Association of intron 4 VNTR polymorphism in the NOS3 gene with rapid cycling and treatment resistance in bipolar disorder: a case-control study

Hasan M. Aytac; Mustafa Pehlivan; Yasemin Oyaci; Sacide Pehlivan

doi:10.17712/nsj.2022.4.20220040

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Table 1

- Sociodemographic characteristics and the Scale Scores of BD patients.

Bipolar disorder	Mean±SD
Age	41.27±11.61
Age of onset	25.47±8.70
Duration of disease	15.93±10.71
Number of hospital	3,68±4.56
Dep. Episode	1.55±2.51
Manic episode	4.48±4.96
Total episode	6.03±5.54
HAM-D	11.36±7.47
YMRS	7.95±8.72
CGI-S	5.01±0.90
CGI-I	2.07±0.84

SD - standard deviation, hospital - hospitalization, Dep - depressive, HAM-D - Hamilton depression rating scale, YMRS - Young mania rating scale, CGI-S - clinical global impression scale-severity, CGI-I - clinical global impression scale-improvement

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Table 2

- Comparison of genotype distributions of NOS3 intron 4 VNTR variants in BD patients with the control group.

Genotypes	Bipolar disorder	Healthy control	OR	95% CI	P-value
NOS3	n=95 (%)	n=95 (%)
b/b	66 (69.5)	77 (81.1)	1.880^*	0.958-3.687^*	.064^*
b/a	25 (26.3)	17 (17.9)	0.610^*	0.304-1.223^*	.162^*
a/a	4 (4.2)	1 (1.1)	0.242^*	0.027-2.207^*	.174^*
Allele
b	157 (82.6)	171 (90)
a	33 (17.4)	19 (10)	1.892^*	1.033-3.463^*	.037^*

OR - odds ratio, CI - confidence interval,

↵* Pearson chi-square

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Table 3

- Comparison of NOS3 genotype and allele frequency distributions of rapid cycling BD patients with non-rapid cycling BD patients and the control groups.

Genotypes	Rapid cycling yes	Rapid cycling no	OR	95% CI	P-value
NOS3	n=20 (%)	n=75 (%)
b/b	9 (45)	57 (76)	0.258^*	0.092-0.722^*	.007^*
b/a	9 (45)	16 (21.3)	3.017^*	1.067-8.534^*	.033^*
a/a	2 (10)	2 (2.7)	0.247&	0.032-1.871&	.194&
Allele
b	27 (67.5)	130 (86.7)
a	13 (32.5)	20 (13.3)	3.130^*	1.389-7.049^*	.004^*
NOS3		Healthy control
b/b	9 (45)	77 (81.1)	0.191^*	0.069-0.530^*	.001^*
b/a	9 (45)	17 (17.9)	3.754&	1.347-10.466&	.016&
a/a	2 (10)	1 (1.1)	10.444&	0.899-121.379&	.078&
Allele
b	27 (67.5)	171(90)
a	13 (32.5)	19 (10)	0.231^*	0.102-0.521^*	.000^*

OR - odds ratio, CI - confidence interval,

↵* Pearson chi-square &Fisher’s Exact Test

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Table 4

- Comparison of NOS3 genotype and allele frequency distributions of treatment resistant BD patients with treatment-responsive BD patients and the control groups.

Genotypes	Treat. Res. yes	Treat. Res. No	OR	95% CI	P-value
NOS3	n=25 (%)	n=70 (%)
b/b	12 (48)	54 (77.1)	3.656	1.396-9.575^*	.007^*
b/a	11 (44)	14 (20)	0.318^*	0.119-0.850^*	.019^*
a/a	2 (8)	2 (2.9)	0.338&	0.045-2.540&	.282&
Allele
b	35 (55.1)	122 (87.1)
a	15 (44.9)	18 (12.9)	2.905^*	1.330-6.346^*	.006^*
NOS3		Healthy control
b/b	12 (48)	77 (81.1)	0.216^*	0.085-0.551^*	.001^*
b/a	11 (44)	17 (17.9)	3.605^*	1.397-9.304^*	.006^*
a/a	2 (8)	1 (1.1)	8.174&	0.710-94.097&	.110&
Allele
b	35 (55.1)	171 (63.9)
a	15 (44.9)	19 (36.1)	0.259^*	0.120-0.559^*	.000^*

Treat - treatment; Res - resistance; OR - odds ratio; CI - confidence interval,

↵* Pearson chi-square&Fisher’s Exact Test

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Table 5

- Comparison of scale scores and clinical parameters regarding the NOS3 intron 4 genotype distributions of BD patients.

Scale Scores and Clinical Parameters	(b/b) (n= 66)		(b/a, a/a) (n=29)		^*P-value
Scale Scores and Clinical Parameters	Median (min-max)	Mean±SD	Median (min-max)	Mean±SD	^*P-value
HAM-D score	9(0-31)	11.39 ±6.96	9(0-34)	11.31±8.67	.771
YMRS score	6(0-37)	7.48±8.08	1(0-35)	9.03±10.10	.575
CGI-S score	5(2-7)	4.96±0.91	5(3-6)	5.10±0.90	.297
CGI-I score	2(1-4)	1.96±0.82	2(1-4)	2.37±0.94	.037
Dep. episode	0(0-12)	1.63±2.65	0(0-9)	1.37±2.19	.604
Manic episode	2.5(0-21)	3.69±3.54	2(1-25)	6.27±6.98	.388
Total episode	4(1-23)	5.31±4.63	4(1-27)	7.65±7.03	.311
Age of onset	23.5(10-52)	25.89±9.34	24(13-44)	24.51±7.06	.647
Duration of disease	13.5(0.5-40)	14.25±9.01	18(1-40)	19.75±13.22	.081
Number of hospt.	2(0-18)	2.75±3.10	2(0-21)	5.79±6.39	.040

SD - standard deviation, min - minimum, max - maximum, CGI-S - clinical global impression scale-severity, CGI-I - clinical global impression scale-improvement, HAM-D - Hamilton depression rating scale, YMRS - Young mania rating scale, dep - depressive, hospt - hospitalization