Kidney Week

Abstract: TH-OR085

Genetic and Epigenetic Analysis in Genes Affecting Mitochondrial Function Are Associated with CKD in an Older Population

Session Information

• Novel Risk Factors for CKD
  October 25, 2018 | Location: 6E, San Diego Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: CKD (Non-Dialysis)

• 1901 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention

Authors

• Mcknight, A.J., Queen's University Belfast, Belfast, United Kingdom

A.J. Mcknight, PhD



Dr McKnight is a Reader in the Centre for Public Health at Queen’s University Belfast (UK). She is a human geneticist and translational scientist whose research has focused on kidney disease for the last 18 years. Dr McKnight is the research lead for the Northern Ireland Genomic Medicine Centre and runs busy NI genomic research laboratories for inherited common, complex diseases with a focus on performing genetic-epigenetic-transcriptomic studies.

• Cappa, Ruaidhri Conall, Queen's University Belfast, Belfast, United Kingdom

Ruaidhri Conall Cappa,

• Smyth, Laura Jane, Queen's University Belfast, Belfast, United Kingdom

Laura Jane Smyth,

• Canadas Garre, Marisa, Queen's University Belfast, Belfast, United Kingdom

Marisa Canadas Garre,

• De campos, Cassio P., Utrecht University, Utrecht, Netherlands

Cassio P. De campos,

• Skelly, Ryan, Queen's University Belfast, Belfast, United Kingdom

Ryan Skelly,

• Cruise, Sharon, Queen's University Belfast, Belfast, United Kingdom

Sharon Cruise,

• Kee, Frank, Queen's University Belfast, Belfast, United Kingdom

Frank Kee,

• Mcguinness, Bernadette, Queen's University Belfast, Belfast, United Kingdom

Bernadette Mcguinness,

• Godson, Catherine, The Conway Institute of Biomolecular and Biomedical, Belfield, Dublin, Ireland

Catherine Godson,

• Maxwell, Alexander P., Queen's University Belfast, Belfast, United Kingdom

Alexander P. Maxwell,

Background

The Northern Ireland COhort for the Longitudinal study of Ageing (NICOLA) is a ten-year project exploring health and lifestyle information in 8,504 people ≥ 50 years of age via a computer assisted personal interview with an associated bioresource. Chronic kidney disease (CKD) affects ~10% of the World’s population and is more prevalent in older individuals. Optimal renal function is critically dependent upon efficient mitochondria, therefore genetic and epigenetic features that lead to mitochondrial dysfunction may influence CKD.

Methods

The discovery cohort comprised 2,567 white European individuals with body mass index ranging from 18.5 - 40 kg/m². Genotyping was performed using Illumina’s Infinium CoreExome array (n=551,839 SNPs directly typed), with data imputed to the Haplotype Reference Consortium. Methylation data was generated using Illumina’s Infinium MethylationEPIC array (866,554 features with single site resolution). PLINK and Partek Genomics Suite were employed to investigate association with eGFR, serum albumin, urea and creatinine. Replication was conducted in an independent cohort of 402 individuals.

Results

SNPs that demonstrated the most evidence for association include an exonic SNP in the mitochondrial genome MT-TL2 gene (rs2853498; A12308G; a key SNP defining mitochondrial Haplogroup U) with increased creatinine levels (P=0.000153, OR=1.185, 95% CI=1.0929-1.2812). SNPs in nuclear genes that influence mitochondrial function include rs77790196 within SLC39A1 (P= 4.4 x10^-07, OR=0.0055, 95% CI=0.0007-0.0412) and rs12564199 within JTB (P=6.6 x10^-07, OR=0.006, 95% CI=0.0008-0.0449) associated with decreased eGFR.
Analysis of epigenetic data identified eight genes demonstrating differential methylation with p<10^-08 and Δβ ±0.2, including ZBED3, ZNF672, and AHCTF1 for participants with early stage CKD compared to individuals with CKD stages 3-5.

Conclusion

These analyses have identified novel associations linking CKD with SNPs and CpG sites. This may serve as a future basis for the development of predictive multi-omic biomarkers and/or increased understanding of CKD pathogenesis.

Funding

• Private Foundation Support