| Izvleček: | <p><b>Introduction:</b> Genome-wide association studies for many cardiovascular traits have primarily identified common variants with small effects, explaining only a small percentage of the total trait variance. The missing heritability may in part be explained by rare variants.</p> <p><b>Methods:</b> The Exome chip includes ~250,000 rare, low-frequency and common variants, thus enables the investigation of rare variant associations.</p> <p>Within large international consortia, we have led Exome chip analyses for blood pressure (BP) and heart rate (HR) in a total of ~350,000 and ~240,000 individuals, respectively.</p> <p><b>Results:</b> We identified 31 novel genetic regions associated with BP or hypertension, including rare missense variants in <i>RMB47</i>, <i>COL21A1</i> and <i>RRAS</i> with larger effects on BP than reported common variants, and <i>A2ML1</i>, a gene containing multiple rare variant associations.</p> <p>A novel low-frequency nonsense variant was identified in ENPEP, which encodes the APA enzyme of the renin-angiotensin-aldosterone system. ENPEP is a therapeutic target, and an ENPEP inhibitor is currently being tested in Phase IIa clinical trials for hypertension.</p> <p>For HR we identified nine novel loci, and new independent associations at some of the 21 published loci.</p> <p><b>Conclusions:</b> We have discovered 40 new loci for BP or HR. Of potential interest is an overlap between genetic associations for BP and HR.</p> <p>An association at MYH6, a new BP locus, is a published association for HR. RNF207 is a novel locus for both BP and HR, and is a published association for QT interval.</p> <p>This suggests there may be some similarities in underlying biological mechanisms, and may inform therapeutic strategies.</p>
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