Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study

Table 1 Strategy for computing the single-nucleotide polymorphism score

	Major allele homozygous genotype	Heterozygous variant genotype	Minor allele homozygous genotype
HTR3A c.-42C>T (rs1062613)	CC	CT	TT
HTR3B c.386A>C (rs1176744)	AA	AC	CC
HTR3C c.489C>A (rs6766410)	CC	CA	AA
HTR3E c.*76G>A (rs56109847)	GG	GA	AA

Table 2 Sociodemographic and symptomatic characteristics of the study participants

	Total	Centers
		Germany	Sweden	United States	United Kingdom	Ireland
n	100.0 (623)	45.1 (281)	18.3 (114)	19.6 (122)	12.4 (77)	4.7 (29)
Age	41.7 ± 16.1 (18, 91)	40.7 ± 16.4 (18, 88)	33.7 ± 11.8 (18, 60)	54.9 ± 14.6 (25, 91)	40.8 ± 11.6 (18, 70)	30.3 ± 8.6 (19, 51)
Sex
Female	69.5 (433)	63.3 (178)	69.3 (79)	77.9 (95)	72.7 (56)	86.2 (25)
IBS subtypes
IBS-C	14.1 (87)	8.9 (25)	12.3 (14)	36.7 (44)	0	13.8 (4)
IBS-D	41.7 (258)	43.4 (122)	19.6 (22)	28.3 (34)	100.0 (77)	10.3 (3)
IBS-M	42.5 (263)	45.6 (128)	67.0 (75)	31.7 (38)	0	75.9 (22)
IBS-U1	1.8 (11)	2.1 (6)	0.9 (1)	3.3 (4)	0	0
Depressive symptoms	-	9.4 ± 5.92	5.2 ± 3.54	13.2 ± 9.65	5.9 ± 4.04	4.3 ± 3.24
Anxiety symptoms	-	7.7 ± 4.83	8.3 ± 4.54	14.6 ± 9.76	9.6 ± 4.64	7.8 ± 4.54
Symptom severity	-	280.3 ± 90.77	297.3 ± 100.57	43.2 ± 16.28	-	-
Somatization symptoms9	14.8±6.3	16.2 ± 7.3	13.3 ± 4.7	13.8 ± 5.0	-	-

Sample size, sex, IBS subtypes, and severity of depressive and anxiety symptoms are presented as % (n). Age is presented as mean ± SD (range). Scores of depressive and anxiety symptoms are presented as mean ± SD.

¹Was not included in the later analysis because of the small sample size.

²Evaluated by the nine-item depression module from the Patient Health Questionnaire.

³Evaluated by the brief measurement for generalized anxiety disorder.

⁴Evaluated by Hospital Anxiety and Depression Scale.

⁵Evaluated by Beck Depression Inventory.

⁶Evaluated by Beck Anxiety Inventory.

⁷Evaluated by irritable bowel syndrome (IBS) symptom severity scale.

⁸Evaluated by the gastrointestinal symptom rating scale for IBS.

⁹Evaluated by the somatization module for the Patient Health Questionnaire.

IBS: Irritable bowel syndrome; IBS-C: Constipation-predominant IBS; IBS-D: Diarrhea-predominant IBS; IBS-M: IBS with mixed bowel habits; IBS-U: Unclassified IBS.

Table 3 Differences between single-nucleotide polymorphisms in depressive and anxiety symptoms, separately analyzed with ANOVA using the dominant model and the recessive model

Models	Mental symptoms	SNPs	Total	Sex		IBS subtypes
				Male	Female	IBS-C	IBS-D	IBS-M
Dominant model	Depressive symptoms	HTR3A c.-42C>T (rs1062613)	2.541	4.149 ↑	0286	0.998	0.376	0.694
		HTR3B c.386A>C (rs1176744)	0.067	0.005	0.198	0.282	0.124	0.232
		HTR3C c.489C>A (rs6766410)	7.475 ↑	0.672	7.040 ↑	0.261	5.670 ↑	2.328
		HTR3E c.*76G>A (rs62625044)	0.054	0.013	0.180	0.208	0.461	0.010
	Anxiety symptoms	HTR3A c.-42C>T (rs1062613)	0.511	0.210	0.280	0.604	0.672	0.162
		HTR3B c.386A>C (rs1176744)	0.926	0.406	0.801	0.468	1.369	0.770
		HTR3C c.489C>A (rs6766410)	6.535 ↑	0.158	7.550 ↑	0.186	13.444 ↑	0.045
		HTR3E c.*76G>A (rs62625044)	1.055	0.429	0.853	0.000	0.495	1.109
	Somatization symptoms	HTR3A c.-42C>T (rs1062613)	0.016	0.141	0.106	0.086	0.017	0.203
		HTR3B c.386A>C (rs1176744)	0.217	0.332	0.326	0.407	0.415	2.125
		HTR3C c.489C>A (rs6766410)	0.784	0.035	1.085	0.269	0.000	1.962
		HTR3E c.*76G>A (rs62625044)	0.002	1.554	0.263	0.128	0.729	0.354
Recessive model	Depressive symptoms	HTR3A c.-42C>T (rs1062613)	0.002	0.421	0.132	0.093	1.320	1.064
		HTR3B c.386A>C (rs1176744)	1.118	2.027	0.107	1.741	0.197	0.744
		HTR3C c.489C>A (rs6766410)	0.047	0.821	0.401	2.306	6.190 ↑	0.676
		HTR3E c.*76G>A (rs62625044)	0.677	-	0.574	0.541	-	-
	Anxiety symptoms	HTR3A c.-42C>T (rs1062613)	0.479	0.027	0.549	0.057	0.315	0.350
		HTR3B c.386A>C (rs1176744)	0.872	0.081	1.691	0.476	0.361	1.923
		HTR3C c.489C>A (rs6766410)	0.028	2.562	0.344	0.570	3.509	2.093
		HTR3E c.*76G>A (rs62625044)	0.216	-	0.179	0.242	-	-
	Somatization symptoms	HTR3A c.-42C>T (rs1062613)	0.217	0.018	0.257	0.138	0.092	0.431
		HTR3B c.386A>C (rs1176744)	6.482 ↑	2.245	3.575	0.142	14.033 ↑	0.341
		HTR3C c.489C>A (rs6766410)	0.468	1.813	0.128	4.715 ↓	0.002	0.113
		HTR3E c.*76G>A (rs62625044)	0.001	-	0.011	0.000	-	-

F values are shown in the table. Arrows represent the direction of the associations. ↑ dependent variable increases from major to minor alleles; ↓ dependent variable decreases from major to minor alleles. The underlined values were significant. Values in bold were “nominally significant” (i.e., lacking significance after false discovery rate multiple testing correction). IBS: Irritable bowel syndrome; IBS-C: Constipation-predominant IBS; IBS-D: Diarrhea-predominant IBS; IBS-M: IBS with mixed bowel habits; SNPs: Single-nucleotide polymorphisms.

Table 4 Association of depressive, anxiety, and somatization symptoms with the single-nucleotide polymorphism score of the four tested polymorphisms

	Total	Sex		IBS subtypes
		Male	Female	IBS-C	IBS-D	IBS-M
Depressive symptoms
F value	7.710	1.336	5.770	1.551	2.159	0.196
P-linear trend value	0.006	0.250	0.017	0.184	0.144	0.659
Anxiety symptoms
F value	2.150	0.028	2.514	1.372	2.400	1.412
P-linear trend value	0.143	0.866	0.114	0.245	0.123	0.236
Somatization symptoms
F value	1.15	0.354	1.028	0.716	2.718	0.628
P-linear trend value	0.283	0.553	0.311	0.614	0.102	0.429

Values in bold were “nominally significant” (i.e., lacking significance after false discovery rate multiple testing correction). IBS: Irritable bowel syndrome; IBS-C: Constipation-predominant IBS; IBS-D: Diarrhea-predominant IBS; IBS-M: IBS with mixed bowel habits.