Association of Heme Oxygenase-1 Gene Polymorphisms with Essential Hypertension and Blood Pressure in the Chinese Han Population

Abstract

Many studies have suggested that heme oxygenase-1 (HMOX1) might be implicated in blood pressure (BP) regulation. We hypothesized that this gene might be responsible for the variation of susceptibility to essential hypertension (EH) and BP and investigated three polymorphisms in HMOX1 (i.e., the (GT)n repeat in the HMOX1 promoter and single-nucleotide polymorphisms (SNPs) rs2071746 and rs2071749) in population-based samples of 789 Han Chinese from Xinjiang, China. The GT repeat numbers ≥33, 27-32, and <27 in the HMOX1 promoter were defined as long (L), middle (M), and short (S) alleles, respectively. The participants carrying SS or SM genotype were sorted into one group, and the participants carrying SL, MM, ML, or LL genotype were sorted into another group. The (GT)n repeat in the HMOX1 promoter showed significant association with EH and BP, whereas SNPs rs2071746 and rs2071749 did not. Compared with the SS+SM (GT)n group, the MM+SL+ML+LL (GT)n group had a lower risk of EH (adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.82; p = 0.002) and lower systolic (128.3 ± 1.3 vs. 132.2 ± 1.0 mm Hg, adjusted p = 0.014) and diastolic BPs (81.7 ± 0.8 vs. 84.5 ± 0.7 mm Hg, adjusted p = 0.009). These findings provide the first genetic evidence for the role of the (GT)n repeat in the HMOX1 promoter in the susceptibility to human EH and the variation of BP.

Introduction

Essential hypertension (EH) is a complex disorder. The multifactorial nature of this disease involves the contribution of various genetic and environmental factors as well as their possible interactions. Oxidative stress has been proposed as the cause of hypertension (Negishi et al., 2000; Rodrigo et al., 2003). Heme oxygenase-1 (HMOX1), the only inducible isoform of heme oxygenases, degrades heme and then generates free iron, biliverdin, and carbon monoxide (CO). HMOX1 induction has potent protective actions against oxidative stress-induced damage both in vitro and in vivo (Le et al., 1999; Yet et al., 2001; Zhang et al., 2002). Sabaawy et al. (2001) observed that human HMOX1 gene transfer may lower blood pressure (BP) in spontaneously hypertensive rats. HMOX1 was also found to play an important beneficial role in attenuating oxidative stress and inflammation by regulating vascular endothelial growth factor in portal hypertensive rats (Angermayr et al., 2006). Vera et al. (2007) reported that induction of HMOX1 may lower BP and superoxide production in the renal medulla of angiotensin II hypertensive mice. It had also been reported that induction of HMOX1 in vivo can suppress nicotinamide adenine dinucleotide phosphate oxidase-derived oxidative stress by mechanisms at least partly mediated by bilirubin (Datla et al., 2007).

Recently, HMOX1-derived CO has been demonstrated to play a pathological role in the development of hypertension (Durante et al., 2006; Ryter et al., 2006). CO has long been recognized to have vasodilating properties. But the endothelial-independent vasorelaxant response produced by CO has a 1000-fold less potency than that produced by nitric oxide (NO) under the same conditions. Vascular HMOX1 expression, as a compensatory response, increases during the development of hypertension, and concomitantly, the release of CO increases, which dose-dependently increases NO release from internal stores. However, high concentrations of CO inhibit NO production by inhibiting endothelial NO synthase (eNOS) activity in vessels, which causes a vasoconstrictive effect.

In this study, we selected three polymorphisms in HMOX1 and conducted association analysis to assess their effects on EH and BP in the Chinese Han population.

Materials and Methods

Study population

The study recruited 789 unrelated Han subjects from four villages of the rural area of Tulupan district in Xinjiang, China. They migrated to the current locations about 50 years ago from Jiangsu Province. All participants were invited to have a physical examination in the morning after an overnight fast. Participants were requested to avoid cigarette smoking, alcohol, tea, and exercise for at least 1 h before their BP measurements. The BP was measured using a standard mercury sphygmomanometer after having been seated for 10 min and with at least 5 min between measurements. Four BP readings were measured by two cardiologists, each taking two measures. The first reading of each physician was discarded, and the second readings of the two physicians were recorded and averaged. Ethnicity was self-reported. All participants completed a questionnaire on personal medical history and family history of hypertension. Secondary hypertension was excluded based on history and physical examination. Fasting venous blood samples from the subjects were taken for biochemical analysis. The local ethics committee approved the study, and all participants were provided written informed consent.

Participants were categorized as hypertensive (Case 1) when they had systolic BP (SBP) ≥140 mm Hg and diastolic BP (DBP) ≥90 mm Hg or were taking antihypertensive therapy. The nonhypertensives were those with both SBP and DBP below 140 mm Hg and 90 mm Hg, respectively, and without a history of hypertension. The control group was selected from the nonhypertensives to ensure that the distributions of age and gender of the controls were not statistically different from those of the hypertensive class (Case 1). Misclassification of BP as a dichotomous variable is probable among participants with BP close to 140/90 mm Hg, the cutoff point; however, participants with higher or lower BP are less likely to be misclassified. To minimize the effects of misclassification, we also tested for association using a case sample (Case 2), as a subset of Case 1 where SBP is ≥160 mm Hg or DBP is ≥100 mm Hg, to validate the association observed. The characteristics of the study population are summarized in Table 1.

Table 1.

General Characteristics of Study Participants

	Case 1	Case 2	NT	Control
n	312	215	477	369
Age, years	56.5 ± 11.4	58.7 ± 10.5^a	50.5 ± 13.3^a	55.2 ± 11.5
Men, %	41.0	42.8	38.6	42.3
BMI, kg/m²	25.6 ± 3.7^a	25.7 ± 3.8^a	24.0 ± 3.3^a	24.1 ± 3.4
WHR	0.891 ± 0.064^a	0.897 ± 0.061^a	0.863 ± 0.065^a	0.872 ± 0.064
SBP, mm Hg	157.4 ± 20.1^a	164.8 ± 18.5^a	119.8 ± 10.8^a	121.4 ± 10.3
DBP, mm Hg	98.4 ± 15.5^a	102.9 ± 16^a	76.7 ± 6.4^a	77.4 ± 6.0
GLU, mmol/L	5.85 ± 1.81^a	5.92 ± 1.72^a	5.41 ± 0.88^a	5.45 ± 0.96
TC, mmol/L	4.08 ± 0.74^a	4.09 ± 0.76^a	3.74 ± 0.70^a	3.84 ± 0.71
TG, mmol/L	1.25 ± 0.71^a	1.25 ± 0.69^a	1.02 ± 0.65^a	1.06 ± 0.68

Values shown are mean ± standard deviation.

p ≤ 0.05 compared with Control, except for NT, which is compared with Case 1.

BMI, body mass index; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; GLU, fasting glucose; TC, total cholesterol; TG, triglycerides; NT, nonhypertensive.

When BP was taken as a quantitative trait in the analysis, only untreated subjects were included. The participants without self-reported use of any type of antihypertensive medication were considered as the untreated. The proportion of untreated participants was 88.6%.

Genotyping

Three polymorphisms [i.e., the (GT)n repeat in the HMOX1 promoter and single-nucleotide polymorphisms (SNPs) rs2071746 and rs2071749] were genotyped in this study. Their information is shown in Table 2. The genotyping method is described for each polymorphism in the Supplementary Materials which are available online at www.liebertonline.com/gtmb. No deviation from Hardy-Weinberg equilibrium (HWE) was observed in all polymorphisms in cases and controls (data not shown).

Table 2.

Genotype and Allele Frequencies of Polymorphisms in the Case and Control Groups

Polymorphisms	Function	Genotype/allele	Case 1	Case 2	Control	p^a	p^b
rs2071746	Promoter region: −413^c	TT	92 (30.0)	65 (30.7)	112 (30.7)	0.970	0.999
		TA	150 (48.9)	102 (48.1)	175 (47.9)
		AA	65 (21.2)	45 (21.2)	78 (21.4)
		T	334 (54.4)	232 (54.7)	399 (54.7)	0.924	0.984
		A	280 (45.6)	192 (45.3)	331 (45.3)
(GT)n repeat	Promoter region: −198^c	Group 1 (SS+SM)	208 (68.0)	147 (69.7)	202 (56.7)	0.003	0.002
		Group 2 (MM+SL+ML+LL)	98 (32.0)	64 (30.3)	154 (43.3)
rs2071749	Intron 3	GG	158 (51.5)	107 (50.5)	185 (51.0)	0.972	0.641
		GA	121 (39.4)	89 (42.0)	143 (39.4)
		AA	28 (9.1)	16 (7.5)	35 (9.6)
		G	437 (71.2)	303 (71.5)	513 (70.7)	0.837	0.773
		A	177 (28.8)	121 (28.5)	213 (29.3)

Test for Case 1-control association.

Test for Case 2-control association.

The positions of variations correspond to positions in HMOX1 with the transcription initiation site set to 1.

Statistical analysis

Three tests, a homozygosity test (Weir, 1992), an exact test (Guo and Thompson, 1992), and a likelihood ratio test (Chakraborty et al., 1991), were performed to examine HWE for the (GT)n repeat of HMOX1, whereas a chi-square test was used to examine HWE for other polymorphisms.

Haplotypes and their frequencies were inferred using PHASE version 2.1.1 software. Based on the inferred haplotype data, we used Arlequin 3.5.1.2 (Excoffier and Lischer, 2010) to calculate |D′| and r² to measure linkage disequilibrium (LD). We adopted the MIDAS program (Gaunt et al., 2006), which yielded similar |D′| and r² compared with Arlequin 3.5.1.2.

Baseline characteristics of the cases and controls were compared using the Student's unpaired t-test for continuous data and Pearson's χ² test for categorical data. Differences in allele and genotype frequencies between cases and controls were compared using Pearson's χ² test. Logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). The analysis was performed either without or with adjustment for age, gender, body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose (GLU), total cholesterol (TC), and triglycerides (TG). One-way analysis of variance and analysis of covariance were conducted to test whether SBP and DBP varied significantly by (GT)n repeat or SNP genotypes. All aforementioned analyses were performed using the Statistical Package for Social Science (SPSS) version 15.0. A two-tailed probability value was used for all analyses, and a two-tailed probability value of ≤0.05 was considered to be significant. Statistical powers, the estimated percentages of studies that would yield a significant effect and reject the null hypothesis that OR was 1.0, were calculated using the Power and Precision version 3 program (Biostat).

Results

Baseline characteristics of participants

Table 1 shows the baseline characteristics of the case and control groups. As shown, BMI, WHR, SBP, DBP, GLU, TC, and TG were significantly higher in hypertensive subjects (Case 1 and Case 2) when compared with the controls (all p ≤ 0.001).

Polymorphisms in the HMOX1 promoter

The distribution of the number of (GT)n repeats in the HMOX1 promoter was trimodal, with one peak located at 23 GT repeats and the other two peaks located closely together at 30 and 34 GT repeats. Therefore, the allele types were grouped into three classes as previously reported (Yamada et al., 2000), namely the short alleles (S: <27 GT), middle alleles (M: 27-32 GT), and long alleles (L: ≥33 GT). SNP rs2071746 (T-413A), located 154 bases upstream of the (GT)n repeats, is another polymorphism in the promoter region of HMOX1. Similar to Japanese (Ono et al., 2003, 2004), A-30 and T-23 were the two major haplotypes of rs2071746-(GT)n repeat in Han Chinese (estimated frequencies: 30.3% and 20.5%, respectively).

As there were only 10 LL carriers among all participants and experiment showed decreasing HMOX1 promoter activity with an increasing number of GT repeats (Chen et al., 2002), the LL carriers were pooled with the ML carriers during the analysis. Considering that the difference of the HMOX1 expression between ML and MM carriers is similar to that between LL and ML carriers, we sorted LL, ML, and MM carriers into one group. Hirai et al. (2003) reported that HMOX1 mRNA expressions induced by hydrogen peroxide stimulation was significantly higher in lymphoblastoid cell lines with SS than those with LL. Further, Okamoto et al. (2006) showed that a cell with SM had higher HMOX1 expression than that with MM under ultraviolet A irradiation. Therefore, we classified the subjects carrying SS or SM GT repeats into Group 1 and the subjects carrying MM, ML, or LL GT repeats into Group 2. Given that a construct carrying more GT repeats expresses HMOX1 less efficiently than that carrying less (Chen et al., 2002), it is reasonable to assume that an SL individual expresses HMOX1 less than an SM individual and as much as an MM individual. We, therefore, classified the subjects carrying SL GT repeats into Group 2. Obviously, the HMOX1 expression of Group 1 (SS+SM) was expected to be higher than that of Group 2 (MM+SL+ML+LL).

HMOX1 polymorphisms and EH

To evaluate the association between HMOX1 polymorphisms and EH, case-control differences in the distribution of genotype and allele frequencies of the polymorphisms were tested. The results are presented in Table 2. As shown, the (GT)n repeat polymorphism at HMOX1 was significantly associated with hypertension, but SNPs rs2071746 and rs2071749 were not. In particular, Group 2 was associated with lower prevalent hypertension (OR, 0.62; 95% CI, 0.45-0.85; p = 0.003; power = 85%) and the association remained after adjustment for age, gender, BMI, WHR, GLU, TC, and TG (OR, 0.58; 95% CI, 0.41-0.82; p = 0.002) (Table 3). This association was also observed when Case 2 and the controls were compared (OR, 0.57; 95% CI, 0.40-0.82; p = 0.002; power = 87%) (adjusted OR, 0.48; 95% CI, 0.32-0.71; p = 3.17 × 10⁻⁴).

Table 3.

Estimates of the Effects of Heme Oxygenase 1 Polymorphisms on Essential Hypertension Using Logistic Regression Analysis

		Case 1-Control				Case 2-Control
Polymorphisms	Genotype/allele	p	OR (95% CI)	p^a	OR (95% CI) ^a	p	OR (95% CI)	p^a	OR (95% CI) ^a
rs2071746	TT	0.970^b	1	0.986^b	1	0.999^b		0.933^b	1
	TA	0.812	1.04 (0.73-1.48)	0.927	1.02 (0.70-1.48)	0.983	1.00 (0.68-1.49)	0.807	1.05 (0.69-1.61)
	AA	0.948	1.01 (0.66-1.56)	0.939	0.98 (0.62-1.55)	0.981	0.99 (0.62-1.60)	0.904	0.97 (0.58-1.62)
	T		1		1		1		1
	A	0.925	1.01 (0.82-1.25)	0.954	0.99 (0.79-1.24)	0.985	1.00 (0.79-1.26)	0.940	0.99 (0.77-1.28)
(GT)n repeat	Group 1 (SS+SM)		1		1		1		1
	Group 2 (MM+SL+ML+LL)	0.003	0.62 (0.45-0.85)	0.002	0.58 (0.41-0.82)	0.002	0.57 (0.4-0.82)	3.17 × 10⁻⁴	0.48 (0.32-0.71)
rs2071749	GG	0.972^b	1	0.859^b	1	0.642^b	1	0.796^b	1
	GA	0.955	0.99 (0.72-1.37)	0.609	0.91 (0.65-1.29)	0.686	1.08 (0.75-1.54)	0.857	1.04 (0.7-1.53)
	AA	0.813	0.94 (0.55-1.61)	0.941	1.02 (0.57-1.82)	0.470	0.79 (0.42-1.5)	0.554	0.81 (0.4-1.64)
	G		1		1		1		1
	A	0.841	0.98 (0.77-1.23)	0.824	0.97 (0.76-1.25)	0.775	0.96 (0.74-1.25)	0.759	0.96 (0.72-1.27)

Adjusted for age, gender, BMI, WHR, GLU, TC, and TG.

p-Value for omnibus test of genotype distribution.

OR, odds ratio; CI, confidence interval.

HMOX1 polymorphisms and BP

We next examined the association of the three HMOX1 polymorphisms with the BP (SBP and DBP) as a quantitative trait in the untreated Han participants. As shown in Table 4, Group 2(MM+SL+ML+LL), in comparison with Group 1 (SS+SM), showed a strong trend for a lower SBP (p = 0.097) (though not statistically significant) and significantly lower DBP (p = 0.035) in an unadjusted analysis. After an adjustment for age, gender, BMI, WHR, GLU, TC, and TG, Group 2 showed significantly lower SBP and DBP (128.3 and 81.7 mm Hg) than Group 1 (132.2 and 84.5 mm Hg) (p = 0.014 and 0.010, respectively). No significant SBP and DBP alterations were found among the groups stratified by genotype of SNPs rs2071746 and rs2071749.

Table 4.

Blood Pressure Stratified by Genotypes Among Untreated Participants

		SBP (mm Hg)		DBP (mm Hg)
Markers and genotypes	n	Unadjusted	Adjusted ^a	Unadjusted	Adjusted ^a
rs2071746
TT	211	130.6 ± 1.5	130.3 ± 1.4	82.7 ± 0.8	82.7 ± 0.9
TA	336	131.5 ± 1.2	131.4 ± 1.1	83.9 ± 0.8	84.0 ± 0.7
AA	143	129.9 ± 1.8	129.6 ± 1.7	83.2 ± 1.1	83.0 ± 1.1
p-Value		0.738	0.607	0.627	0.538
(GT)n repeat
Group 1 (SS+SM)	424	132.0 ± 1.1	132.2 ± 1.0	84.3 ± 0.7	84.5 ± 0.7
Group 2 (MM+SL+ML+LL)	256	129.2 ± 1.2	128.3 ± 1.3	82.0 ± 0.7	81.7 ± 0.8
p-Value		0.097	0.014	0.035	0.010
rs2071749
GG	366	130.7 ± 1.2	131.2 ± 1.1	83.3 ± 0.7	83.6 ± 0.7
GA	260	131.6 ± 1.3	130.6 ± 1.2	84.0 ± 1.0	83.6 ± 0.8
AA	62	129.5 ± 2.5	129.4 ± 2.5	82.6 ± 1.6	83.0 ± 1.7
p-Value		0.761	0.791	0.706	0.954

Values of SBP and DBP are mean ± standard error.

Adjusted for age, gender, BMI, WHR, GLU, TC, and TG.

Discussion

In the present study, we genotyped the (GT)n repeat and SNPs rs2071746 and rs2071749 of the HMOX1 gene in the Han population and observed that the (GT)n repeat in the HMOX1 promoter was significantly associated with EH and BP (both SBP and DBP), whereas the other two SNPs were not. To our knowledge, there were no previous studies on the association of the (GT)n repeat in the HMOX1 promoter with EH and BP until now.

In this study, Group 2 consisting of the subjects carrying MM, SL, ML, or LL GT repeats at the HMOX1 (GT)n repeat polymorphism was found to be associated with low prevalence of hypertension in the Han population. The classifications of the HMOX1 (GT)n repeats vary among studies, most lacking convincing explanation. On the basis of previous association and function studies as well as our genotyping result, we divided the participants into two groups and proposed that the HMOX1 expression of Group 1 consisting of the subjects carrying SS or SM GT repeats might be higher than that of Group 2. We conjectured that vascular HMOX1 expression and the release of CO of Group 1 may increase excessively in the presence of oxidative stress or other bad conditions, which could inhibit eNOS and finally cause vessel constriction. On the contrary, HMOX1 expression of Group 2 may increase moderately in the presence of oxidative stress or other bad conditions, which may release CO and increase NO released from internal stores, but not inhibit eNOS activity. NO together with CO could cause vessel vasodilation. Thus, the risk of hypertension of Group 1 may increase, whereas that of Group 2 may decrease. Nevertheless, further investigations are needed to confirm the rationality of the present classification and mechanism postulated above.

The AA genotype of SNP rs2071746 (T-413A), another polymorphism in the promoter region of HMOX1, has been shown to be associated with an increased incidence of hypertension in Japanese women (Ono et al., 2003). However, this association could not be validated in this study, even stratified by gender (data not shown). In a meta-analysis of the two studies, rs2071746 did not show association with EH even stratified by gender (data not shown). SNP rs2071746 was not included in any published genome-wide association study (GWAS) of hypertension and/or BP. We also searched the SNPs in or near HMOX1, which are in strong LD with rs2071746 (r² > 0.8) in the HapMap populations, in published GWAS of hypertension and/or BP. One published GWAS of hypertension and/or BP has evaluated SNP rs2269533, which is in strong LD with rs2071746 (r² > 0.8) in the HapMap European American in Utah (CEU), Han Chinese in Beijing (CHB), and Japanese in Tokyo (JPT) populations (Adeyemo et al., 2009). However, it failed to detect rs2269533 as associated with hypertension and BP.

The A-30 and T-23 haplotypes were the two major haplotypes of rs2071746-(GT)n repeat in HMOX1 in the Han population of this study and Japanese population. A luciferase reporter assay conducted by Ono et al. (2003) indicated that the promoter carrying the A-30 haplotype had eightfold greater activity than the T-23 haplotype. Later, Ono et al. (2004) renewed their assay by showing that the promoter activities of the A-30 and A-23 haplotypes were significantly higher than those of the T-23 and T-30 haplotypes, which led to the conclusion that the T-413A polymorphism might be responsible for the promoter activity. Notably, unlike the functional experiments of the (GT)n repeat, which have been mentioned in the Results section, Ono et al. only measured the basal promoter activities without any stimulation and only performed luciferase reporter assays, which are less perfect than the assays using human cells carrying different (GT)n repeats. The T-413A polymorphism may only affect the basal HMOX1 level, but it may not necessarily lead to varied HMOX1 expression under stimulation. Further functional experiments are necessary to make sure how the promoter activities of the A-30 and T-23 haplotypes change after hydrogen peroxide or other stimulation.

The present study showed that SNP rs2071749 was not associated with EH, which is consistent with the findings of Yun et al. (2009). SNP rs2071749 was also included in seven published GWASs of hypertension and/or BP (Burton et al., 2007; Adeyemo et al., 2009; Levy et al., 2009; Newton-Cheh et al., 2009; Org et al., 2009; Sabatti et al., 2009; Zhang et al., 2009). However, all of them failed to detect rs2071749 as associated with hypertension and BP.

The two SNPs (i.e., rs2071746 and rs2071749) in the present study were able to capture 5 of 8 (62.5%) common SNPs of HMOX1 (chromosome 22: 34102087-34122194 bp) at r² > 0.80, and 8 of 8 (100%) of HMOX1 at r² > 0.65, when the Han Chinese population in the HapMap was used as a reference (HapMap release 24, November 2008, NCBI Build 36). Therefore, we did not examine comprehensively all common SNPs spanning across HMOX1. We recognize that there may be additional variants in HMOX1 that may affect the susceptibility to EH, such as SNP rs9607267 in intron 2 (Yun et al., 2009). However, the present study included the (GT)n repeat in the HMOX1 promoter, which is an important and known functional common variant, and first investigated its effects on EH and BP.

In summary, the present study showed that the (GT)n repeat in the HMOX1 promoter is associated with EH, SBP, and DBP. These observations, if confirmed, may provide new clues to further explore the etiology of EH and regulation of BP.

Footnotes

Acknowledgments

This work was supported by grants from the National Outstanding Youth Science Foundation of China (30625016), National Science Foundation of China (30890034), 863 Program (2007AA02Z312), the National Natural Science Foundation of China (30500291), and the Science and Technology Commission of Shanghai Municipality (04dz14003). L. Jin was also supported by the Center for Evolutionary Biology and Shanghai Leading Academic Discipline Project (B111).

Disclosure Statement

No competing financial interests exist.

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