Genetic Polymorphisms of Endothelial Nitric Oxide Synthase Associated with Hypertension and Blood Homocysteine Levels

Figures & data

Table 1 Characteristics, Biochemical Parameters, and Lifestyle Factors of the Study Population

Characteristics	All (N = 370)	Normal Blood Pressure Group (N = 103)	High Blood Pressure Group (N = 267)
Age, years^#	58 (56–60)	58 (56–60)	58 (54–62)
BMI, kg/m^2	25.56 ± 4.13	23.89 ± 3.29	26.21 ± 4.24*
Waist circumference, cm	93.46 ± 10.74	88.96 ± 9.43	95.20 ± 10.72*
Waist-to-hip-ratio	0.94 ± 0.06	0.93 ± 0.06	0.95 ± 0.05*
Systolic blood pressure, mmHg	132.29 ± 9.04	116.98 ± 3.07	139.55 ± 9.47*
Diastolic blood pressure, mmHg	78.09 ± 4.87	70.15 ±4.15	83.66 ± 7.91*
Triglyceride, mg/dL	148.89 ± 99.23	131.96 ± 64.59	155.43 ± 109.98*
Total cholesterol, mg/dL	200.30 ± 41.75	203.76 ± 36.35	198.97 ± 43.65
LDL-C, mg/dL	133.20 ± 39.25	140.09 ± 33.92	150.54 ± 40.87*
HDL-C, mg/dL	52.43 ± 13.03	51.63 ± 13.05	52.74 ± 13.04
Fasting plasma glucose, mg/dL	101.37 ± 21.72	95.52 ± 18.09	103.62 ± 22.60
HbA1C, %	5.93 ± 0.84	5.80 ± 0.72	5.97 ± 0.88
Uric acid, mg/dL	6.29 ± 0.99	5.78 ± 1.29	6.22 ± 1.09
Blood urea nitrogen, mg/dL^#	13.35 (9.85–17.55)	13.40 (9.90–17.60)	13.20 (9.70–17.40)
Creatinine, mg/dL^#	1.00 (0.80–1.16)	0.98 (0.92–1.02)	1.00 (0.95–1.8)
HCY, µmol/L	17.87 ± 4.52	17.01 ± 5.60	18.96 ± 3.95
Smokingม N (%)
Nonsmokers	172 (46.9)	43 (41.7)	129 (48.3)
Ex-smokers	46 (12.4)	21 (20.4)	25 (9.4)
Smokers	152 (41.1)	39 (37.9)	113 (42.3)
Alcohol consumption, N (%)
Nondrinkers	72 (19.5)	23 (22.3)	49 (18.4)
Ex-drinkers	88 (23.8)	24 (23.3)	64 (24.0)
Occasional-drinkers	145 (39.2)	37 (35.9)	108 (40.4)
Current drinkers	65 (17.6)	19 (18.4)	46 (17.2)
Family history related to hypertension, N (%)
Yes	195 (52.7)	43 (41.7)	152 (56.9)
No	175 (47.3)	60 (58.3)	115 (43.1)

Notes: ^#Data were presented as median and interquartile range in parenthesis. *p < 0.05 compared with the normal blood pressure group.

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HCY, homocysteine; LDL, low-density lipoprotein; HbA1C, glycosylated hemoglobin A1C.

Table 2 Comparison Between Clinical and Biochemical Parameters Among Two Groups Based on Homocysteine Levels

Characteristics	Normal Blood Pressure Group (N = 103)		High Blood Pressure Group (N = 267)
	HCY < 15 µmol/L (N = 37)	HCY ≥15 µmol/L (N = 66)	HCY < 15 µmol/L (N = 57)	HCY ≥ 15 µmol/L (N = 210)
BMI, kg/m^2	23.67 ± 3.45	24.02 ± 3.22	25.72 ± 4.38	26.34 ± 4.20
Waist circumference, cm	87.83 ± 10.52	89.53 ± 8.78	94.49 ± 12.17	95.41 ± 10.33
SBP, mmHg	116.58 ± 8.48	122.57 ± 4.33	138.47 ± 13.62	145.57 ± 15.72*
DBP, mmHg	68.43 ± 6.34	74.13 ± 4.97	78.16 ± 9.76	82.65 ± 9.49*
Triglyceride, mg/dL	123.86 ± 16.32	130.06 ± 20.24	131.50 ± 57.78	161.91 ± 119.52*
Total cholesterol, mg/dL	168.59 ± 22.01	170.23 ± 26.31	199.80 ± 46.83	198.73 ± 42.85
LDL-C, mg/dL	119.23 ± 13.06	126.44 ± 6.41	141.02 ± 36.73	139.56 ± 32.52
HDL-C, mg/dL	53.21 ± 11.45	50.72 ± 13.87	51.89 ± 11.60	52.97 ± 13.42
Fasting blood glucose, mg/dL	99.18 ± 10.10	93.46 ± 6.14	103.49 ± 30.48	106.65 ± 20.02
HbA1C, %	5.04 ± 0.35	5.12 ± 0.53	5.95 ± 1.02	5.49 ± 0.84
Uric acid, mg/dL	6.07 ± 1.20	5.96 ± 1.13	6.38 ± 1.33	6.24 ± 1.26
Blood urea nitrogen, mg/dL^#	12.85 (9.57–15.84)	13.40 (10.33–16.41)	13.43 (10.45–16.17)	13.49 (10.21–16.48)
Creatinine, mg/dL^#	0.92 (0.82–1.00)	0.94 (0.84–1.09)	0.99 (0.84–1.13)	1.01 (0.86–1.09)

Notes: ^#Data were presented as median and interquartile range in parenthesis. *p < 0.05, compared with the HCY < 15 µmol/L group.

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HCY, homocysteine; LDL, low-density lipoprotein; HbA1C, glycosylated hemoglobin A1C.

Table 3 Analysis of the Associations Between eNOS Genotypes and Blood Pressure

SNP (rs)	Genotype	N	SBP (mmHg)	DBP (mmHg)
eNOS rs1799983	GG	249	133.85 ± 16.40	77.78 ± 8.53
	GT	105	146.90 ± 18.94*	83.01 ± 10.18*
	TT	16	153.10 ± 17.76**	88.29 ±11.50**
eNOS rs2070744	TT	210	136.44 ± 17.71	78.48 ± 9.03
	TC	158	143.48 ± 21.46*	83.96 ± 10.46*
	CC	3	153.83 ± 14.02**	87.30 ± 3.62**

Notes: *p < 0.05 and **p < 0.001 compared with rs1799983 GG and rs2070744 TT, respectively.

Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 4 Association of ENOS Polymorphisms with the Risk of Hypertension (≥ 130/80 mmHg) by Inheritance Mode (Odd Ratios Were Adjusted for BMI, WC, WHR, TG and LDL-C)

SNP	Model	Genotype	Normal Blood Pressure Group, n (%)	High Blood Pressure Group, n (%)	OR (95% CI)	P value
rs1799983	Codominant	GG	122 (85.9)	127 (55.7)	1.00	0.0001
		GT	19 (13.4)	86 (37.7)	4.49 (2.53–7.95)
		TT	1 (0.7)	15 (6.6)	15.97 (2.03–125.92)
	Dominant	GG	122 (85.9)	127 (55.7)	1.00
		GT-TT	20 (14.1)	101 (44.3)	5.05 (2.89–8.81)	0.0001
	Recessive	GG-GT	141 (99.3)	213 (93.4)	1.00
		TT	1 (0.7)	15 (6.6)	10.87 (1.39–85.12)	0.0019
	Overdominant	GG-TT	123 (86.6)	142 (62.3)	1.00
		GT	19 (13.4)	86 (37.7)	4.01 (2.37–7.08)	0.0001
	Log-additive	–	–	–	4.38 (2.61–7.36)	0.001
rs2070744	Codominant	TT	123 (86.6)	172 (75.4)	1.00
		TC	19 (13.4)	53 (23.2)	2.16 (1.19–3.90)	0.0095
		CC	0 (0)	3 (1.3)	NA
	Dominant	TT	123 (86.6)	172 (75.4)	1.00	0.0048
		TC-CC	19 (13.4)	56 (24.6)	2.26 (1.25–4.07)
	Recessive	TT-TC	142 (100)	225 (98.7)	1.00	0.12
		CC	0 (0)	3 (1.3)	NA
	Overdominant	TT-CC	123 (86.6)	175 (76.8)	1.00
		TC	19 (13.4)	53 (23.2)	2.13 (1.18–3.85)	0.0098
	Log-additive	–	–	–	2.27 (1.28–4.03)	0.0033

Table 5 Interaction Analysis of ENOS Polymorphisms with the Risk of Hypertension in Relation to Hyperhomocysteinemia (Odd Ratios Were Adjusted for BMI, WC, WHR, TG and LDL-C)

SNP		Plasma HCY < 15 µmol/L			Plasma HCY ≥ 15 µmol/L
eNOS		Normal Blood Pressure Group (N)	High Blood Pressure Group (N)	OR (95% CI)	Normal Blood Pressure Group (N)	High Blood Pressure Group (N)	OR (95% CI)
rs1799983	GG	44	23	1.00	78	104	2.43 (1.35–4.38)
	GT	7	16	4.75 (1.69–13.36)	12	70	10.58 (4.76–23.51)
	TT	1	3	6.02 (0.58–62.44)	0	12	----
p value for interaction = 0.42
rs2070744	TT	45	28	1.00	78	144	2.78 (1.60–4.82)
	TC	7	14	3.23 (1.15–9.05)	12	39	4.88 (2.18–10.93)
	CC	0	0	---	0	3	---
p value for interaction = 0.34

Abbreviations: HCY, homocysteine; OR, odd ratio.

Table 6 Haplotype Analysis of ENOS Polymorphism and Risk of Hypertension (Odd Ratios Were Adjusted for BMI, WC, WHR, TG and LDL-C)

Haplotype	Frequency	OR (95% CI)	OR (95% CI)	OR (95% CI)
		Total	Plasma HCY < 15 µmol/L	Plasma HCY ≥ 15 µmol/L
GT	0.757	1.00	1.00	2.88 (1.50–5.52)
TT	0.136	5.04 (2.70–9.41)	5.76 (1.79–18.56)	13.78 (5.68–33.45)
GC	0.057	2.46 (1.13–5.35)	8.09 (1.50–43.55)	4.70 (1.75–12.61)
TC	0.048	4.08 (1.63–10.20)	2.76 (0.63–12.06)	16.35 (3.73–71.65)
p value for global haplotype association = 0.001			p value for interaction = 0.03