Sage Journals: Discover world-class research

Abstract

Introduction:

The aldosterone synthase (CYP11B2)-344T>C gene polymorphism has been reported to influence the risk of atrial fibrillation (AF) in many studies; however, the results remain controversial and ambiguous.

Materials and methods:

We therefore carried out a meta-analysis of published case-control studies to investigate the association between CYP11B2-344T>C polymorphism and AF susceptibility. Electronic searches were conducted on links between this variant and AF in several databases. Odds ratios (ORs) and 95% confidence intervals (CIs) for homozygous, dominant model, recessive model and allele were calculated to estimate the strength of associations in fixed and random effect models. Heterogeneity and publication bias were also assessed.

Results:

A total of nine case-control studies were identified. The C allele was associated with an increased susceptibility risk of AF compared with the T allele among hypertension populations (OR=1.26; 95% CI=1.09–1.45). The contrast of homozygotes and the recessive model produced the same pattern of results as the allele contrast. In the hypertension population, a significant association was found for the genetic models that were examined.

Conclusions:

Our pooled data suggest a significant association exists between CYP11B2-344T>C polymorphism and AF among hypertension populations.

Keywords

Angiotensin-converting enzyme gene CYP11B2 atrial fibrillation polymorphisms meta-analysis

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased mortality and morbidity.¹ However, the etiology of most cases of AF remains unknown due to probable multifactorial mechanisms of pathogenesis. AF is likely influenced by the genetic background.^2–4 AF often occurs in association with hypertension, coronary heart disease, valvular heart disease, and heart failure.⁵

In addition to regulating sodium balance and volume homeostasis, aldosterone, the principal mineralocorticoid hormone, also plays a major role in the cardiac fibrosis and remodeling.^6,7 The aldosterone synthase (CYP11B2) gene (a 9-exon gene localized to chromosome 8q22) contains a common -344T>C polymorphism (a thymidine-to-cytosine substitution) within its promoter region (rs1799998).⁸ The C allele has been associated with increased binding to steroidogenic transcription factor 1⁹ and with increased aldosterone synthase activity.^10,11

However, the role of CYP11B2-344T>C polymorphsim in the development of AF has been investigated with conflicting results. Previous studies have suggested an association between the CYP11B2-344T>C polymorphism with an increased risk of AF.^12–14 However, other studies have failed to confirm such an association.^15,16 The exact relationship between the CYP11B2-344T>C polymorphism and susceptibility to AF is not entirely established. Therefore, we performed a meta-analysis of all eligible studies to derive a more precise estimation of the association between the CYP11B2-344T>C polymorphism and AF.

Methods

Publication search and data extraction

The electronic databases PubMed, Embase, Web of Science, and CNKI (China National Knowledge Infrastructure) were searched for studies to include in the present meta-analysis, using the terms: ‘‘aldosterone synthase,’’ ‘‘CYP11B2,’’ ‘‘genotype,’’ ‘‘-344T>C,’’ ‘‘atrial fibrillation,’’ and ‘‘polymorphism.’’ An upper date limit of 31 March 2014 was used, but no earlier date limit was applied. Articles included in the meta-analysis were in any language, studied human subjects, were published in the primary literature and had no obvious overlap of subjects with other studies. We excluded studies with the same data or overlapping data by the same authors. Only published studies with full text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was used in this meta-analysis.

The following information was extracted from each study: first author, year of publication, ethnicity of study population, and the number of cases and controls for the -344T>C genotype. We did not define a minimum number of patients as a criterion for inclusion of a study in our meta-analysis. The studies included had to meet the following criteria: (a) evaluation of the CYP11B2 -344T>C polymorphism and AF risk; (b) case-control study (AF group vs control group).

Statistical analysis

The meta-analysis examined the overall association for the allele contrasts, the contrast of homozygotes, and the recessive and dominant models. The effect of the association was indicated as an odds ratio (OR) with its corresponding 95% confidence interval (CI). Pooled OR was estimated using fixed and random effects models. Heterogeneity between studies was tested using the Q statistic. Heterogeneity was considered statistically significant if p<0.10. Heterogeneity was quantified using the I² metric, which was independent of the number of studies in the meta-analysis (I²<25% no heterogeneity; I² = 25–50% moderate heterogeneity; and I²>50% large or extreme heterogeneity). Begg’s funnel plot and Egger’s test were performed to assess the publication bias in the literature. Hardy-Weinberg equilibrium (HWE) was checked in the control group of the eligible studies by the chi-square test. All calculations were performed using STATA 10.0.

Results

Study characteristics

We found 11 published articles addressing the relationship between CYP11B2-344T>C and AF.^12
–22 The studies were published between 2008–2014 (see Table 1). The Orenes-Pinero et al. study did not contain available genotype data in AF cases for estimating an OR and 95% CI.²² This study was excluded from this meta-analysis. Ten studies were conducted in various populations of different ethnicities: eight studies were conducted in Chinese populations, one study was in an African American population,²¹ and one study was in a Caucasian population.¹⁷ Four studies were conducted in hypertension populations.^15,16,18,19 In a study of the -344T>C polymorphism,¹⁷ the distribution of genotypes in the control group was not in HWE (p<0.05), indicating genotyping errors and/or population stratification (Table 1). This study was excluded from this meta-analysis to clarify the effect of CYP11B2-344T>C on the risk of AF.

Table 1.

Study characteristics.

First author	Year	Country	Source of controls	Ethnicity	Sample size		Genotype frequency of cases/controls			HWE
					Cases	Controls	TT	TC	CC
Amir¹⁷	2008	Israel	Population	Caucasian	63	270	13/54	25/152	25/64	0.036
Bress²¹	2013	USA	Heart failure	African American	37	157	22/109	10/46	5/2	0.237
Hu¹²	2011	China	Population	Asian	115	123	56/77	48/41	11/5	0.875
Huang¹⁸	2009	China	EH	Asian	97	529	44/266	43/223	10/40	0.471
Jin¹⁹	2012	China	EH	Asian	202	200	75/68	78/105	49/27	0.174
Lei¹³	2013	China	Population	Asian	150	150	68/90	75/56	7/4	0.169
Sun¹⁵	2011	China	EH	Asian	310	310	130/150	157/138	23/22	0.196
Wang¹⁶	2011	China	EH	Asian	405	398	150/136	156/208	99/54	0.067
Zhang¹⁴	2009	China	Population	Asian	120	120	56/75	59/43	5/2	0.131
Zhang²⁰	2012	China	Population	Asian	193	297	97/139	77/122	19/36	0.254

EH: essential hypertension; HWE: Hardy-Weinberg equilibrium.

The studies provided 1629 cases and 2284 controls for -344T>C. For the whole case groups, the frequency of TT-homozygous individuals was 42.8%. However, 43.2% of TC-heterozygous individuals and 14.0% of CC-homozygous individuals displayed the -344T>C polymorphism. In whole control groups, the frequencies of TT-homozygous individuals, TC-heterozygous individuals, and CC-homozygous individuals were 48.6%, 43.0%, and 8.4%, respectively. The 344T allelic frequencies in the case and control groups were 64.4% and 70.1%, respectively.

Meta-analysis results

All comparisons were listed in Table 2. Overall, the C allele was significantly associated with a increased risk of AF compared with the T allele (OR=1.26; 95% CI=1.09–1.45). The contrast of homozygotes and the recessive model produced similar results. Moderate heterogeneity (I²=43%, p=0.08) was detected among the nine studies. To eliminate heterogeneity, we divided the nine studies into different source of controls and ethnic subgroups. Subsequently, heterogeneity disappeared in subgroups of hypertension subjects, which revealed that most of the studies could not be grouped. In the analysis stratified by hypertension subjects, the C allele was associated with an increased susceptibility risk of AF compared with the T allele (OR=1.18; 95% CI=1.04–1.33). No heterogeneity (I²=0%, p=1.0) was detected among the four studies. The contrast of homozygotes and the recessive model produced the same pattern of results as the allele contrast.

Table 2.

Odds ratios (ORs) and heterogeneity results for the genetic contrasts of CYP11B2-T344C polymorphisms for atrial fibrillation (AF).

	Population	OR			I² (%)	p value
		Fixed effects (95% CI)	Random effects (95% CI)	p		Q test
Alleles	All	1.22 (1.10–1.35)	1.26 (1.09–1.45)	0.001	43	0.08
	Chinese	1.20 (1.09–1.33)	1.23 (1.07–1.41)	0.003	40	0.11
	EH	1.18 (1.04–1.33)	1.18 (1.04–1.33)	0.01	0	1
Homozygous (CC vs TT)	All	1.54 (1.22–1.93)	1.64 (1.15–2.32)	0.006	44	0.07
	Chinese	1.48 (1.17–1.86)	1.48 (1.12–1.94)	0.005	17	0.30
	EH	1.54 (1.18–2.03)	1.54 (1.17–2.03)	0.002	0	0.86
Recessive model (CC vs TT and TC)	All	1.66 (1.34–2.06)	1.68 (1.17–2.40)	0.005	52	0.03
	Chinese	1.61 (1.29–1.99)	1.55 (1.14–2.10)	0.006	37	0.13
	EH	1.76 (1.37–2.26)	1.70 (1.24–2.32)	0.0009	29	0.24
Dominant model (CC and TC vs TT)	All	1.17 (1.02–1.33)	1.23 (0.99–1.52)	0.02	57	0.02
	Chinese	1.16 (1.01–1.32)	1.22 (0.97–1.52)	0.09	61	0.01
	EH	1.04 (0.88–1.24)	1.04 (0.84–1.29)	0.69	31	0.23

CI: confidence interval; EH: essential hypertension.

Publication bias

Begg’s funnel plot and Egger’s test were performed to assess the publication bias in the literature. Evaluation of publication bias for the 344C allele versus the T allele showed that the Egger test was not significant (p=0.323). These results do not indicate a potential for publication bias.

Discussion

Genetic susceptibility to AF has been the focus of research in the scientific community. Recently, genetic variants of the CYP11B2 gene have received attention in the etiology of AF.^12–21 It has been demonstrated that the CYP11B2 gene is expressed in human cardiovascular tissue, so that high expression of the aldosterone synthase gene may cause a high tissue aldosterone concentration, which subsequently causes atrial fibrosis, conduction heterogeneity, and increases the substrate for the development of AF. The role of CYP11B2-344T>C polymorphsim in the development of AF has been investigated with conflicting results. The sample size, difference of cardiovascular disease, and ethnicity may explain the different result. This meta-analysis summarized all of the available data on the association between CYP11B2-344T>C and AF, including a total of 1629 cases and 2284 controls. Our results indicate evidence for an association between CYP11B2-344T>C and the risk of pathogenesis in AF. In the hypertension population, a significant association was found for the genetic models that were examined. In addition, heterogeneity disappeared when the population was viewed as separate groups, which suggested that the effect of the C allele on the risk of AF might be in association with hypertension. Genetic variation of the CYP11B2 gene has been demonstrated to affect the transcription of CYP11B2 in vitro,⁹ can modulate the expression of the enzyme,¹⁰ and has been linked to increased aldosterone production as well as increased serum aldosterone level.²⁴ Aldosterone plays a major role in the cardiac fibrosis and remodeling.^6,7

In an effort to shed light on the impact of CYP11B2-344T>C on AF, the data were pooled from available published trials for meta-analysis. A previous meta-analysis displayed several errors.²³ Firstly, Hu et al. had updated their research in 2011,¹² so that 115 cases were included in our study. Secondly, some studies were not included in that analysis. Thirdly, the Amir et al. study was included in that analysis,¹⁷ whose distributions of genotypes in the control groups were not in HWE.

Heterogeneity is a potential problem when interpreting the results from any meta-analysis. Heterogeneity can result from study differences such as the selection of controls, age distribution, and lifestyle factors. There are major differences in the genetic background within the different populations that have been studied. Therefore, further investigation is required to assess further stratifications.

Considering the limitations of this meta-analysis, our results should be interpreted with caution. Firstly, our results are based on unadjusted estimates. A more precise analysis should be conducted using individual data, which would allow researchers to adjust covariates including age, ethnicity, and different cardiovascular disease. Secondly, other genes encoding ion channels, angiotensinogen and angiotensin-converting enzyme (ACE) may also modulate the risk of AF.

In conclusion, our pooled data suggest evidence for a major role of CYP11B2-344T>C in the pathogenesis of AF among hypertension populations.

Footnotes

Conflict of interest

The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence their work, there is no professional or other personal interest of any nature or kind in any product, service and company that could be construed as influencing the position presented in, or the review of, the article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Fye

. Tracing atrial fibrillation–100 years. N Engl J Med 2006; 355: 1412–1414.

Tsai

Lai

Lin

. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 2004; 109: 1640–1646.

Ogimoto

Hamada

Nakura

. Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy. J Hum Genet 2002; 47: 184–189.

Tsai

Hwang

Chiang

. Renin-angiotensin system gene polymorphisms and atrial fibrillation: A regression approach for the detection of gene-gene interactions in a large hospitalized population. Cardiology 2008; 111: 1–7.

Fatkin

Otway

Vandenberg

. Genes and atrial fibrillation: A new look at an old problem. Circulation 2007; 116: 782–792.

Weber

Brilla

Campbell

. Myocardial fibrosis: Role of angiotensin II and aldosterone. Basic Res Cardiol 1993; 88: S107–S124.

Funck

Wilke

Rupp

. Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol 1997; 432: 35–44.

White

Hautanen

Kupari

. Aldosterone synthase (CYP11B2) polymorphisms and cardiovascular function. J Steroid Biochem Mol Biol 1999; 69: 409–412.

White

Slutsker

. Haplotype analysis of CYP11B2. Endocr Res 1995; 21: 437–442.

10.

Brand

Chatelain

Mulatero

. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension 1998; 32: 198–204.

11.

White

Rainey

. Editorial: Polymorphisms in CYP11B genes and 11-hydroxylase activity. J Clin Endocrinol Metab 2005; 90: 1252–1255.

12.

Chen

Peng

. Relation between aldosterone synthase gene polymorphism and atrial fibrillation in Chinese elderly Han population. Zhonghua Lao Nian Xin Xue Guan Bing Za Zhi 2011; 13: 347–348.

13.

Lei

Zhang

Ding

. Association of aldosterone synthase ( CYP11B2) gene-344 C/T polymorphism with atrial fibrillation in the Tujia population in China. Wuhan Da Xue Xue Bao 2013; 34: 381–384.

14.

Zhang

Min

Zen

. Association of aldosterone synthase gene -344C/T polymorphism with atrial fibrillation. Lin Chuang Xin Xue Guan Bing Za Zhi 2009; 25: 919–922.

15.

Sun

Yang

Hou

. Relationship between -344T/C polymorphism in the aldosterone synthase gene and atrial fibrillation in patients with essential hypertension. J Renin Angiotensin Aldosterone Syst 2011; 12: 557–563.

16.

Wang

Jin

Zheng

. The relationship between polymorphism of aldosterone synthase gene–344T/C and AF in patients with EH. Zhonghua Lao Nian Xin Xue Guan Bing Za Zhi 2011; 13: 205–207.

17.

Amir

Paz

. Aldosterone synthase gene polymorphism as a determinant of atrial fibrillation in patients with heart failure. Am J Cardiol 2008; 102: 326–329.

18.

Huang

Gai

Yang

. Functional polymorphisms in ACE and CYP11B2 genes and atrial fibrillation in patients with hypertensive heart disease. Clin Chem Lab Med 2009; 47: 32–37.

19.

Jin

Wang

Liu

. Relation between aidosterone synthase gene T-344C polymorphism and atrial fibrillation. Zhong Wai Jian Kang Wen Zhai 2012; 9: 59–60

20.

Zhang

Liu

. Association of angiotensin-converting enzyme gene I/D and CYP11B2 gene -344T/C polymorphisms with lone atrial fibrillation and its recurrence after catheter ablation. Exp Ther Med 2012; 4: 741–747.

21.

Bress

Han

Patel

. Association of aldosterone synthase polymorphism (CYP11B2–344T>C) and genetic ancestry with atrial fibrillation and serum aldosterone in African Americans with heart failure. PLoS One 2013; 8: e71268.

22.

Orenes-Piñero

Hernández-Romero

Romero-Aniorte

. Prognostic value of two polymorphisms in non-sarcomeric genes for the development of atrial fibrillation in patients with hypertrophic cardiomyopathy. QJM 2014; 107: 613–621.

23.

Zhou

. CYP11B2 T-344C gene polymorphism and atrial fibrillation: A meta-analysis of 2,758 subjects. PLoS One 2012; 7: e50910.

24.

Pojoga

Gautier

Blanc

. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens 1998; 11: 856–860.

Relationship between CYP11B2 -344T>C polymorphsim and atrial fibrillation: A meta-analysis

Abstract

Introduction:

Materials and methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Publication search and data extraction

Statistical analysis

Results

Study characteristics

Meta-analysis results

Publication bias

Discussion

Footnotes

Conflict of interest

Funding

References