairs) were studied. A DNA sample was obtained and genotyped for 5 SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at α<0.003 and point-wise level of α<0.05.. SNP associations in a combined cohort of n=199 pairs (replication cohort plus 86 pairs previously reported), were also examined. Results In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with 2 medications for NAS (adjusted OR=0.5, p=0.04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p=0.04); mothers with the PNOC rs351776 A allele had infants who were treated more often with 2 medications (adjusted OR 2.3, p=0.004) with longer hospitalization by 3.3 days (p=0.01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR 0.5, p=0.02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold. Conclusions and Scientific Significance We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS.

Epigenetic variation in OPRM1 gene in opioid‐exposed mother‐infant dyads

“…Percent methylation at each of the 20 CpG sites was determined. DNA was genotyped for OPRM1 118A>G (rs1799971) as part of a custom‐designed microarray at the BU Genomics laboratory …”

“…NAS is a highly variable condition with genetic factors appearing to play a key role. Previous studies examined candidate genes and associations between single nucleotide polymorphisms (SNPs) and NAS severity, finding associations between variants in opioid receptor genes ( OPRM1 , OPRK1 , PNOC ) and stress response genes ( COMT ) and differences in NAS outcomes …”

Genomics and Neonatal Opioid Withdrawal Syndrome

“…A study by Wachman et al (2013) postulates that an association exists in NAS infants who possess specific SNPs in the COMT gene. This COMT gene is associated with the endogenous stress pathway and plays an essential role in opioid addiction and withdrawal (Wachman et al, 2017;Wachman & Farrer, 2019). Researchers found that the COMT gene and SNPs with the G allele in affected infants were associated with less need for pharmacologic treatment and shorter LOS due to a decrease in COMT enzyme activity (Cole et al, 2017;Wachman et al, 2013) (Table 1).…”

Suggestions for Model‐Informed Precision Dosing to Optimize Neonatal Drug Therapy

“…28,29 Unique neonatal conditions like neonatal abstinence syndrome can be studied only in the newborn population, where outcomes have shown to be dependent on the genotype of the mother and the infant. 32 In addition, there is a dynamic temporal interplay between developmental and pharmacogenomic factors. Determining the age when genetic variations become the predominant factor for differences in drug response is crucial to evidencebased dosing algorithms in neonates.…”