Box 2.
Genetic Modulation of Important Effectors in CHF.
|
Effector
Gene |
Details |
CV
Risk |
Polymorphisms*
PHENOTYPE |
c:B:A:H (%) | Notes |
|---|---|---|---|---|---|
| AT (AGT) | Precursor for AT - I | + | M235T Inc AT levels & hypertension |
? | • More studies needed to define importance of variations in serum AT levels & AT II generation |
| Renin (REN) | Cleaves AT to AT-II | + | Hind III:Bgl 1 Probably adverse |
? | • More studies needed to define importance of variations in serum AT levels & AT II generation |
| AT – I (AGT1) | Precursor for AT - II | + | ? | ? | • ? |
| ACE (ACE) | Cleaves AT-I to AT-II Hydrolysis of bradykinin |
++ | Ins/Del Intron 16 (I/D) 50% variation in serum ACE level |
40-48 37-43 58-70 |
• Tissues ACE up to 2x higher DD>ID • Polymorphism can affect efficacy of multiple RAAS blockers |
| AT – II (AGT2) | Most potent effector Aldosterone production |
+++ | Not Know | ? | • More studies needed of serum levels and health in some groups to guide future discussions |
| ATR (AGTR1/2) | 2 main receptors | + | A1166 C Treatment resistant HT |
25 5 |
• ATR-Type 2 not well studied • Irbesartan levels could be affected |
| Aldosterone | Steroid hormone for fluid and BP regulation Potent Effector |
+++ | CYPIIB2 – key enzyme in biosynthesis ↑LV size/LVH |
? | • No know polymorphism of aldosterone gene |
| NKR (TACR 2) | Neurokinin. No mutation NK-1R. NK-2R probably relevant | Gly231Glu:Arg375His Increase cough |
? | • Identify those benefit from ATRA first line | |
| eNOS (NOS3) | Key non-protein regulator of vascular health | +++ | Asp298Glu(Glu894Asp?) Unclear – probably not as significant on its own |
22 7 |
• More studies of effects in association with other comorbidities and genetic alterations • Data on endothelial benefits of therapies could be expanded • Importance of psychosocial health on NO could be expanded |
| β1 (ADRB1) | Inotropy, chrontrophy Apoptosis and myocardial toxicity with prolonged stimulation |
+++ | Arg389Gly: Ser49GLY Adverse Gain of function: Protective |
24-34:12-16 39-46:23-28 20-30:14 31-33:20-21 |
• Regional prevalence probably worth exploring due to potential impact on CHF outcomes • Potential for lower efficacy of carvedilol not metoprolol. Other agents unclear. |
| β2 (ADRB2) | Potential cardioprotection | + | Gln27Glu:Gly16Arg Probably adverse |
25:39 19:49 9:51 |
• Unclear if added information here would be a ‘game changer’ for regional HF care • High prevalence may suggest worth exploring |
| α1 (ADRA1D) | Vasoconstriction | + | T1848A:A1905G α1a Arg347/492Cys Unclear |
46:38 12:70 |
• Unclear if added information here would be a ‘game changer’ for regional HF care |
| α2 (ADRA2C) | Potential cardiotoxicity | + | α2c Del322-325 Probably adverse |
4 43 |
• Potential racial importance when combine with β1 polymorphisms as shown in Black patients. |
| GRK (GRK5) | Potential cardiotoxicity | + | Gln41Leu Protective |
2 24 |
• Potential racial importance with benefits of ββ more marked in some blacks post-transplant |
| GNBP (GNB 3) | Potential cardiotoxicity | + | C825T Probably adverse |
39 91 |
• Potential racial importance as confounder to treatment outcomes |