Publications by authors named "Adrienne Tin"

94 Publications

Mapping the pathways underlying the associations of albuminuria with cognitive decline and dementia.

Authors:
Adrienne Tin

EBioMedicine 2021 Oct 11;72:103623. Epub 2021 Oct 11.

Department of Medicine and The Memory Impairment and Neurodegenerative Dementia (MIND) Center, Jackson, University of Mississippi Medical Center, MS, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103623DOI Listing
October 2021

Hypertensive Diseases in Pregnancy and Kidney Function Later in Life: The Genetic Epidemiology Network of Arteriopathy (GENOA) Study.

Mayo Clin Proc 2021 Sep 23. Epub 2021 Sep 23.

University of Mississippi Medical Center, Department of Medicine, Division of Cardiology, Jackson, MS. Electronic address:

Objective: To evaluate the relationship between hypertensive diseases in pregnancy and kidney function later in life.

Methods: We evaluated measured glomerular filtration rate (mGFR) using iothalamate urinary clearance in 725 women of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Women were classified by self-report as nulliparous (n=62), a history of normotensive pregnancies (n=544), a history of hypertensive pregnancies (n=102), or a history of pre-eclampsia (n=17). We compared adjusted associations among these four groups with mGFR using generalized estimating equations to account for familial clustering. Chronic kidney disease (CKD) was defined as mGFR of less than 60 mL/min per 1.73 m or urinary albumin-creatinine ratio (UACR) greater than or equal to 30 mg/g.

Results: Among women with kidney function measurements (mean age, 59±9 years, 52.9% African American), those with a history of hypertensive pregnancy had lower mGFR (-4.66 ml/min per 1.73 m; 95% CI, -9.12 to -0.20) compared with women with a history of normotensive pregnancies. Compared with women with a history of normotensive pregnancies, women with a history of hypertensive pregnancy also had higher odds of mGFR less than 60 ml/min per 1.73 m (odds ratio, 2.09; 95% CI, 1.21 to 3.60). Additionally, women with a history of hypertensive pregnancy had greater odds for chronic kidney disease (odds ratio, 4.89; 95% CI, 1.55 to 15.44), after adjusting for age, race, education, smoking history, hypertension, body mass index, and diabetes.

Conclusion: A history of hypertension in pregnancy is an important prognostic risk factor for kidney disease. To our knowledge, this is the first and largest investigation showing the association between hypertensive diseases in pregnancy and subsequent kidney disease using mGFR in a large biracial cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocp.2021.07.018DOI Listing
September 2021

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases.

J Am Soc Nephrol 2021 Sep 21. Epub 2021 Sep 21.

J Coresh, Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, United States.

Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020111599DOI Listing
September 2021

Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study.

Neurology 2021 09 4;97(11):e1123-e1131. Epub 2021 Aug 4.

From the Departments of Medicine (K.J.S., A.T., B.G.W., M.E.G., T.H.M.) and Data Science (C.S., J.S.), University of Mississippi Medical Center, Jackson; Departments of Neurology (K.A.W.) and Epidemiology (A.R.S.), The Johns Hopkins University, Baltimore, MD; Mayo Clinic (S.Y.), Jacksonville, FL; Stroke Branch (R.F.G.), National Institute of Neurological Disorders and Stroke Intramural Program, National Institutes of Health, Bethesda, MD; and Departments of Health Sciences Research (M.M.M.) and Neurology (M.M.M., D.K.), Mayo Clinic, Rochester, MN.

Background And Objectives: To evaluate the association between midlife plasma amyloid-β (Aβ, Aβ, Aβ:Aβ) and risk of mild cognitive impairment (MCI) and dementia.

Methods: Plasma Aβ and Aβ were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ, Aβ, and Aβ:Aβ ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011-2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, , hypertension, diabetes, and body mass index.

Results: A total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ:Aβ was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46-0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77-0.98), whereas every 1-SD increase in plasma Aβ (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01-1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ and Aβ increased from midlife to late life, but changes were not associated with cognitive outcomes.

Discussion: Midlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456355PMC
September 2021

Mendelian Randomization Analysis as a Tool to Gain Insights into Causes of Diseases: A Primer.

J Am Soc Nephrol 2021 Oct 16;32(10):2400-2407. Epub 2021 Jun 16.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Many Mendelian randomization (MR) studies have been published recently, with inferences on the causal relationships between risk factors and diseases that have potential implications for clinical research. In nephrology, MR methods have been applied to investigate potential causal relationships of traditional risk factors, lifestyle factors, and biomarkers from omics technologies with kidney function or CKD. This primer summarizes the basic concepts of MR studies, highlighting methods used in recent applications, and emphasizes key elements in conducting and reporting of MR studies that are important for interpreting the results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020121760DOI Listing
October 2021

Association between Circulating Protein C Levels and Incident Dementia: The Atherosclerosis Risk in Communities Study.

Neuroepidemiology 2021 2;55(4):306-315. Epub 2021 Jun 2.

Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Introduction: Hemostasis depends on the delicate balance between coagulants and anticoagulants. Higher levels of circulating coagulants have been associated with higher risk of cerebral infarctions and dementia. In contrast, higher levels of circulating protein C, an endogenous anticoagulant, have been associated with lower risk of cerebral infarctions, and the association between protein C levels and the risk of dementia is unknown. The goal of this study was to evaluate the association of circulating protein C levels in midlife and late life with incident dementia.

Methods: Circulating protein C levels were measured using blood samples collected at the midlife baseline (1987-1989) and the late-life baseline (2011-2013) among 14,462 and 3,614 participants, respectively, in the Atherosclerosis Risk in Communities study. Protein C levels were measured using enzyme-linked immunosorbent assay at midlife and a modified aptamer-based assay at late life. Participants were followed up to 2013 from midlife and up to 2017 from late life. Incident dementia was ascertained during the follow-up periods using in-person cognitive and functional assessment, informant interviews, and International Classification of Diseases codes at hospitalization discharge and on death certificates. Cause-specific Cox regression models were used to evaluate the association between quintiles of circulating protein C and incident dementia.

Results: From midlife (mean age of 54), 1,389 incident dementia events were observed over a median follow-up of 23 years. From late life (mean age of 75), 353 incident dementia events were observed over a median follow-up of 4.9 years. At both midlife and late life, circulating protein C had an inverse association with incident dementia after adjusting for demographic, vascular, and hemostatic risk factors, incident stroke as time-dependent covariate, and incorporating stabilized weights based on propensity scores (quintile 5 vs. quintile 1 as the reference, midlife hazard ratio 0.80, 95% confidence interval 0.66-0.96, p value for trend 0.04; late-life hazard ratio 0.84, 95% confidence interval: 0.55-1.28, p value for trend 0.04).

Discussion/conclusion: Circulating protein C has an inverse association with incident dementia independent of established risk factors, including stroke. Our results suggest studying anticoagulants in addition to coagulants can increase our understanding on the relationship between hemostasis and dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000516287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292178PMC
June 2021

Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension.

Kidney Int 2021 08 8;100(2):430-439. Epub 2021 Apr 8.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2021.03.026DOI Listing
August 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Variants, N-Acetylated Amino Acids, and Progression of CKD.

Clin J Am Soc Nephrol 2020 12;16(1):37-47

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

Background And Objectives: Genetic variants in , a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two -associated metabolites, N--acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in , N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts.

Design, Setting, Participants, & Measurements: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; =962), the Atherosclerosis Risk in Communities (ARIC) study (=1050), and Bio, an electronic health record-linked biorepository (=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (=1624).

Results: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N--acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study.

Conclusions: We demonstrate significant associations between an gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.08600520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792648PMC
December 2020

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Division of Nephrology, University of Washington, Seattle, Washington, USA; Kidney Research Institute, University of Washington, Seattle, Washington, USA.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

Low Serum Magnesium is Associated with Incident Dementia in the ARIC-NCS Cohort.

Nutrients 2020 Oct 9;12(10). Epub 2020 Oct 9.

Department of Epidemiology, Emory University School of Public Health, Atlanta, GA 30322, USA.

Higher serum magnesium is associated with lower risk of multiple morbidities, including diabetes, stroke, and atrial fibrillation, but its potential neuroprotective properties have also been gaining traction in cognitive function and decline research. We studied 12,040 participants presumed free of dementia in the Atherosclerosis Risk in Communities (ARIC) study. Serum magnesium was measured in fasting blood samples collected in 1990-1992. Dementia status was ascertained through cognitive examinations in 2011-2013, 2016-2017, and 2018-2019, along with informant interviews and indicators of dementia-related hospitalization events and death. Participants' cognitive functioning capabilities were assessed up to five times between 1990-1992 and 2018-2019. The cognitive function of participants who did not attend follow-up study visits was imputed to account for attrition. We identified 2519 cases of dementia over a median follow-up period of 24.2 years. The lowest quintile of serum magnesium was associated with a 24% higher rate of incident dementia compared to those in the highest quintile of magnesium (HR, 1.24; 95% CI, 1.07, 1.44). No relationship was found between serum magnesium and cognitive decline in any cognitive domain. Low midlife serum magnesium is associated with increased risk of incident dementia, but does not appear to impact rates of cognitive decline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12103074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600951PMC
October 2020

Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.

Genome Med 2020 09 28;12(1):84. Epub 2020 Sep 28.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

Methods: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

Results: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.

Conclusions: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523322PMC
September 2020

Race, APOL1 Risk Variants, and Clinical Outcomes among Older Adults: The ARIC Study.

J Am Geriatr Soc 2021 01 7;69(1):155-163. Epub 2020 Sep 7.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background/objectives: APOL1 high-risk genotypes confer an increased risk for kidney disease, but their clinical significance among older adults remains unclear. We aimed to determine whether APOL1 genotype status (high risk = 2 risk alleles; low risk = 0-1 risk alleles) and self-reported race (Black; White) are associated with number of hospitalizations, incident chronic kidney disease (CKD), end-stage renal disease (ESRD), and mortality among older adults participating in a community-based cohort study.

Design: Observational longitudinal cohort study.

Setting: The Atherosclerosis Risk in Communities (ARIC) study.

Participants: Community-dwelling older adults (mean age = 75.8 years; range = 66-90 years).

Results: Among 5,564 ARIC participants (78.2% White, 19.1% APOL1 low-risk Black, and 2.7% APOL1 high-risk Black), the proportion with creatinine and cystatin C-based estimated glomerular filtration rate (eGFR ) below 60 mL/min/1.73 m at baseline was 40.6%, 34.8%, and 43.2%, respectively. Over a mean follow-up of 5.1 years, APOL1 high-risk Blacks had a 2.67-fold higher risk for ESRD compared with low-risk Blacks (95% confidence interval [CI] = 1.05-6.79) in models adjusted for age and sex. This association was no longer significant upon further adjustment for baseline eGFR and albuminuria (hazard ratio [HR] = 1.08; 95% CI = .39-2.96). Rate of hospitalizations and risks of mortality and incident CKD did not differ significantly by APOL1 genotype status. Compared with Whites, Blacks had 1.85-fold and 3.45-fold higher risks for incident CKD and ESRD, respectively, in models adjusted for age, sex, eGFR , and albuminuria. These associations persisted after additional adjustments for clinical/socioeconomic factors and APOL1 genotype (incident CKD: HR = 1.38; 95% CI = 1.06-1.81; ESRD: HR = 3.20; 95% CI = 1.16-8.86).

Conclusion: Among older Black adults, APOL1 high-risk genotypes were associated with lower kidney function and therefore higher risk of ESRD. Racial disparities in incident kidney disease persisted in older age and were not fully explained by APOL1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.16797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855571PMC
January 2021

Integration of GWAS Summary Statistics and Gene Expression Reveals Target Cell Types Underlying Kidney Function Traits.

J Am Soc Nephrol 2020 10 6;31(10):2326-2340. Epub 2020 Aug 6.

Institute of Genetic Epidemiology, Medical Center-University of Freiburg, Freiburg, Germany

Background: Genetic variants identified in genome-wide association studies (GWAS) are often not specific enough to reveal complex underlying physiology. By integrating RNA-seq data and GWAS summary statistics, novel computational methods allow unbiased identification of trait-relevant tissues and cell types.

Methods: The CKDGen consortium provided GWAS summary data for eGFR, urinary albumin-creatinine ratio (UACR), BUN, and serum urate. Genotype-Tissue Expression Project (GTEx) RNA-seq data were used to construct the top 10% specifically expressed genes for each of 53 tissues followed by linkage disequilibrium (LD) score-based enrichment testing for each trait. Similar procedures were performed for five kidney single-cell RNA-seq datasets from humans and mice and for a microdissected tubule RNA-seq dataset from rat. Gene set enrichment analyses were also conducted for genes implicated in Mendelian kidney diseases.

Results: Across 53 tissues, genes in kidney function-associated GWAS loci were enriched in kidney (=9.1E-8 for eGFR; =1.2E-5 for urate) and liver (=6.8·10 for eGFR). In the kidney, proximal tubule was enriched in humans (=8.5E-5 for eGFR; =7.8E-6 for urate) and mice (=0.0003 for eGFR; =0.0002 for urate) and confirmed as the primary cell type in microdissected tubules and organoids. Gene set enrichment analysis supported this and showed enrichment of genes implicated in monogenic glomerular diseases in podocytes. A systematic approach generated a comprehensive list of GWAS genes prioritized by cell type-specific expression.

Conclusions: Integration of GWAS statistics of kidney function traits and gene expression data identified relevant tissues and cell types, as a basis for further mechanistic studies to understand GWAS loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609008PMC
October 2020

Urine 6-Bromotryptophan: Associations with Genetic Variants and Incident End-Stage Kidney Disease.

Sci Rep 2020 06 22;10(1):10018. Epub 2020 Jun 22.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-66334-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308283PMC
June 2020

A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure.

Kidney Int 2020 09 23;98(3):708-716. Epub 2020 May 23.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA. Electronic address:

Blood pressure and kidney function have a bidirectional relation. Hypertension has long been considered as a risk factor for kidney function decline. However, whether intensive blood pressure control could promote kidney health has been uncertain. The kidney is known to have a major role in affecting blood pressure through sodium extraction and regulating electrolyte balance. This bidirectional relation makes causal inference between these two traits difficult. Therefore, to examine the causal relations between these two traits, we performed two-sample Mendelian randomization analyses using summary statistics of large-scale genome-wide association studies. We selected genetic instruments more likely to be specific for kidney function using meta-analyses of complementary kidney function biomarkers (glomerular filtration rate estimated from serum creatinine [eGFRcr], and blood urea nitrogen from the CKDGen Consortium). Systolic and diastolic blood pressure summary statistics were from the International Consortium for Blood Pressure and UK Biobank. Significant evidence supported the causal effects of higher kidney function on lower blood pressure. Based on the mode-based Mendelian randomization method, the effect estimates for one standard deviation (SD) higher in log-transformed eGFRcr was -0.17 SD unit (95 % confidence interval: -0.09 to -0.24) in systolic blood pressure and -0.15 SD unit (95% confidence interval: -0.07 to -0.22) in diastolic blood pressure. In contrast, the causal effects of blood pressure on kidney function were not statistically significant. Thus, our results support causal effects of higher kidney function on lower blood pressure and suggest preventing kidney function decline can reduce the public health burden of hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784392PMC
September 2020

Genome-Wide Association Studies of CKD and Related Traits.

Clin J Am Soc Nephrol 2020 11 14;15(11):1643-1656. Epub 2020 May 14.

MIND Center, University of Mississippi Medical Center, Jackson, Mississippi

The past few years have seen major advances in genome-wide association studies (GWAS) of CKD and kidney function-related traits in several areas: increases in sample size from >100,000 to >1 million, enabling the discovery of >250 associated genetic loci that are highly reproducible; the inclusion of participants not only of European but also of non-European ancestries; and the use of advanced computational methods to integrate additional genomic and other unbiased, high-dimensional data to characterize the underlying genetic architecture and prioritize potentially causal genes and variants. Together with other large-scale biobank and genetic association studies of complex traits, these GWAS of kidney function-related traits have also provided novel insight into the relationship of kidney function to other diseases with respect to their genetic associations, genetic correlation, and directional relationships. A number of studies also included functional experiments using model organisms or cell lines to validate prioritized potentially causal genes and/or variants. In this review article, we will summarize these recent GWAS of CKD and kidney function-related traits, explain approaches for downstream characterization of associated genetic loci and the value of such computational follow-up analyses, and discuss related challenges along with potential solutions to ultimately enable improved treatment and prevention of kidney diseases through genetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.00020120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646230PMC
November 2020

Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans.

J Am Soc Nephrol 2020 01 14;31(1):102-116. Epub 2019 Nov 14.

Division of Nephrology, Department of Medicine and

Background: encodes glutathione S-transferase -1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: We generated a knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic on renal inflammation.

Results: knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the deletion variant.

Conclusions: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019050449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935006PMC
January 2020

Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay.

J Appl Lab Med 2019 07 22;4(1):30-39. Epub 2019 Jan 22.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Background: There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized.

Methods: We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired -tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR).

Results: The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences ( < 1.4 × 10, 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31).

Conclusions: Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1373/jalm.2018.027086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814271PMC
July 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Copy Number Is Not Associated With Risk of Kidney Failure in a Large Cohort.

Front Genet 2019 30;10:765. Epub 2019 Aug 30.

Genomic Medicine Institute, Geisinger, Danville, PA, United States.

Deletion of is common in populations and has been asserted to associate with chronic kidney disease progression in some research studies. The association needs to be validated. We estimated copy number using whole exome sequencing data in the DiscovEHR cohort. Kidney failure was defined as requiring dialysis or receiving kidney transplant using data from the electronic health record and linkage to the United States Renal Data System, or the most recent eGFR < 15 ml/min/1.73 m. In a cohort of 46,983 unrelated participants, 28.8% of blacks and 52.1% of whites had 0 copies of . Over a mean of 9.2 years follow-up, 645 kidney failure events were observed in 46,187 white participants, and 28 in 796 black participants. No significant association was observed between copy number and kidney failure in Cox regression adjusting for age, sex, BMI, smoking status, genetic principal components, or comorbid conditions (hypertension, diabetes, heart failure, coronary artery disease, and stroke), whether using a genotypic, dominant, or recessive model. In sensitivity analyses, copy number was not associated with kidney failure in participants that were 45 years or older at baseline, had baseline eGFR < 60 ml/min/1.73 m, or with baseline year between 1996 and 2002. In conclusion, we found no association between copy number and kidney failure in a large cohort study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.00765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728412PMC
August 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

J Am Soc Nephrol 2019 10 5;30(10):2027-2036. Epub 2019 Aug 5.

Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Two coding variants in the apo L1 gene () are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results.

Methods: We conducted a two-stage individual participant data meta-analysis to assess the association of kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts.

Results: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by genotype. genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index.

Conclusions: In this large, two-stage individual participant data meta-analysis, kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019030240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779370PMC
October 2019

Serum Urate, Genetic Variation, and Prostate Cancer Risk: Atherosclerosis Risk in Communities (ARIC) Study.

Cancer Epidemiol Biomarkers Prev 2019 07;28(7):1259-1261

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Evidence is mounting that intraprostatic inflammation influences prostate cancer development. Uric acid crystals depositing in the prostate could result in injury and inflammation, increasing prostate cancer risk.

Methods: Included were 6,574 men ages 45-64 years who enrolled in the Atherosclerosis Risk in Communities study in 1987 to 1989. We used Cox proportional hazards regression to estimate the association of serum urate concentration alone and to improve accuracy, jointly with a genetic risk score (GRS, = 4,983) derived from variants predictive of urate concentration, with prostate cancer ( = 813) risk.

Results: Serum urate concentration or joint categories of urate concentration and GRS were not associated with prostate cancer risk ( = 0.3). Results were generally similar by race and after excluding users of medications that influence uric acid.

Conclusions: Serum urate alone and with a urate-associated GRS were not associated with prostate cancer risk.

Impact: It is unlikely that circulating urate concentration influences prostate cancer development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608724PMC
July 2019

Heritability analysis of nontraditional glycemic biomarkers in the Atherosclerosis Risk in Communities Study.

Genet Epidemiol 2019 10 19;43(7):776-785. Epub 2019 Jun 19.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals). Pedigree-based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44-0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP-based heritabilities (representing heritability from common variants) were lower than pedigree-based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree-based, 1.00 SNP-based) and glycated albumin and 1,5-AG (0.50 pedigree-based, 0.47 SNP-based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5-AG and a portion of this heritability likely comes from common variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763360PMC
October 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans.

Hum Genomics 2019 05 15;13(1):21. Epub 2019 May 15.

Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants.

Results: Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis.

Conclusions: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40246-019-0205-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521376PMC
May 2019

Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study.

Sci Rep 2019 04 11;9(1):5941. Epub 2019 Apr 11.

Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Serum 1,5-anhydroglucitol (1,5-AG) is an emerging biomarker used to monitor glycemic control in persons with diabetes. We performed whole-exome sequencing, examining the association between rare, coding genetic variants and 1,5-AG among European ancestry (N = 6,589) and African ancestry (N = 2,309) participants without diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Five variants representing 3 independent signals on chromosome 17 in SLC5A10, a glucose transporter not previously known to transport 1,5-AG, were associated with 1,5-AG levels up to 10.38 µg/mL lower per allele (1,5-AG range 3.4-32.8 µg/mL) in the European ancestry sample and validated in the African ancestry sample. Together these variants explained 6% of the variance in 1,5-AG. Two of these variants (rs61741107, p = 8.85E-56; rs148178887, p = 1.13E-36) were rare, nonsynonymous, and predicted to be damaging or deleterious by multiple algorithms. Gene-based SKAT-O analysis supported these results (SLC5A10 p = 5.13E-64 in European ancestry, validated in African ancestry, p = 0.006). Interestingly, these novel variants are not associated with other biomarkers of hyperglycemia or diabetes (p > 0.2). The large effect sizes and protein-altering, multiple independent signals suggest SLC5A10 may code for an important transporter of 1,5-AG in the kidney, with a potential nonglucose-related effect on 1,5-AG, impacting its clinical utility as a diabetes biomarker in this subpopulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-42202-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459884PMC
April 2019

Association of Variants with Blood Pressure in the Atherosclerosis Risk in Communities Study.

Int J Hypertens 2019 18;2019:2137629. Epub 2019 Feb 18.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

[] encodes dimethylaniline monooxygenase [N-oxide-forming] 3, which breaks down nitrogen-containing compounds, and has been implicated in blood pressure regulation. Studies have reported conflicting results of the association of a common nonsynonymous variant, E158K (rs2266782), with hypertension. We examined the associations of E158K, along with rare and low frequency exonic variants (minor allele frequency [MAF]<5%) in with hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP). We included 7,350 European Americans and 2,814 African Americans in the Atherosclerosis Risk in Communities (ARIC) study with exome sequencing of . The association of variants with SBP and DBP was tested using single variant and gene-based tests followed by the replication or interrogation of significant variants in ancestry-specific cohorts based on Bonferroni corrected thresholds. E158K had significant association with higher SBP in African Americans in ARIC (p=0.03), and two low frequency variants had significant association with higher SBP in African Americans (rs200985584, MAF 0.1%, p=0.0003) and European Americans (rs75904274, MAF 1.7%, p=0.006). These associations were not significant with additional samples: E158K in a meta-analysis of SBP of African ancestry (N=30,841, p=0.43) that included ARIC participants and the two low frequency variants in an independent ancestry-specific exome sequencing study of blood pressure (rs200985584, p=0.94; rs75904274, p=0.81). Our study does not support the association of E158K and low frequency variants in with blood pressure and demonstrates the importance of replication in genetic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/2137629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397986PMC
February 2019
-->