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Hypertension Genetics

By Ronald Steriti, ND, PhD


A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism.
Overall, the C677T polymorphism was significantly associated with hypertension (H) or hypertension in pregnancy (HIP) (H & HIP: OR = 1.26, 95% CI = 1.17-1.34; H: OR = 1.36, 95% CI = 1.20-1.53; HIP: OR = 1.21, 95% CI = 1.08-1.32).
This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians. (Yang et al., 2014)


Participants included 123 Saudi hypertensive cases (83 males and 40 females) in addition to 250 (142 males and 108 females) unrelated healthy controls from the same locality.
Total cases showed significantly higher carriage rate for the mutant allele 677T compared to controls (40.7% vs. 26%, OR=1.9, 95% CI= 1.2-3.1) with a lower frequency of the wild type 677CC genotype (59.3% vs. 74%, p=0.004). The same was observed among cases-subgroups of hypertension associated with obesity with a notably higher odds ratio (OR=2.6, 95% CI=1.3-5.01, p=0.004).
Total cases showed also significantly higher frequency of mutant 1298 C allele carriage rate compared to controls (59.3% vs. 42.4%, OR=1.98, 95% CI= 1.3-3.1) with a lower frequency of the normal AA genotype (40.7% vs. 57.6%, p=0.003).
The same was observed among cases-subgroups of hypertension associated with both diabetes and obesity and among cases of hypertension with obesity, also with higher odds ratio (OR=2.6 and 2.2 respectively). (Alghasham et al., 2012)


Data on 20 qualified studies totalling 4461 Chinese subjects were meta-analyzed.
In overall allelic/genotypic models, carriers of 677T or 677TT were consistently at significantly increased risk of developing hypertension and HIP. (Niu et al., 2012)

Vitamin D Receptor (VDR)

A prospective analyses among 1,211 was conducted in US men that were free of baseline hypertension. During 15.3-year follow-up, 695 men developed incident hypertension.
After multivariable adjustment, the hazard ratios (HRs) and 95 % CIs for hypertension across increasing quartiles of plasma vitamin D metabolites were 1.00 (ref), 0.94 (0.69-1.27), 0.69 (0.50-0.96), and 0.82 (0.60-1.13) for 25(OH)D (p, trend: 0.43), and 1.00, 0.92 (0.66-1.27), 1.12 (0.82-1.54), and 1.19 (0.86-1.63) for 1,25(OH)2D (p, trend: 0.16).
Compared with carriers of VDR BsmI bb, carriers of bB or BB had a HR of 1.25 (1.04-1.51) for hypertension. For VDR FokI polymorphism, compared with carriers of FF and Ff combined, carriers of ff had a HR of 1.32 (1.03-1.70).
The relation between plasma 25(OH)D and risk of hypertension did not differ by VDR BsmI and FokI polymorphisms.
In a prospective cohort of men, evidence suggested an inverse association between plasma 25(OH)D and risk of hypertension. Associations were also found between VDR BsmI and FokI polymorphisms with hypertension risk. (Wang et al., 2013)

Vitamin D Receptor (VDR)

Two hundred and eighty clinically diagnosed hypertensive patients and 200 normotensive healthy controls were analyzed.
The genotype distribution and allele frequencies of Fok I (T/C) [rs2228570] VDR polymorphism differed significantly between patients and controls (chi(2) of 18.0; 2 degrees of freedom; P = 0.000).
FF genotype and allele F were at significantly greater risk for developing hypertension and the risk was elevated for both the sexes, cases with positive family history and habit of smoking.
VDR gene Fok I polymorphism is associated with the risk of developing essential hypertension. (Swapna et al., 2011)

Apolipoprotein A1 (APOA1)

APOA1 polymorphisms were analyzed in 334 individuals from a Brazilian elderly cohort. -75G allele showed significant association with hypertension (P = 0.001).
An association between +83C allele and obesity was observed (P = 0.040) and this allele also showed an association with hypertension in the presence of cardiovascular disease (P = 0.047). (Chen et al., 2009)

Apolipoprotein E4 (APOE4)

Overall, 12 studies with 14 study groups totalling 1532 hypertensive patients and 2172 controls were identified.
The results expand previous findings and show that ApoE varepsilon4 allele is associated with a two-fold increased risk of developing hypertension in Chinese. (Niu and Qi, 2011) (Niu et al., 2009)

Glutathione S-Transferase (GSTM1, GSTT1, GSTP1)

1015 Slovenian subjects (Caucasians) with type 2 diabetes with/without EAH were enrolled in the cross-sectional study.
GSTM1-null and GSTT1-null genotypes were found to be associated with essential arterial hypertension in patients with type 2 diabetes. (Petrovic and Peterlin, 2014)

Glutathione S-Transferase (GSTM1, GSTT1, GSTP1)

In an Italian population sample, 193 hypertensive subjects and 210 healthy controls were recruited.
Among GST polymorphisms, only the frequency of the GSTT1 null phenotype was significantly higher in hypertensive patients than in normotensive participants. GSTT1 null individuals were significantly associated with increased risk of hypertension [P < 0.001; adjusted OR 2.24 (1.43-3.50)].
In sex-based analysis, the risk was significantly higher in female hypertensives [P < 0.001; adjusted OR 3.25 (1.78-5.95)] but not in male subjects.  (Polimanti et al., 2011)

Glutathione S-Transferase (GSTM1, GSTT1, GSTP1)

A study included 40 newly-diagnosed, untreated, essential hypertensive patients and 40 normotensive subjects.
The results showed that GSTM1-ve/GSTT1-ve is a potential genetic factor to predict development of essential hypertension and permit early therapeutic intervention. (Bessa et al., 2009)

Glutathione S-Transferase (GSTM1, GSTT1, GSTP1)

GSTM1 genotype was evaluated in 49 patients with resistant hypertension and compared with selected patients with controlled hypertension (n=232) and healthy participants (n=110).
Null GSTM1 genotype occurred more frequent in patients with resistant hypertension than those with controlled hypertension (57.1 vs 39.7%; P=0.03; RR 1.96; 95% CI 1.04-3.69) suggesting that null GSTM1 genotype may predispose to resistant hypertension. (Cruz-Gonzalez et al., 2009)

Cytochrome P-450 (CYP2C9)

A study of 217 moderately hypertensive Finnish men that participated in the double-blind, cross-over, placebo-controlled GENRES Study found that the CYP2C9*3 allele was associated with lower activity of the renin-angiotensin-aldosterone system in hypertensive men, which may reflect a more efficient sodium reabsorption capacity. (Donner et al., 2009)

Aromatase (CYP19A1)

A study confirmed that rs700518 and rs10046, as well as a haplotype constructed with rs1870049 and rs10046, in the human CYP19A1 gene can be used as genetic markers for gender-specific essential hypertension. (Shimodaira et al., 2008)



Alghasham, A., et al. (2012), ‘Association of MTHFR C677T and A1298C gene polymorphisms with hypertension’, Int J Health Sci (Qassim), 6 (1), 3-11. PubMedID: 23267299
Bessa, S. S., E. M. Ali, and S. M. Hamdy (2009), ‘The role of glutathione S- transferase M1 and T1 gene polymorphisms and oxidative stress-related parameters in Egyptian patients with essential hypertension’, Eur J Intern Med, 20 (6), 625-30. PubMedID: 19782926
Chen, E. S., et al. (2009), ‘Apolipoprotein A1 gene polymorphisms as risk factors for hypertension and obesity’, Clin Exp Med, 9 (4), 319-25. PubMedID: 19408098
Cruz-Gonzalez, I., et al. (2009), ‘An association between resistant hypertension and the null GSTM1 genotype’, J Hum Hypertens, 23 (8), 556-58. PubMedID: 19279659
Donner, KM, et al. (2009), ‘CYP2C9 genotype modifies activity of the renin-angiotensin-aldosterone system in hypertensive men.’, J Hypertens, 27 (10), 2001-9. PubMedID: 19593208
Niu, W., et al. (2009), ‘The relationship between apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls’, Hypertens Res, 32 (12), 1060-66. PubMedID: 19816504
Niu, W. Q. and Y. Qi (2011), ‘Meta-based evidence for apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphism in association with hypertension among Chinese’, J Hum Hypertens, 25 (12), 725-31. PubMedID: 21228824
Niu, W. Q., Y. G. You, and Y. Qi (2012), ‘Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis’, J Hum Hypertens, 26 (4), 259-67. PubMedID: 21346782
Petrovic, D. and B. Peterlin (2014), ‘GSTM1-null and GSTT1-null genotypes are associated with essential arterial hypertension in patients with type 2 diabetes’, Clin Biochem, PubMedID: 24685594
Polimanti, R., et al. (2011), ‘Glutathione S-transferase variants as risk factor for essential hypertension in Italian patients’, Mol Cell Biochem, 357 (1-2), 227-33. PubMedID: 21656129
Shimodaira, M., et al. (2008), ‘Association study of aromatase gene (CYP19A1) in essential hypertension’, Int J Med Sci, 5 (1), 29-35. PubMedID: 18274619
Swapna, N., et al. (2011), ‘Risk conferred by FokI polymorphism of vitamin D receptor (VDR) gene for essential hypertension’, Indian J Hum Genet, 17 (3), 201-6. PubMedID: 22345993
Wang, L., et al. (2013), ‘A prospective study of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and risk of hypertension in men’, Eur J Nutr, 52 (7), 1771-79. PubMedID: 23262750
Yang, B., et al. (2014), ‘Associations of MTHFR Gene Polymorphisms with Hypertension and Hypertension in Pregnancy: A Meta-Analysis from 114 Studies with 15411 Cases and 21970 Controls’, PLoS One, 9 (2), e87497. PubMedID: 24505291



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