Genotype-phenotype landscape of Sodium taurocholate cotransporting polypeptide deficiency in Yunnan Province, China: A five-year retrospective, multi-ethnic cohort study

Table 1 Demographic and clinical characteristics of the study population

Variable	Patient cohorts (n = 125)
Gender
Female	56
Male	69
Age of onset (months)
0-2	54
2-4	35
4-6	10
6-12	16
12-24	3
24-36	5
> 36	2
Weight (kg)	6.44 ± 2.46 (1.67-14.00)
Thyroid function
Normal	104
Abnormal	21
Gene
HOM	83
HET	25
Compound HET	17
Ethnic group
Han Chinese	73
China’s ethnic minorities	52
Region (Yunnan Province)
Kunming city	49
Other regions	76

Table 2 Comparison of the serum biochemical indices among the paediatric groups

Indices	Reference ranges	Paediatric patients			P value
		(0-2 months), n = 54	(2-4 months), n = 35	(> 4 months), n = 36
TBA	0-15 µmol/L	178.8 ± 60.87a	128.54 ± 81.26b	141.15 ± 77.92	a vs b, P = 0.0002
TBIL	0-26 µmol/L	84.08 ± 67.86a	43.41 ± 46.8b	9.28 ± 4.22c	a vs b, P = 0.0030; b vs c, P < 0.0001; a vs c, P < 0.0001
IBIL	0-14 µmol/L	63.49 ± 57.21a	33.87 ± 44.37b	5.71 ± 3.3c	a vs b, P = 0.0122; b vs c, P < 0.0001; a vs c, P = 0.0004
GGT	5-19 U/L	128.53 ± 112.17a	87.2 ± 127.38b	22.57 ± 30.45c	a vs c, P < 0.0001; b vs c, P = 0.0054
ALP	146-500 U/L	425.48 ± 157.45a	343.93 ± 133.28b	261.16 ± 93.14c	a vs b, P = 0.0148; b vs c, P = 0.0041; a vs c, P < 0.0001
DBIL	0-10 µmol/L	20.74 ± 38.75	9.54 ± 11.28	4.14 ± 3.35	NS
ALT	7-30 U/L	37.50 ± 29.95	42.44 ± 48.95	40.69 ± 39.15	NS
AST	14-44 U/L	64.24 ± 54.81	64.44 ± 54.09	56.17 ± 22.54	NS
AFP	< 200 µg/L	5472.47 ± 12515.0	1515.87 ± 2992.81	72.72 ± 183.27	NS
Vit A	1.05-2.8 µmol/L	1.467 ± 0.55	1.79 ± 0.73	2.00 ± 0.58	NS
Vit D	50-147 nmol/L	79.60 ± 34.71	97.75 ± 37.55	122.52 ± 35.44	NS
Vit E	16.25-33.5 µmol/L	26.25 ± 8.19	29.0 ± 7.01	29.23 ± 7.14	NS
Zinc	3.7-7.3 mg/L	3.91 ± 0.59	3.47 ± 0.9	4.33 ± 0.49	NS
Fe	373.5-557.2 mg/L	399.35 ± 30.26	631.93 ± 890.43	409.24 ± 32.72	NS

^aP < 0.05, values with the same superscript letter are not significantly different.

^bP < 0.05, values with the same superscript letter are not significantly different.

^cP < 0.05, values with the same superscript letter are not significantly different.

Statistical analysis of the three age groups’ data indicators was performed using one-way ANOVA with Bartlett’s test, supplemented by Brown-Forsythe and Tukey post-hoc corrections to assess significance. TBA: Total bile acid; TBIL: Total bilirubin; IBIL: Indirect bilirubin; DBIL: Direct bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein; NS: Not significant.

Table 3 Spectrum of homozygous, heterozygous, and compound heterozygous variants in 125 affected individuals

	Father	Mother	ACMG classification
Proband (n = 17)	Compound heterozygous
c.800C>T, c.185C>T	c.800C>T	c.800C>T, c.185C>T	c.185C>T: VUS
c.800C>T, c.944-32G>C	c.944-32G>C	c.800C>T	c.944-32G>C: VUS
c.800C>T, c.944-32G>C	c.800C>T	c.944-32G>C	c.944-32G>C: VUS
c.800C>T, c.263T>C	c.263T>C	c.800C>T	c.944-32G>C: VUS
c.800C>T, c.682_683del	c.682_683del	c.800C>T	c.682_683del: LP
c.799T>C, c.800C>T	c.800C>T	c.799T>C	c.799T>C: VUS
c.800C>T, c.263T>C	c.800C>T	c.263T>C	c.263T>C: P
c.800C>T, c.54delT	c.800C>T	c.54delT	c.54delT: LP
c.800C>T, c.54delT	c.800C>T	c.54delT	c.54delT: LP
c.800C>T, c.402G>A	c.800C>T	c.800C>T, c.402G>A	c.402G>A: VUS
c.422dupA, c.800C>T	c.800C>T	c.422dupA	c.422dupA: VUS
c.422dupA, c.800C>T	c.800C>T	c.422dupA	c.422dupA: VUS
c.997G>A, c.800C>T	c.997G>A, c.800C>T	c.800C>T	c.997G>A: VUS
c.997G>A, c.800C>T	c.997G>A, c.800C>T	c.800C>T	c.997G>A: VUS
c.800C>T, c.54del	c.54del	c.800C>T	c.54del: LP
c.800C>T, c.263T>C	c.800C>T	c.263T>C	c.263T>C: P
c.800C>T, c.413T>C	c.800C>T, c.413T>C	c.800C>T	c.413T>C: VUS
Proband (n = 25)	Heterozygous
c.800C>T		c.800C>T	c.800C>T: P
c.800C>T	c.800C>T
c.263T>C	c.263T>C		c.263T>C: P
c.800C>T		c.800C>T
c.800C>T		c.800C>T
c.800C>T		c.800C>T
c.745C>T		c.745C>T	c.745C>T: VUS
c.800C>T		c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T		c.800C>T
c.800C>T	c.800C>T
c.800C>T		c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
c.800C>T		c.800C>T
c.800C>T		c.800C>T
c.800C>T	c.800C>T
c.800C>T		c.800C>T
c.800C>T	c.800C>T
c.800C>T	c.800C>T
Proband (n = 83)	homozygous
c.800C>T	c.800C>T	c.800C>T	c.800C>T: P

P: Pathogenic; LP: Likely pathogenic; VUS: Variant of uncertain significance.

Table 4 Multivariable-adjusted associations between gene variants and serum biochemical indices in 84 pediatric participants

	Model 1			Model 2			Model 3
Characteristic	Beta	95%CI	P value	Beta	95%CI	P value	Beta	95%CI	P value
Gene	TBA
1	82	31-132	0.002	83	31-134	0.002	86	26-147	0.007
2	-2.0	-58 to 54	> 0.9	-2.1	-59 to 55	> 0.9	-6.1	-72 to 60	0.9
3	95	36-155	0.002	95	35-155	0.003	95	23-166	0.011
	GGT
1	-182	-284 to -80	< 0.001	-176	-279 to -73	0.001	-253	-380 to -125	< 0.001
2	-189	-302 to -76	0.002	-189	-303 to -76	0.002	-255	-394 to -116	< 0.001
3	-149	-269 to -29	0.017	-149	-270 to -29	0.017	-244	-393 to -95	0.002
	AFP
1	800	-4142 to 5741	0.8	1294	-3717 to 6305	0.6	490	-7846 to 8826	> 0.9
2	-441	-5886 to 5004	0.9	-447	-5883 to 4988	0.9	-1149	-9866 to 7568	0.8
3	6,416	207-12624	0.048	6349	150-12547	0.050	5334	-350 to 14619	0.3
	Vit D
1	-24	-56 to 7.6	0.14	-27	-59 to 5.1	0.10	-18	-55 to 19	0.4
2	-4.1	-40 to 32	0.8	-4.0	-39 to 32	0.8	-0.91	-41 to 40	> 0.9
3	-43	-81 to -3.7	0.035	-42	-81 to -3.8	0.035	-35	-80 to 10	0.13
	Vit E
1	-13	-19 to -7.5	< 0.001	-13	-19 to -7.4	< 0.001	-15	-22 to -8.1	< 0.001
2	-7.8	-14 to -1.5	0.018	-7.8	-14 to -1.4	0.019	-9.3	-17 to -1.9	0.017
3	-14	-23 to -6.1	0.001	-14	-23 to -6.0	0.001	-16	-25 to -6.6	0.002

Model 1: Gene. Model 2: Adjust: Age. Model 3: Adjust: Age, ethnicity, location. Total sample size = 84, Model 1 sample size = 84, Model 2 sample size = 84, Model 3 sample size = 84. P for trend of total bile acid, gamma-glutamyl transferase, alpha-fetoprotein, Vit D and Vit E across ordered gene categories. Error: Subscript out of bounds. TBA: Total bile acid; GGT: Gamma-glutamyl transferase; AFP: Alpha-fetoprotein; CI: Confidence interval.

Table 5 Logistic-regression associations between gene variants and thyroid dysfunction in 84 pediatric participants

	Model 1			Model 2			Model 3
Characteristic	OR	95%CI	P value	OR	95%CI	P value	OR	95%CI	P value
Gene
1	0.07	0.01-0.42	0.006	0.07	0.01-0.45	0.007	0.14	0.01-1.58	0.12
2	0.17	0.02-1.18	0.085	0.17	0.02-1.33	0.10	0.42	0.03-5.62	0.5
3	0.11	0.01-0.96	0.060	0.11	0.01-0.96	0.060	0.40	0.02-6.60	0.5

Model 1: Gene. Model 2: Adjust: Age. Model 3: Adjust: Age, ethnicity, location. Total sample size = 84, Model 1 sample size = 84, Model 2 sample size = 84, Model 3 sample size = 84. OR: Odds ratio; CI: Confidence interval.

Table 6 Sex-stratified multivariable linear regression: Associations between genotypes and serum biochemical indices in male pediatric participants

	Model 1			Model 2			Model 3
Characteristic	Beta	95%CI	P value	Beta	95%CI	P value	Beta	95%CI	P value
Gene	TBA
1	108	3.1-214	0.051	109	2.2-216	0.053	206	69-342	0.007
2	30	-78 to 138	0.6	29	-80 to 139	0.6	105	-37 to 246	0.2
3	92	-28 to 211	0.14	91	-30 to 212	0.15	176	26-326	0.031
	AST
1	18	-6.0 to 42	0.2	18	-6.1 to 43	0.2	55	28-82	< 0.001
2	17	-7.7 to 42	0.2	17	-8.2 to 42	0.2	51	22-79	0.002
3	14	-14 to 41	0.3	13	-14 to 41	0.3	49	19-79	0.004
	ALP
1	-317	-484 to -150	< 0.001	-305	-463 to -148	< 0.001	-349	-611 to -87	0.016
2	-262	-433 to -90	0.005	-271	-433 to -109	0.002	-293	-565 to -21	0.046
3	-354	-544 to -165	< 0.001	-359	-538 to -181	< 0.001	-375	-662 to -87	0.018
	Vit A
1	0.40	-0.59 to 1.4	0.4	0.34	-0.61 to 1.3	0.5	0.12	-1.2 to 1.5	0.9
2	0.28	-0.73 to 1.3	0.6	0.32	-0.65 to 1.3	0.5	0.40	-1.0 to 1.8	0.6
3	1.1	0.00-2.2	0.060	1.1	0.07-2.2	0.046	0.94	-0.55 to 2.4	0.2

Model 1: Gene. Model 2: Adjust: Age. Model 3: Adjust: Age, ethnicity, location. Total sample size = 41, Model 1 sample size = 41, Model 2 sample size = 41, Model 3 sample size = 41. P for trend for the effect of GENE on total bile acid, aspartate aminotransferase, alkaline phosphatase, and Vit A levels in the stratum of males (GENDER = 1). Error: Subscript out of bounds. TBA: Total bile acid; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; CI: Confidence interval.

Table 7 Sex-stratified multivariable linear regression: Associations between genotypes and serum biochemical indices in female pediatric participants

	Model 1			Model 2			Model 3
Characteristic	Beta	95%CI	P value	Beta	95%CI	P value	Beta	95%CI	P value
Gene	TBA
1	89	28-150	0.007	89	27-152	0.008	76	-8.3 to 160	0.089
2	13	-65 to 92	0.7	13	-67 to 93	0.7	-1.9	-96 to 92	> 0.9
3	104	33-175	0.007	104	32-176	0.007	97	0.44-194	0.059
	GGT
1	-215	-373 to -56	0.012	-210	-372 to -48	0.015	-346	-565 to -128	0.004
2	-223	-428 to -19	0.039	-223	-431 to -16	0.041	-307	-551 to -64	0.020
3	-172	-357 to 13	0.076	-172	-359 to 15	0.079	-327	-578 to -76	0.016
	AFP
1	1589	-6335 to 9513	0.7	2004	-6132 to 10140	0.6	-1748	-16919 to 13422	0.8
2	-273	-10648 to 10102	> 0.9	-253	-10761 to 10255	> 0.9	-1385	-17234 to 14463	0.9
3	11291	916-21666	0.043	11147	629-21665	0.049	9749	-6415 to 25914	0.3
	Vit D
1	-34	-70 to 2.3	0.075	-33	-70 to 4.3	0.092	-5.9	-50 to 38	0.8
2	-9.3	-56 to 37	0.7	-9.3	-56 to 38	0.7	-0.01	-49 to 49	> 0.9
3	-66	-110 to -21	0.007	-66	-111 to -21	0.007	-34	-88 to 19	0.2
	Vit E
1	-15	-23 to -7.5	< 0.001	-15	-24 to -7.2	0.001	-22	-34 to -10	0.003
2	-8.8	-19 to 1.2	0.10	-8.8	-19 to 1.4	0.10	-11	-22 to -0.48	0.060
3	-18	-35 to -0.72	0.052	-18	-36 to -0.37	0.056	-23	-42 to -4.8	0.027
	Fe
1	-34	-58 to -8.9	0.018	-36	-62 to -11	0.015	-58	-100 to -15	0.032
2	-36	-68 to -3.8	0.045	-36	-69 to -3.7	0.047	-44	-84 to -4.0	0.068
3	-25	-72 to 22	0.3	-25	-73 to 22	0.3	-48	-106 to 9.4	0.15
	Thyroid dysfunction
1	0.06	0.00-0.55	0.017	0.08	0.01-0.71	0.030	0.23	0.01-5.14	0.3
2	1.00	0.07-13.8	> 0.9	1.00	0.07-14.0	> 0.9	1.57	0.08-41.5	0.8
3	0.10	0.00-1.20	0.094	0.17	0.01-2.43	0.2	0.45	0.01-16.0	0.7

Model 1: Gene. Model 2: Adjust: Age. Model 3: Adjust: Age, ethnicity, location. Total sample size = 43, Model 1 sample size = 43, Model 2 sample size = 43, Model 3 sample size = 43. P for trend for the effect of Gene on total bile acid, gamma-glutamyl transferase, alpha-fetoprotein, Vit A, Vit D, Fe and thyroid dysfunction levels in the stratum of males (GENDER = 0). Error: Subscript out of bounds. TBA: Total bile acid; GGT: Gamma-glutamyl transferase; AFP: Alpha-fetoprotein; CI: Confidence interval.