Association of Candidate Diabetic Kidney Disease Loci with T2D-ESKD after Adjustment for <i>APOL1</i> G1/G2.

1<p>hg18;</p>2<p>Eff, effective number of SNPs per locus;</p>3<p>RA, reference allele;</p>4<p>OR, odds ratio;</p>5<p>95% CI, 95% confidence interval;</p>6<p>P_Add, additive p-value;</p>7<p>P_emp, empiric p-value;</p>*<p>imputed SNP.</p

Association of Candidate Diabetic Kidney Disease Loci with T2D-ESKD.

1<p>hg18;</p>2<p>Eff, effective number of SNPs per locus;</p>3<p>RA, reference allele;</p>4<p>OR, odds ratio;</p>5<p>95% CI, 95% confidence interval;</p>6<p>P_Add, additive p-value;</p>7<p>P_emp, empiric p-value;</p>*<p>imputed SNPs.</p

Clinical Characteristics of Study Participants.

*<p>compared to control subjects.</p

Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. As many genes associate with DKD, multi-omics approaches were employed to narrow the list of functional genes, gene products and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNAseq) dataset and Mendeley Data on human kidney cortex biopsy proteomics were utilized. R package Seurat was used to analyze scRNAseq and subset proximal tubule cells. PathfindR was applied for pathway analysis in cell type-specific differentially expressed genes and R limma package was used to analyze differential protein expression in kidney cortex. A total of 790 differentially expressed genes were identified in proximal tubule cells, including 530 upregulated and 260 downregulated transcripts. Compared with differentially expressed proteins, 24 genes/proteins were in common. An integrated analysis combining protein quantitative trait loci (pQTL), GWAS hits (estimated glomerular filtration rate) and a plasma metabolomics analysis was performed using baseline metabolites predictive of DKD progression in our longitudinal Diabetes Heart Study samples. Aldo-keto reductase family 1 member A1 gene (AKR1A1) was revealed as a potential molecular hub for DKD cellular dysfunction in several cross-linked pathways featured by deficiency of this enzyme.</p

Characteristics and single-SNP association results for AIR_g SNPs in IRASFS.

<p>Characteristics and single-SNP association results for AIR_g SNPs in IRASFS.</p

Top meta-analyzed interactions with AIR_g SNPs regressed on T2D risk in ARIC, CARDIA, JHS, MESA, and WFSM.

<p>Top meta-analyzed interactions with AIR_g SNPs regressed on T2D risk in ARIC, CARDIA, JHS, MESA, and WFSM.</p

A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS)

<div><p>Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (n_max = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10^-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (<i>IDH1)</i> was associated with WAIST (rs34218846, MAF = 6.8%, P_DOM = 1.62x10^-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (<i>ZGRF1</i>; SNP rs1471880, MAF = 48.1%, P_DOM = 1.00x10^-8) were strongly associated with WHR. The exact biological function of <i>ZGRF1</i> and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10^-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (n_max = 4156) and the strongest signal was rs1471880 (P_DOM = 8.38x10^-6) in <i>ZGRF1</i> with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (<i>IDH1 and ZGRF1</i>) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, <i>IDH1</i> and <i>ZGRF1</i> warrant further evaluation.</p></div

Significant signals of association from genome-wide and exome chip association analyses in IRASFS.

<p>^aSNP identified from GWAS</p><p>^bSNP identified from exome chip</p><p>^cDominant Model</p><p>^dRecessive Model</p><p>^eMinor allele frequency based on the entire population</p><p>^fMinor/Major allele on the positive strand</p><p>Significant signals of association from genome-wide and exome chip association analyses in IRASFS.</p

Demographic characteristics of the study populations.

<p>^aHTN-IR has only 139 individuals with PBF measurements</p><p>^bValues are expressed as the mean ± standard deviation</p><p>^cIncludes 161 diabetics</p><p>Abbreviations: IRASFS, Insulin Resistance Atherosclerosis Family Study; IRAS, Insulin Resistance Atherosclerosis Study; TRIPOD, Troglitazone in Prevention of Diabetes Study; BetaGene, Family-based study of obesity, insulin resistance, and beta-cell dysfunction; HTN-IR, Hypertension-Insulin Resistance Family Study; MACAD, Mexican-American Coronary Artery Disease Study; NIDDM-Athero, NIDDM-Atherosclerosis Study.</p><p>Demographic characteristics of the study populations.</p

Regional plot of <i>IDH1</i> for association with waist circumference.

<p>(A). Analysis results in IRASFS for SNPs from genome-wide and exome chip datasets as well as de novo genotyping of the region; (B). Conditioned on rs34218846.–log₁₀(p-values) under the best fit model are indicated on the left-hand Y axis. Association analyses were computed with adjustments for age, gender, recruiting center, and admixtures with SNP rs34218846 as an additional covariate in panel B. The recombination rates are indicated on the right-hand Y axis based on HapMap. The color of each SNP annotates its correlation (r²) with the index SNP and was taken from the 1000 Genomes AMR population. A circle denotes intronic and intergenic SNPs, a triangle denotes a missense SNP, and a square denotes a SNP in the untranslated region (UTR).</p