Sex and Gender Differences in Overlap Syndrome of Functional Gastrointestinal Disorder and Effect of Genetic Polymorphisms in South Korea: A Long-term Follow-up Study

Abstract

Background/aims: Overlap functional gastrointestinal disorder (FGID) is associated with more severe gastrointestinal symptoms and lower quality of life. The aim of this study is to evaluate clinical features of non-erosive reflux disease (NERD), functional dyspepsia, irritable bowel syndrome, their overlap in terms of sex and gender, and to assess the risk factors, including genetic polymorphisms.

Methods: A total of 494 FGIDs and 239 controls were prospectively enrolled between 2004 and 2020. FGIDs were diagnosed based on the Rome III criteria and symptoms were evaluated using a questionnaire. Follow-up questionnaires were conducted to determine the change of symptoms during the 75.8-month mean observation period. Risk factors including genetic polymorphisms in neurotransmitter receptor (SLC6A4 5-HTTLPR, GNB3, ADRA2A, CCKAR, and TRPV1) and cytokine (TNFA and IL10) genes.

Results: NERD was more prevalent in men, and functional dyspepsia in women. Overlap FGIDs (n = 239) were more prevalent than nonoverlap FGIDs (n = 255) in women (P = 0.019). Anxiety and depression scores were higher in the overlaps (P = 0.012 and P < 0.001, respectively). Symptoms were more frequent and severe in the overlap FGIDs than in the non-overlaps (P < 0.001). During followup, symptoms progressed more frequently in the overlap FGIDs, especially in patients with the L/S genotype of SLC6A4 5-HTTLPR and anxiety/depression.

Conclusions: Overlap FGID patients need attention given their association with anxiety/depression and more severe symptoms, especially in women. Genetic polymorphisms also may be associated with certain symptoms of overlap FGIDs.

Keywords: Dyspepsia; Female; Irritable bowel syndrome; Male; Polymorphism.

Figure 1

Proportions of subjects with functional gastrointestinal disorders (FGIDs) (A) and distribution of FGIDs according to sex (B). The prevalence of non-erosive reflux disease (NERD) was significantly higher in men and that of functional dyspepsia (FD) was significantly higher in women. IBS, irritable bowel syndrome. *P < 0.001 compared with women NERD, ^#P < 0.001 compared with men FD. FGID (n = 494), NERD (n = 304), FD (n = 308), irritable bowel syndrome (IBS) (n = 180), and non-overlap FGIDs (n = 255), overlap FGIDs (n = 239).

Figure 2

Changes in functional gastrointestinal disorder (FGID) symptoms during the follow-up period. Most FGID symptoms such as epigastric pain (C), bloating (D), loose or watery stool (F), incomplete defecation (H) and urgency (I) improved; however, symptoms of early satiation (A), postprandial fullness (B), hard or lump stool (E), and defecation straining (G) were aggravated in the overlap FGID group in the second follow-up visit. Symptoms were analyzed in the follow-up 1 (f/u1) (38.7 ± 22.1 months) and follow-up 2 (f/u2) 37.1 ± 21.0 months (J) periods.

Figure 3

Changes in epigastric pain symptom severity according to anxiety and depression during the follow-up period. There were no differences in symptoms between the non-overlap and overlap functional gastrointestinal disorder (FGID) in anxiety (–) and depression (–) groups (A and C), however, differences between the non-overlap and overlap FGID were revealed during the follow-up period in anxiety (+) and depression (+) groups (B and D). There was no change in symptom severity in both non-overlap and overlap FGIDs during the follow-up period in the anxiety group (B). (+), patients has anxiety or depression; (–), patients has no anxiety or depression; f/u, follow-up.

Figure 4

Changes in severity of upper gastrointestinal symptoms during the follow-up period according to the serotonin transporter gene-linked long polymorphic region (SLC6A4 5-HTTLPR) gene polymorphism. Early satiation (A) and postprandial fullness (C) were most severe in patients with the SLC6A4 5-HTTLPR L/S genotype and were found to worsen. Epigastric pain symptoms (B) in patients with the SLC6A4 5-HTTLPR L/L genotype were maintained and did not deteriorate or improve. L, long allele of the SLC6A4 5-HTTLPR gene; S, short allele of the SLC6A4 5-HTTLPR gene; f/u, follow-up.

Figure 5

Effect of the serotonin transporter gene-linked long polymorphic region (SLC6A4 5-HTTLPR) gene polymorphism on the severity of epigastric pain in patients with overlap syndrome. Early satiation and epigastric pain symptoms in the non-overlap functional gastrointestinal disorder (FGID) group were not related to the SLC6A4 5-HTTLPR genotype (A, C). In the overlap FGID group, L/L and L/S genotypes elicited more severe symptoms than the S/S genotype (B, D). L, long allele of the SLC6A4 5-HTTLPR gene; S, short allele of the SLC6A4 5-HTTLPR gene; f/u, follow-up.