Genetic and epigenetic analysis in genes affecting mitochondrial function are associated with chronic kidney disease in an older population

Amy Jayne McKnight, Ruaidhri Conall Cappa, Laura Jane Smyth, Marisa Cañadas Garre, Cassio P. De Campos, Ryan Skelly, Sharon Cruise, Frank Kee, Bernadette McGuinness, Catherine Godson, Alexander P. Maxwell

Research output: Contribution to conferenceAbstractpeer-review

Abstract

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.

Original languageEnglish
Publication statusPublished - 25 Oct 2018
EventAmerican Society of Nephrology Conference 2018 - San Diego Convention Centre, San Diego, United States
Duration: 23 Oct 201828 Oct 2018

Conference

ConferenceAmerican Society of Nephrology Conference 2018
Abbreviated titleASN
Country/TerritoryUnited States
CitySan Diego
Period23/10/201828/10/2018

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