RAAS and adrenergic genes in heart failure: Function, predisposition and survival implications

Table 1 Effect of adrenergic gene polymorphisms on the predisposition to patients with heart failure

Gene/SNP	Ref.	Cases/controls	Ethnic group	Association	Risk allele frequency
β adrenergic receptor type 1
Arg389Gly	[50]	201/141	Mixed	No	0.74 vs 0.76
	[51]	256/230	Italian	No	0.69 vs 0.73
	[52]	189/378	Italian	Yes	0.74 vs 0.67
	[53]	91/119	Japanese	No	0.80 vs 0.81
	[54]	78/84	African-American	No	0.52 vs 0.56
	[54]	81/105	Caucasians	No	0.74 vs 0.76
	[55]	426/395	French	No	0.77 vs 0.75
	[56]	403/429	South Africans	No	0.70 vs 0.69
	[57]	260/230	Italian	No	0.69 vs 0.73
Ser49Gly	[50]	201/141	Mixed	No	0.15 vs 0.15
	[58]	184/77	Swedish	No	0.18 vs 0.13
	[52]	189/378	Italian	Yes	0.14 vs 0.08
	[53]	91/119	Japanese	No	0.16 vs 0.16
β adrenergic receptor type 2
Gly16Arg	[51]	256/230	Italian	No	0.61 vs 0.60
	[52]	189/378	Italian	Yes	0.67 vs 0.59
	[59]	259/212	Mixed	No	0.60 vs 0.63
	[60]	520/328	Mixed	Yes	0.62 vs 0.59
Gln27Glu	[51]	256/230	Italian	No	0.32 vs 0.31
	[52]	189/378	Italian	No	0.38 vs 0.33
	[59]	259/212	Mixed	No	0.44 vs 0.42
	[60]	520/328	Mixed	No	0.42 vs 0.40
	[61]	58/111	Canadians	No	0.41 vs 0.47
Thr164Ile	[52]	189/378	Italian	No	0.02 vs 0.01
	[59]	259/212	Mixed	No	0.02 vs 0.01
	[60]	520/328	Mixed	No	0.01 vs 0.01
5’LC-Arg19Cys	[52]	189/378	Italian	No	0.36 vs 0.31
α adrenergic receptor type 2
Del 322-325	[53]	91/119	Japanese	Yes	0.04 vs 0.11
	[54]	78/84	African-Americans	Yes	0.61 vs 0.41
	[54]	81/105	Caucasians	No	0.10 vs 0.04
	[56]	403/429	South Africans	No	1.00 vs 1.00
G-protein receptor kinase 5
Gln41Leu	[35]	242/107	African-Americans	No	0.76 vs 0.77
	[35]	568/406	European-Americans	No	0.98 vs 0.99

SNP: Single nucleotide polymorphism.

Table 2 Effect of renin-angiotensin-aldosterone system gene polymorphisms on the predisposition to patients with heart failure

Gene/SNP	Ref.	Cases/controls	Ethnic group	Association	Risk allele frequency
Angiotensin-converting enzyme
I/D	[62]	214/79	Caucasian	Yes	0.58 vs 0.56
	[63]	193/77	Swedish	No	0.57 vs 0.56
	[64]	229/230	Italian	No	0.58 vs 0.60
	[65]	99/364	Caucasian	No	0.57 vs 0.54
	[66]	157/225	South-Africans	No	0.64 vs 0.69
	[67]	90/287	Czech	No	0.54 vs 0.57
	[68]	79/102	Chinese Han	No	0.43 vs 0.40
	[69]	104/183	Chinese	No	0.36 vs 0.37
	[70]	433/401	French	No	0.54 vs 0.57
	[71]	88/122	Japanese	No	0.39 vs 0.36
	[61]	58/111	Canadians	No	0.64 vs 0.62
Angiotensinogen
M235T	[66]	157/225	South-Africans	No	0.83 vs 0.87
	[72]	158/200	Czech	No	0.51 vs 0.43
	[72]	40/63 (women)	Czech	Yes	0.56 vs 0.39
	[70]	433/401	French	No	0.40 vs 0.43
	[71]	88/122	Japanese	No	0.80 vs 0.80
	[61]	58/111	Canadians	Yes	0.48 vs 0.31
T174M	[70]	433/401	French	No	0.12 vs 0.14
	[71]	88/122	Japanese	No	0.05 vs 0.10
	[61]	58/111	Canadians	Yes	0.18 vs 0.10
G(-6)A	[72]	158/200	Czech	No	0.59 vs 0.58
Angiotensin-II type 1 receptor
A1166C	[70]	433/401	French	No	0.28 vs 0.28
	[61]	58/111	Canadians	No	0.31 vs 0.33
	[73]	193/77	Swedish	No	0.29 vs 0.30
A-153G	[70]	433/401	French	No	0.16 vs 0.19
Aldosterone
T-344C	[66]	157/225	South-Africans	No	0.21 vs 0.18
	[70]	433/401	French	No	0.43 vs 0.46
	[61]	58/111	Canadians	No	0.39 vs 0.45

SNP: Single nucleotide polymorphism; T174M: Threonine to methionine substitution in position 174.

Table 3 Effect of adrenergic gene polymorphisms on survival of patients with heart failure

Ref.	Sample, design1	Endpoints	Follow-up (mo)	Mortality rate (%)	SNP	Main findings
β adrenergic receptor type 1
[15]	10402	AD, HZ	48	19	Arg389Gly	Increased survival in Arg389 homozygous treated with bucindolol
[58]	1843	AD, HT	24-60	38	Ser49Gly	Decreased survival in Ser49Ser patients
[76]	6002	AD, HZ	7-17	26	Arg389Gly	No association with endpoints
[50]	2013	AD, CD	18-62	28	Arg389Gly, Ser49Gly	Increased survival in Arg389 allele carriers on high dose beta-blockers
[77]	4443	CD, HT	41 (median)	25	Arg389Gly, Ser49Gly	No association with endpoints
[78]	2273	AD, HT	48	18	Arg389Gly, Ser49Gly	No association with endpoints
[79]	6373	AD, HT	35 (mean)	23	Arg389Gly, Ser49Gly	No association with endpoints
β adrenergic receptor type 2
[59]	2593	AD, HT	22 (mean)		Gly16Arg, Gln27Glu, Thr164Ile	Increased risk of death in Thr164Ile patients
[77]	4443	CD, HT	41 (median)	25	Gly16Arg, Thr164Ile	No association with endpoints
[78]	2273	AD, HT	48	18	Gly16Arg, Gln27Glu	Increased risk of death (haplotype)
[80]	313	AD, HT	24	3	Thr164Ile	Worsening HF in Thr164Ile patients
[81]	4433	AD	36 (median)		Thr164Ile	Improved survival in Thr164Thr patients treated with beta-blockers
α adrenergic receptor type 2
[78]	2273	AD, HT	48	18	Del322-325	No association with endpoints
[79]	6373	AD, HT	35 (median)	23	Del322-325	No association with endpoints
[82]	3453	AD, HT	60 (mean)	18	Del322-325	Reduced risk of death and end-points
G-protein kinase receptor 5
[35]	3752	AD, HT	30 (mean)		Gln41Leu	Increased survival in Leu41 African-American patients treated with beta-blockers. No impact on Caucasians

¹Study design;

²Placebo controlled randomized trial;

³Non-randomized, single group assignment. SNP: Single nucleotide polymorphism; AD: All cause mortality; CD: Cardiac mortality; HT: Heart transplantation; HZ: Hospitalizations.

Table 4 Effect of renin-angiotensin-aldosterone system gene polymorphisms on survival of patients with heart failure

Ref.	Sample, design1	Endpoints	Follow-up (mo)	Mortality rate (%)	SNP	Main findings
Angiotensinogen
[75]	822	AD, HZ	12	24	M235T	No association with endpoints
[78]	2273	AD, HT	48	18	M235T	No association with endpoints
[83]	4513	AD	48	49.7	M235T, T174M	Increased mortality in 174M patients
Angiotensin-converting enzyme
[75]	822	AD, HZ	12	24	I/D	No association with endpoints
[73]	1943	AD, HT	60	42	I/D	Increased risk of death in DD patients
[78]	2273	AD, HT	48	18	I/D	No association with endpoints
[84]	3283	AD, HT	3-38	23	I/D	Decreased survival in D allele patients untreated with beta-blockers. No differences in treated patients
[85]	4793	AD, HT	3-62	28.6	I/D	Decreased survival in D allele patients untreated with β-blockers. No differences in treated patients and decreased impact with high dose ACE inhibitors
[86]	3233	AD, HZ	10 (median)	9.6	I/D	Associated with severity of disease (NYHA class)
Angiotensin-II receptor type 1
[73]	1943	AD, HT	60	42	A1166C	Not associated with end-points. Increased risk of mortality as haplotype (ACE DD)
[75]	822	AD, HZ	12	24	A1166C	No correlation with mortality rate
[78]	2273	AD, HT	48	18	A1166C	No association with endpoints
Aldosterone
[87]	3542	AD, HZ	12	3.4	-344 T/C	Decreased survival in C allele patients. Isosorbide dinitrate and hydralazine improved composite score in TT genotype but had no impact on C allele

¹Study design;

²Placebo controlled randomized trial;

³Non-randomized, single group assignment. SNP: Single nucleotide polymorphism; AD: All cause mortality; CD: Cardiac mortality; HT: Heart transplantation; HZ: Hospitalizations; ACE: Angiotensin-converting enzyme.