Epigenome-Wide Association (DNA Methylation) Study of Sex Differences in Normal Human Kidney

Abstract

Studies have identified epigenetic sex differences in several human tissues and have implicated epigenetic factors in the regulation of tissue-specific expression. Studies have also shown that women and men respond differently to various drugs, thereby influencing the pharmacokinetics, pharmacodynamics, adverse reactions, efficacy, and safety of a drug. Using Illumina Human Methylation450 BeadChip kit, we investigated the influence of sex on DNA methylation patterns in normal human kidneys (16 females and 15 males). We then related the methylome to mRNA expression levels in kidney structure/function and Drug Metabolizing Enzyme and Transporter (DMET) genes (32 females and 59 males). Our findings indicate that 429 methylated sites on autosomal chromosomes had significant sex-specific differences in the normal human kidney. Methylated sites in/near regions associated with DMET genes or with genes involved in renal structure/function and disease were identified for subsequent analysis. Validation of 2 DMETs genes (POR and ABCA3) and 2 renal structure/function/disease genes (LAMA5 and PLAT) exhibited significant sex-specific differences in mRNA expression. Our results highlight sitespecific sexual dimorphisms (epigenetic-based) in normal human kidney. Importantly, we provide a reference methylome for normal human kidney, which may be utilized to improve our understanding of renal disease and assessing the overall safety and effectiveness of a drug in the kidney.

OUP accepted manuscript

“…Given that DNAm patterns vary widely between tissues and even between cell types within a tissue ( 72 , 73 ), we examined if sCMRs discovered and validated in blood also showed significant sex differences in DNAm in other tissues and cell types. We leveraged multiple publicly available datasets of somatic tissues and regions (buccal, kidney, liver and brain— hippocampus, cerebellum, temporal lobe, occipital lobe and frontal lobe) as well as isolated blood cell types (monocytes, CD4 and CD8 T cells) ( 43–47 ). In each dataset, the DNAm levels of each sCMR were compared between males and females and sites having a Welch test P -value < 0.05 and showing the same direction of change observed in blood were deemed significant (Figure 5C and D ) ( Supplementary Table S2 ).…”

“…The consistency of sex differences in DNAm levels at sCMRs across tissues and immune cell types was examined using a series of datasets ( 43–47 ) (Table 1 ). For these analyses only samples labeled ‘control’ were used.…”