Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project

Abstract

The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10-7) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10-6) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…In addition to sequence variations in OT pathway genes, epigenetic modifications of the OXTR gene have recently attracted considerable attention in clinical, behavioral, and cognitive neurosciences (Kumsta et al, 2013) and have been associated with different phenotypes including maternal PPD (Bell et al, 2015; Kimmel et al, 2016), amygdala reactivity (Puglia et al, 2015), autism (Gregory et al, 2009), and social anxiety disorder (Ziegler et al, 2015) amongst others. Briefly, epigenetics encompasses a set of biochemical modifications of genome function (e.g., histone modifications, DNA methylation, or the effects of small non-coding RNAs, e.g., micro RNAs) that interfere with transcriptional or translational events and can therefore regulate gene expression.…”

“…Methylation-induced downregulation of the OTR was also confirmed in post mortem cortical brain tissue of male patients with autism spectrum disorders (Gregory et al, 2009). Two recent studies revealed a role for OXTR DNA methylation in peripheral blood cells to predict risk for PPD (Bell et al, 2015; Kimmel et al, 2016). GG homozygous (rs53576) women, who were not depressed during pregnancy had an almost 3-fold risk ( adjusted OR: 2.63 ) to develop PPD for every 10% increase of DNA methylation at a CpG dinucleotide located on intron 1, 934 basepairs upstream of the translation start site (CpG −934) compared to A allele carriers.…”

“…GG homozygous (rs53576) women, who were not depressed during pregnancy had an almost 3-fold risk ( adjusted OR: 2.63 ) to develop PPD for every 10% increase of DNA methylation at a CpG dinucleotide located on intron 1, 934 basepairs upstream of the translation start site (CpG −934) compared to A allele carriers. Hypermethylation of this specific CpG has been shown to be associated with reduced OTR expression in the cortex of deceased autism patients (Gregory et al, 2009), suggesting that hypermethylation measured in peripheral tissue of this specific CpG may partly reflect OTR expression regulation in brain tissue (Bell et al, 2015). In contrast, another study found lower OXTR DNA methylation in an intronic region (cg 12695586) in women with high depressive symptoms both pre- and postpartum compared to women with PPD symptoms only (Kimmel et al, 2016).…”

“…DNA methylation of the OXTR gene may be moderated by environmental contingencies, like poor maternal care in childhood (Beery et al, 2015; Unternaehrer et al, 2015), and genotype (Bell et al, 2015). However, comparability between studies is difficult because they differ greatly in target sequences and partly show effects that are not in the expected direction.…”

“…Taken together, it would be premature to draw general conclusions from the reported findings. Nevertheless, based on the exciting initial empirical evidence (Bell et al, 2015; Kimmel et al, 2016; Puglia et al, 2015), epigenetic modifications of the OXTR gene clearly deserve further attention when considering the role of OT-related intergenerational transmission pathways in the future.…”