• analgesic therapy
• birthweight
• genetics
• gluocose
• newborn
• SLC2A1
• SNPs

In the last decade several studies have indicated the first thousand days of life as a critical time window in which the foundations for health, growth and neurodevelopment are laid. One of the most important parameters that are considered in this period is the exposure of the newborn to painful stimuli. Painful treatments in newborns have been associated with behavioral disorders and long-term complications at later ages. One of the most effective non-pharmacological analgesic treatments in newborns is the oral administration of a glucose-based solution a few minutes before painful procedures. However, some newborns still perceive pain despite the analgesic treatment, suggesting the involvement of host genetic factors in the response to the therapy. Another fundamental parameter is birth weight, which plays a key role in healthy growth and proper development, the alterations of which have been associated with a higher risk of developing various pathologies, later in life.
In this study, the effect of single nucleotide polymorphisms (SNPs) of the SLC2A1, SLC2A2 and SLC6A2 genes on response to the analgesic therapy and weight during the first four years of life was evaluated. These genes encode proteins that carry glucose and norepinephrine. Glucose, in addition to being crucial to induce the analgesic effect, is associated to weight changes in the child. Norepinephrine is a hormone that acts on dietary behavior, affecting the sense of satiety; it also involves several metabolic processes in which glucose is present.
The study population consisted of 1421 healthy newborns with Apgar score>7 and gestational age of at least 37 weeks. Cord-blood samples were collected at the Division of Neonatology of the Santa Chiara Hospital of Pisa. The ABC score was used to evaluate the effectiveness of the analgesic therapy and several clinical and anthropometric variables, both maternal and neonatal, were collected to assess whether these could influence the analgesic therapy and weight in the first four years of life. Genomic DNA was extracted from blood samples through an automated extraction process and genotyped in 384-well plates using a hot-start PCR protocol with TaqMan probes.
The effect of the SNPs on the response to the therapy was investigated using different logistic regression models. In a first analysis newborns responding to the therapy were compared to non-responding subjects (ABC score>0). In a second analysis, responding newborns were compared with non-responding newborns characterized by a high intensity of pain (ABC score>4). Finally, an ordinal logistic regression model was used to assess whether polymorphisms affected the likelihood of moving from one ABC score category to the next with a higher score (considering all ABC scoring categories).
In this preliminary research we found that eight polymorphisms influenced the response to the therapy; among them the most interesting result was the increased risk of higher ABC score for the G allele carriers of the SNP rs11052974 (OR=4.63, p=4.68x10-4).
We also found three SNPs affecting weight, among which the most promising was rs11210769, whose T allele resulted in weight gain at both one and two years (beta=0.383, p=0.014; beta=0.635, p=0.012). Using data provided by bioinformatics tools, it has been observed that allelic variants of SLC2A1 associated with a higher probability of not responding to therapy, may involve a different expression of SLC2A1 itself, by increasing the expression of the antisense gene SLC2A1-AS1.
Several studies confirm that the release of dopamine is closely related to the modulation of pain and weight at birth. It is therefore possible that these allelic variants, causing a reduction in the expression of SLC2A1, may exert an effect on the complex characteristics considered in this study (response to analgesic therapy and weight in the first 4 years of life) through a different regulation of the dopaminergic system.