Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22

<jats:p><jats:italic>Background</jats:italic>. The coronary heart disease (CHD) risk locus on 21q22 (lead SNP rs9982601) lies within a “gene desert.” The aim of this study was to assess if this locus is associated with CHD risk factors and to identify the functional variant(s) and gene(s) involved.<jats:italic>Methods</jats:italic>. A phenome scan was performed with UCLEB Consortium data. Allele-specific protein binding was studied using electrophoretic mobility shift assays. Dual-reporter luciferase assays were used to assess the impact of genetic variation on expression. Expression quantitative trait analysis was performed with Advanced Study of Aortic Pathology (ASAP) and Genotype-Tissue Expression (GTEx) consortium data.<jats:italic>Results</jats:italic>. A suggestive association between QT interval and the locus was observed (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi mathvariant="normal">r</mml:mi><mml:mi mathvariant="normal">s</mml:mi><mml:mn mathvariant="normal">9982601</mml:mn><mml:mo> </mml:mo><mml:mo> </mml:mo><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.04</mml:mn></mml:math>). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:math>= 4.82 × 10<jats:sup>−3</jats:sup>) compared to the common allele. The minor allele of rs9982601 was associated with higher expression of the closest upstream genes (<jats:italic>SLC5A3</jats:italic>1.30-fold increase<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:math>= 3.98 × 10<jats:sup>−5</jats:sup>;<jats:italic>MRPS6</jats:italic>1.15-fold increase<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:math>= 9.60 × 10<jats:sup>−4</jats:sup>) in aortic intima media in ASAP. Both rs9982601 and rs28451064 showed a suggestive association with<jats:italic>MRPS6</jats:italic>expression in relevant tissues in the GTEx data.<jats:italic>Conclusions</jats:italic>. A candidate functional variant, rs28451064, was identified. Future work should focus on identifying the pathway(s) involved.</jats:p>