Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Banawalikar, N.; Adiga, S.; Adiga, U.; Shenoy, V.; Kumari, S.; Shetty, P.; Shetty, S.; Sharmila, K.P.

doi:10.1590/1414-431X2021e11097

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Brazilian Journal of Medical and Biological Research

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Research Article • Braz. J. Med. Biol. Res. 54 (9) • 2021 • https://doi.org/10.1590/1414-431X2021e11097 copy

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Authorship SCIMAGO INSTITUTIONS RANKINGS

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

UGT1A6; Genetic polymorphism; Sodium valproate; Clinical outcome

Genotype	Actual values	Expected values	P-value
T19G
TT	26	30.5	6.58
TG	37	28.0
GG	2	6.5
A541G
AA	33	32.6	0.0716
AG	26	26.9
GG	6	5.5
A552C
AA	28	27.1	0.2184
AC	28	29.7
CC	9	8.2

Genotype UGT1A6	Polymorphism pattern	Polymorphism	Clinical outcome		P-value
			Responders (N=53) (81.5%)	Non-responders (N=12) (18.5%)
T19G	TT	40%	20 (37.8%)	6 (50%)	0.318
	TG	57%	32 (60.4%)	5 (41.6%)
	GG	3%	1 (1.8%)	1 (8.4%)
A541G	AA	51%	28 (52.8%)	5 (41.6%)	0.568
	AG	40%	21 (39.6%)	5 (41.6%)
	GG	9%	4 (7.6%)	2 (16.8%)
A552C	AA	43%	23 (43.4%)	5 (41.6%)	0.952
	AC	43%	23 (43.4%)	5 (41.6%)
	CC	14%	7 (13.2%)	2 (16.8%)

Gene loci	Pattern	Probability of poor response	Clinical outcome (N, %)		Relative risk	P-value
			Good (N=53) (81.5%)	Poor (N=12) (18.5%)
T19G	Wild	0.23	20 (37.8%)	6 (50%)	1.53	0.52
	Mutant	0.15	33 (62.2%)	6 (50%)
A541G	Wild	0.15	28 (52.8%)	5 (41.6%)	0.71	0.54
	Mutant	0.21	25 (47.2%)	7 (58.4%)
A552C	Wild	0.17	23 (43.4%)	5 (41.6%)	1.01	>0.99
	Mutant	0.18	30 (56.4%)	7 (58.4%)

Gene loci	Seizure type	Gene pattern	Clinical outcome		Relative risk	P-value
			Good N=52 (80%)	Poor N=13(20%)
T19G	GTCS	Wild	11 (21.2%)	5 (38.5%)	2.25	0.25
		Mutant	30 (57.7%)	6 (46.1%)
	FSAI	Wild	9 (17.3%)	1 (7.7%)	0.42	0.30
		Mutant	2 (3.8%)	1 (7.7%)
A541G	GTCS	Wild	22 (42.4%)	5 (38.5%)	0.92	>0.99
		Mutant	19 (36.5%)	6 (46.1%)
	FSAI	Wild	6 (11.5%)	0	0	0.46
		Mutant	5 (9.6%)	2 (15.4%)
A552C	GTCS	Wild	16 (30.8%)	5 (38.5%)	1.47	0.50
		Mutant	25 (48.1%)	6 (46.1%)
	FSAI	Wild	7 (13.5%)	0	0	0.19
		Mutant	4 (7.6%)	2 (15.4%)

Parameters	2 years			6-12 years			12-18 years
	Basal	6 months	P-value	Basal	6 months	P-value	Basal	6 months	P-value
Albumin (g/dL)	4.3±0.33	4.2±0.33	0.674	4.5±0.39	4.4±0.26	0.363	4.6±0.28	4.6±0.24	0.984
Total protein (g/dL)	6.8±0.37	7.2±0.60	0.117	7.4±0.74	7.4±0.5	0.974	7.5±0.49	7.7±0.3	0.745
SGOT (IU/L)	33.8±10	28.3±7.8	0.215	27.2±7	26.9±9.5	0.04*	26.7±15	23.2±5	0.326
SGPT (IU/L)	14.7±6	14.5±7.2	0.091	11.6±4	12±4.8	0.009*	16.3±16	13.1±3.6	0.173
ALP (IU/L)	219±93	186±49	0.881	198±53	217±76	0.267	177±84	158±78	0.578
Bil Dir (mg/dL)	0.07±0.03	0.09±0.04	0.565	0.16±0.1	0.11±0.05	0.034*	0.14 ±0.13	0.12±0.08	0.028*
Bil Tot (mg/dL)	0.2±0.1	0.2±0.1	0.496	0.34±0.3	0.32±0.14	0.002*	0.38±0.2	0.32±0.2	0.032*
Urea (mg/dL)	23.6±9.4	19.2±9.1	0.928	21.3±6.5	21.3±7.4	0.850	20.1±7.7	20.1±7.2	0.915
Creat (mg/dL)	0.40±0.2	0.35±0.2	0.242	0.53±0.2	0.36±0.1	0.017*	0.64±0.2	0.53±0.1	0.119
Amylase (IU/L)	84.4±32	73.3±29	0.301	93.3±54	84.8±27	0.012*	87.3±36	90.3±44	0.038*
Platelet (Lk/cum)	2.9±0.33	2.7±0.47	0.167	2.8±0.78	2.5±0.45	0.342	2.8±0.32	2.7±0.35	0.092

Genotype UGT1A6	Chinese				Japanese	Caucasian	Indian	Indian
	Hung et al. (10) (n=162)	Guo et al. (11) (n=98)	Chu et al. (12) (n=242)	Xing et al. (13) (n=534)	Saeki et al. (14) (n=195)	Lampe et al. (15) (n=100)	Jain et al. (16) (n=80)	Current study (n=65)
T19G
TT	62.4%	54.3%	NS	NS	NS	NS	45%	40%
TG	30.9%	39.4%	NS	NS	NS	NS	39%	57%
GG	6.8%	6.4%	NS	NS	NS	NS	16%	3%
A541G
AA	64.8%	56.4%	65%	60%	62%	46%	49%	51%
AG	29.6%	39.4%	33%	35%	33%	43%	39%	40%
GG	5.6%	4.3%	2%	5%	5%	11%	12%	9%
A552C
AA	62.9%	55.3%	57%	57%	NS	48%	44%	43%
AC	30.3%	39.4%	39%	37%	NS	42%	40%	43%
CC	6.8%	4.3%	4%	6%	NS	10%	16%	14%

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[1] Correspondence: S. Adiga: <adigapharma@nitte.edu.in>