Faculty school or centre title here Epigenetic Modifications

Faculty, school or centre title here Epigenetic Modifications in Essential Hypertension Ingrid Wise Faculty of Science and Technology Ph. D supervisor: Prof. Fadi Charchar Associate supervisors: Dr. Scott Nankervis and Associate Prof. Mark Myers

Clinical manifestation of hypertension - Largest single contributor to global burden of disease. - Treatment ineffecdtive in some patients. - BP = SYS ≥ 140 mm. Hg DIA ≥ 90 mm. Hg - 2 forms of hypertension: - Secondary 5 -15% - Essential 85 -95%

High blood pressure physiology Hypertension is a multifactorial polygenic condition. SNS Large arterial stiffness Cardiac output High venous return Salt & H 2 O balance

High blood pressure and the kidney Increased sodium and fluid retention RAAS SNS

Epigenetics HISTONE MODIFICATION DNA METHYLATION mi. RNAs 5’ 3’

DNA METHYLATION Modifications Nucleosome DNA Methylation 5’ A C G T A T G T T A T C G A T T T C C G A T T C G 3’

Previous research Global genomic DNA methylation Measures the amount of 5 -methyl cytosine (5 m. C) present in a DNA sample. Decreased levels of 5 m. C in peripheral blood correlated to an increase in blood pressure. Smolarek, I. et al. Medical Science Monitor Basic Research 2010, 16, CR 149 -CR 155.

Previous research Genome-wide association and replication study Identified genetic variants at 12 new loci that correlated to blood pressure modulation. Genes associated with new loci included those involved in vascular smooth muscle and renal function. DNA methylation in blood closely correlated to methylation patterns in various other tissues (liver, muscle, subcutaneous and visceral fat). Kato, N. , et al. Nature Genetics 2015, 47, 1282 -1293.

TRANSLATE study participants DNA and RNA samples • 300 human renal samples. • Tissue collected from unaffected pole of kidney. • Mixed sex, aged 30 -86 years. • Caucasian

Hypothesis Global methylation percentages within the kidney will correlate to the hypertensive phenotype.

Study 1 – Global methylation investigation: a comparison between peripheral blood and kidney tissue DNA Aim 1: Identify if methylation levels in DNA from peripheral blood and the kidney are correlated. Aim 2: Compare global methylation status in the kidney DNA between normotensive and hypertensive participants.

Study 1 – Global methylation investigation: a comparison between peripheral blood and kidney tissue DNA ELISA ASSAY Quantify the total amount of 5 m. C in a DNA sample Not loci specific

Study 1 – results to date Significant negative correlation between renal 5 m. C% and blood pressure readings. - SBP: r=-0. 25, P = <0. 05 - DBP: r=-0. 32, P = <0. 01 - Adj SBP: P = <0. 05 - Adj DBP: P = <0. 01 No significant correlation was found between peripheral blood 5 m. C% and blood pressure readings.

Ethics All participants of the TRANSLATE study provided written consent for the utilisation of their kidney tissue. Approved by local Bioethical Committee, and Material Transfer Agreement has been signed between the University of Manchester and Federation University Australia.

Thank you Study participants for their generous donations. University of Queensland Dr. Alex Nield Prof. Fadi Charchar Dr. Scott Nankervis As. Prof. Mark Myers Prof. Maciej Tomaszewski & University of Manchester Dr. Priscilla Prestes Scott Booth Michelle Maier Dr. Josh Denham

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