Sleep quality, BDNF genotype and gene expression in individuals with chronic abdominal pain

Swarnalatha Y Reddy, Nat A Rasmussen, Nicolaas H Fourie, Rebecca S Berger, Angela C Martino, Jessica Gill, Ryan Longchamps, Xiao Min Wang, Margaret M Heitkemper, Wendy A Henderson, Swarnalatha Y Reddy, Nat A Rasmussen, Nicolaas H Fourie, Rebecca S Berger, Angela C Martino, Jessica Gill, Ryan Longchamps, Xiao Min Wang, Margaret M Heitkemper, Wendy A Henderson

Abstract

Background: Sleep quality and genetics may contribute to the etiology of gastrointestinal (GI) symptoms. Individuals with impaired sleep often have a number of associated symptoms including chronic abdominal pain (CAP). The current study examined the interactions of brain-derived neurotrophic factor (BDNF) genotype with sleep quality in persons with CAP and healthy controls. In addition, associations among sleep quality, BDNF genotype, and gene expression were explored in the participants.

Methods: Data were collected on 59 participants (46% male, 61% White, 26.9 ± 6.6 years; CAP (n=19) and healthy controls (n=40)). Participants with CAP reported poorer sleep quality compared to healthy controls. BDNF genotype, categorized as Val/Val homozygotes versus the Met carriers.

Results: Microarray analysis found twenty-four differentially expressed genes by a two-fold magnitude in participants with poor sleep quality compared to good sleep quality, and seven differentially expressed genes comparing CAP to healthy control. Three specific genes in the pain group overlap with sleep quality, including insulin-like growth factor 1 (IGF1), spermatogenesis associated serine-rich 2-like (SPATS2L), and immunoglobulin heavy constant gamma 1 or mu (IGHG1/// IGHM). BDNF was shown to have an interaction effect with GI and sleep symptoms.

Conclusions: Participants with CAP reported poor sleep quality compared to healthy controls. The role of the BDNF Met allele on differential gene expression was not distinct as main factor, but impacted interactions with sleep quality and CAP. Down-regulation of IGF1, SPATS2L, and IGHG1 expression may be related to the etiology of poor sleep quality and CAP.

Trial registration: Clinicaltrial.gov # NCT00824941.

Figures

Figure 1
Figure 1
Intersection of two lists of significant genes. Venn diagram showing the overlap of most differentially expressed genes of the sleep quality (poor sleep vs. good sleep, total of 24) and pain groups (CAP vs. healthy control, total of 7). The gene names and probeset IDs are provided for the pain group, and also that overlap with the sleep quality group. Although 5 genes overlap, gene names are available for three: IGF1, SPATS2L, and IGHG1///IGHM.
Figure 2
Figure 2
Expression patterns of IGF1, SPATS2L, and IGHG1 /// IGHM for sleep and pain groups. Distribution of the intensity values for sleep quality and pain groups of the differentially expressed gene: (a) IGF1, (b) SPATS2L and, (c) IGHG1 /// IGHM. The y-axis represents the log2 normalized least square mean of the gene expression intensity. The samples are colored by sleep quality (good sleep in red and poor sleep in blue).
Figure 3
Figure 3
Sources of variation of the significant genes. Effect of various factors and the interactions across the differentially expressed genes: (a) IGF1, (b) SPATS2L, and (c) IGHG1 /// IGHM. Factors of ANOVA model and random error are on the x-axis and mean squared F Ratio (measure of variance) of the gene on the y-axis. Average mean square values for each factor and interaction are provided.
Figure 4
Figure 4
Functional network associated with the differentially expressed genes. Schematic diagram of a gene network related to differential expression of sleep quality group (good sleep versus poor sleep). Coloring of genes is based on differential expression (fold changes are shown), down-regulation in green and, up-regulation in red. Genes with no coloring are added from Ingenuity knowledge database. Direct and indirect relationships are shown by solid and dashed lines, respectively. The arrow indicates specific directionality of interactions. Gene associations with some of the digestive system development functions are shown.
Figure 5
Figure 5
Molecular paths and interactions of the significant genes. Specific interactions for the genes IGF1, IGHM, and SPATS2L were generated from Ingenuity knowledge database related to gastrointestinal diseases. Red coloring indicates up-regulated genes for the pain group (CAP vs. healthy control). Direct and indirect relationships are shown by solid and dashed lines, respectively. Potential biomarkers are shown.

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