Hypertension and the roles of the 9p21.3 risk locus: Classic findings and new association data

Juan E Gallo; Juan E Ochoa; Helen R Warren; Elizabeth Misas; Monica M Correa; Jaime A Gallo-Villegas; Gabriel Bedoya; Dagnóvar Aristizábal; Juan G McEwen; Mark J Caulfield; Gianfranco Parati; Oliver K Clay

doi:10.1016/j.ijchy.2020.100050

Hypertension and the roles of the 9p21.3 risk locus: Classic findings and new association data

Int J Cardiol Hypertens. 2020 Dec:7:100050. doi: 10.1016/j.ijchy.2020.100050. Epub 2020 Sep 15.

Authors

Juan E Gallo^{1

2}, Juan E Ochoa^{1

3

4}, Helen R Warren^{5

6}, Elizabeth Misas^{1

7}, Monica M Correa⁸, Jaime A Gallo-Villegas^{8

9}, Gabriel Bedoya⁷, Dagnóvar Aristizábal^{1

8}, Juan G McEwen^{1

9}, Mark J Caulfield^{5

6}, Gianfranco Parati^{3

4}, Oliver K Clay^{1

10}

Affiliations

¹ Cellular & Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia.
² Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia.
³ Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.
⁴ Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
⁵ Clinical Pharmacology Department, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁶ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Queen Mary University of London, London, UK.
⁷ Institute of Biology, Universidad de Antioquia, Medellín, Colombia.
⁸ SICOR, Medellín, Colombia.
⁹ School of Medicine, Universidad de Antioquia, Medellín, Colombia.
¹⁰ Translational Microbiology and Emerging Diseases (MICROS), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Abstract

Background: The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP).

Theory: In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus.

Results: We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a 'hypertension island' that spans less than 60 kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions.

Conclusion: Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk.

Keywords: 1 KG, 1000 Genomes Project; BP, blood pressure; Blood pressure levels; CVD, cardiovascular disease; DBP, diastolic blood pressure; EGFR, epidermal growth factor receptor; GWAS, genome wide association studi(es); Genotype-phenotype associations; Haplotypes; MAF, minor allele frequency; RAS, renin angiotensin system; SBP, systolic blood pressure; SNP, single nucleotide polymorphism; TGF-β, transforming growth factor beta; VSMC, vascular smooth muscle cell(s); bp, base pair; kb, kilobase pair.

Abstract

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