NAT2*6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

Table 1 Characteristics of pulmonary TB patients included in the study

Characteristics	TB
Number of patients	100
Age range (yr)	22-94
Age (mean ± SD)	64.0 ± 17.4
Gender (male/female)	56/44
Body mass index (kg/m2)	20.3 ± 2.9

Table 2 Five Haplotypes composed of four SNPs in NAT2

Haplotype	SNP
	C282T	C481T	G590A	G857A
NAT2*4	-	-	-	-
NAT2*6A	+	-	+	-
NAT2*7B	+	-	-	+
NAT2*11	-	+	-	-
NAT2*13	+	-	-	-

Plus or minus symbols for C282T, C481T, G590A, and G857A indicate the presence or absence of SNPs.

Table 3 Clinical characteristics and laboratory data of TB patients with or without adverse effect

	Hepatotoxicity			Skin rash			Eosinophilia
Clinical data	Present	Absent	P	Present	Absent	P	Present	Absent	P
	(n = 18)	(n = 82)		(n = 25)	(n = 75)		(n = 34)	(n = 66)
Age (mean ± SD)	60.8 ± 17.7	64.7 ± 17.3	0.3942	63.6 ± 18.1	64.7 ± 17.3	0.9028	63.3 ± 19.5	64.4 ± 16.3	0.7598
Gender (M/F)	9/9	47/35	0.6081	12/13	44/31	0.3640	25/9	31/35	0.0186
Body mass index (kg/m2)	19.6 ± 2.3	20.5 ± 3.1	0.2721	19.8 ± 2.5	20.6 ± 3.1	0.2626	19.8 ± 2.9	20.6 ± 3.0	0.2684
Baseline values
ALT (IU/L)	18.0 ± 10.4	21.1 ± 16.6	0.4527	23.1 ± 25.8	19.7 ± 10.4	0.3392	25.9 ± 24.4	17.8 ± 6.8	0.6571
AST (IU/L)	29.1 ± 26.8	26.8 ± 23.3	0.7188	31.3 ± 39.2	25.9 ± 15.9	0.3268	35.4 ± 38.5	23.0 ± 7.8	0.4277
TB (mg/dL)	0.48 ± 0.19	0.64 ± 0.43	0.1115	0.61 ± 0.44	0.61 ± 0.39	0.9874	0.62 ± 0.44	0.61 ± 0.38	0.9490
Creatinine (mg/dL)	0.64 ± 0.13	0.88 ± 1.10	0.3482	0.72 ± 0.28	0.87 ± 1.13	0.5121	0.82 ± 0.47	0.84 ± 1.17	0.9092
Eosinophils (/μL)	105.1 ± 120.6	115.5 ± 121.8	0.7434	104.7 ± 93.7	116.6 ± 129.3	0.6750	141.3 ± 133.4	99.3 ± 112.6	0.1011
During TB chemotherapy
Peak ALT (IU/L)	316.2 ± 281.7	40.0 ± 19.5	< 0.0001	147.8 ± 281.7	61.6 ± 88.1	0.0245	129.6 ± 284.1	59.2 ± 75.4	0.3885
Peak AST (IU/L)	294.5 ± 353.6	36.7 ± 21.5	< 0.0001	139.7 ± 222.9	73.1 ± 128.9	0.1325	116.3 ± 175.9	76.0 ± 149.3	0.2107
Peak TB (mg/dL)	1.20 ± 1.16	0.74 ± 0.53	0.0101	0.78 ± 0.47	0.84 ± 0.77	0.7039	0.92 ± 0.89	0.77 ± 0.58	0.3241
Peak Creatinine (mg/L)	0.76 ± 0.13	0.96 ± 1.23	0.4742	0.81 ± 0.13	0.97 ± 1.28	0.5316	0.87 ± 0.31	0.96 ± 1.36	0.7098
Peak Eosinophils (/μL)	692.4 ± 929.1	461.1 ± 844.7	0.4538	668.4 ± 773.9	447.5 ± 885.1	0.0058	1028.1 ± 1327.9	232.1 ± 114.9	< 0.0001

Table 4 Distributions of NAT2-haplotypes in TB patients with and without adverse effect

	Hepatotoxicity					Skin rash					Eosinophilia
Haplotype	Present(%)	Absent(%)	OR	95% CI	P	Present(%)	Absent(%)	OR	95% CI	P	Present(%)	Absent(%)	OR	95% CI	P
NAT2*4	16 (44.4)	120 (73.2)	0.265	0.129-0.546	< 0.001	34 (68.0)	102 (68.0)	1.00	0.503-1.987	1.000	45 (66.2)	91 (68.9)	0.880	0.472-1.642	0.688
NAT2*6A	14 (38.9)	29 (17.7)	3.535	1.648-7.585	0.001	12 (24.0)	31 (20.7)	1.22	0.570-2.607	0.609	15 (22.0)	28 (21.2)	1.052	0.517-2.138	0.889
NAT2*7B	6 (16.7)	15 (9.1)	2.235	0.818-6.104	0.117	4 (8.0)	17 (11.3)	0.70	0.226-2.170	0.537	8 (11.8)	13 (9.9)	1.227	0.482-3.124	0.667
Total number	36	164				50	150				68	132

Table 5 Distribution of NAT2-diplotypes in TB patients with and without adverse effect

	Hepatotoxicity					Skin rash					Eosinophilia
Diplotype	Present(%)	Absent(%)	OR	95% CI	P	Present(%)	Absent(%)	OR	95% CI	P	Present(%)	Absent(%)	OR	95% CI	P
NAT2*4/*4	4 (22.2)	42 (51.2)	0.272	0.083-0.897	0.032	12 (48.0)	34 (45.3)	1.113	0.449-2.757	0.817	14 (41.2)	32 (48.5)	0.744	0.322-1.717	0.488
NAT2*4/*6A	7 (38.9)	23 (28.1)	1.632	0.564-4.726	0.366	7 (28.0)	23 (30.7)	0.879	0.323-2.394	0.801	11 (32.4)	19 (28.9)	1.183	0.484-2.894	0.713
NAT2*4/*7B	1 (5.6)	13 (15.9)	0.312	0.038-2.555	0.278	3 (12.0)	11 (14.7)	0.793	0.203-3.108	0.740	6 (17.6)	8 (12.1)	1.554	0.492-4.909	0.453
NAT2*6A/*6A	2 (11.1)	2 (2.4)	5.000	0.655-38.152	0.121	2 (8.0)	2 (2.7)	3.174	0.423-23.812	0.261	1 (2.9)	3 (4.5)	0.636	0.064-6.360	0.700
NAT2*6A/*7B	3 (16.6)	2 (2.4)	8.000	1.230-52.023	0.029	1 (4.0)	4 (5.3)	0.74	0.079-6.945	0.792	2 (5.9)	3 (4.5)	1.313	0.209-8.257	0.772
NAT2*7B/*7B	1 (5.6)	0 (0)	-	-	-	0 (0)	1 (1.3)	-	-	-	0 (0)	1 (1.5)	-	-	-
Total number	18	82				25	75				34	66