Publications by authors named "Josyf C Mychaleckyj"

108 Publications

Oral rotavirus vaccine shedding as a marker of mucosal immunity.

Sci Rep 2021 Nov 5;11(1):21760. Epub 2021 Nov 5.

Translational Global Infectious Diseases Research Center, Larner College of Medicine, University of Vermont, 95 Carrigan Drive, Stafford 208, Burlington, VT, 05405, USA.

Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of RVA diarrhea through 2 years of life (RR 0.616, 95% CI 0.392-0.968). Further development of controlled human infection models for group A rotaviruses, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.
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http://dx.doi.org/10.1038/s41598-021-01288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571310PMC
November 2021

Population sequencing data reveal a compendium of mutational processes in the human germ line.

Science 2021 08 12;373(6558):1030-1035. Epub 2021 Aug 12.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.
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http://dx.doi.org/10.1126/science.aba7408DOI Listing
August 2021

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

J Am Soc Nephrol 2021 10 14;32(10):2634-2651. Epub 2021 Jul 14.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Results: Protein coding variants in the hydroxysteroid 17- dehydrogenase 14 gene (), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (=4196; value=3.3 × 10). The gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

Conclusions: gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
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http://dx.doi.org/10.1681/ASN.2020101457DOI Listing
October 2021

Genetic landscape of Gullah African Americans.

Am J Phys Anthropol 2021 08 19;175(4):905-919. Epub 2021 May 19.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Objectives: Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah.

Materials And Methods: We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture.

Results: Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations.

Discussion: This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.
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http://dx.doi.org/10.1002/ajpa.24333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286328PMC
August 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 04 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 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.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

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

Association of Genotypes With Measures of Microvascular and Endothelial Function, and Blood Pressure in MESA.

J Am Heart Assoc 2020 09 27;9(17):e017039. Epub 2020 Aug 27.

Kidney Health Research Collaborative Department of Medicine University of California San Francisco CA.

Background high-risk genotypes are associated with increased risk for hypertension-attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by status; less is known about the variants' associations with systemic vascular and endothelial function. Whether risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross-sectional associations of risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow-mediated dilation, n=777). Using linear mixed-effects models, we studied longitudinal associations of risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% high-risk) Black participants in MESA (Multi-Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000-2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow-mediated dilation in participants with high- versus low-risk genotypes (>0.05 for all). Over a mean follow-up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by risk status (between-group differences of -0.20, -0.14, and -0.25, respectively; >0.05 for all). Conclusions Among Black participants in MESA, high-risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.
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http://dx.doi.org/10.1161/JAHA.120.017039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660790PMC
September 2020

Maternal Secretor Status Affects Oral Rotavirus Vaccine Response in Breastfed Infants in Bangladesh.

J Infect Dis 2021 Oct;224(7):1147-1151

The University of Vermont Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.

Secretor status controls mucosal histo-blood group antigen expression and is associated with susceptibility to rotavirus (RV) diarrhea, with nonsecretors less susceptible to symptomatic infection. The role of breast milk secretor status on oral live-attenuated RV vaccine response in breastfed infants has not been explored. In a monovalent G1P[8] RV vaccine (Rotarix) trial in Bangladesh, RV-specific plasma immunoglobulin A antibody seroconversion rates were higher among infants of maternal nonsecretors (39%) than infants of maternal secretors (23%; P = .001). Maternal status remained a significant predictor when correcting for infant status (P = .002). Maternal secretor status should be considered when interpreting oral RV vaccine responses in low- and middle-income settings. Clinical Trials Registration. NCT01375647.
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http://dx.doi.org/10.1093/infdis/jiaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561252PMC
October 2021

Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.

Diabetes 2020 04 23;69(4):771-783. Epub 2020 Jan 23.

Research Division, Joslin Diabetes Center, Boston, MA

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes ( = 3.7 × 10). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD ( = 585, = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total = 3059, = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin ( for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on expression in many tissues. In summary, we have found a common regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
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http://dx.doi.org/10.2337/db19-0973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085251PMC
April 2020

The core clock gene, Bmal1, and its downstream target, the SNARE regulatory protein secretagogin, are necessary for circadian secretion of glucagon-like peptide-1.

Mol Metab 2020 01 21;31:124-137. Epub 2019 Nov 21.

Department of Physiology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Objectives: The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted from intestinal L-cells upon nutrient intake. While recent evidence has shown that GLP-1 is released in a circadian manner in rats, whether this occurs in mice and if this pattern is regulated by the circadian clock remain to be elucidated. Furthermore, although circadian GLP-1 secretion parallels expression of the core clock gene Bmal1, the link between the two remains largely unknown. Secretagogin (Scgn) is an exocytotic SNARE regulatory protein that demonstrates circadian expression and is essential for insulin secretion from β-cells. The objective of the current study was to establish the necessity of the core clock gene Bmal1 and the SNARE protein SCGN as essential regulators of circadian GLP-1 secretion.

Methods: Oral glucose tolerance tests were conducted at different times of the day on 4-hour fasted C57BL/6J, Bmal1 wild-type, and Bmal1 knockout mice. Mass spectrometry, RNA-seq, qRT-PCR and/or microarray analyses, and immunostaining were conducted on murine (m) and human (h) primary L-cells and mGLUTag and hNCI-H716 L-cell lines. At peak and trough GLP-1 secretory time points, the mGLUTag cells were co-stained for SCGN and a membrane-marker, ChIP was used to analyze BMAL1 binding sites in the Scgn promoter, protein interaction with SCGN was tested by co-immunoprecipitation, and siRNA was used to knockdown Scgn for GLP-1 secretion assay.

Results: C57BL/6J mice displayed a circadian rhythm in GLP-1 secretion that peaked at the onset of their feeding period. Rhythmic GLP-1 release was impaired in Bmal1 knockout (KO) mice as compared to wild-type controls at the peak (p < 0.05) but not at the trough secretory time point. Microarray identified SNARE and transport vesicle pathways as highly upregulated in mGLUTag L-cells at the peak time point of GLP-1 secretion (p < 0.001). Mass spectrometry revealed that SCGN was also increased at this time (p < 0.001), while RNA-seq, qRT-PCR, and immunostaining demonstrated Scgn expression in all human and murine primary L-cells and cell lines. The mGLUTag and hNCI-H716 L-cells exhibited circadian rhythms in Scgn expression (p < 0.001). The ChIP analysis demonstrated increased binding of BMAL1 only at the peak of Scgn expression (p < 0.01). Immunocytochemistry showed the translocation of SCGN to the cell membrane after stimulation at the peak time point only (p < 0.05), while CoIP showed that SCGN was pulled down with SNAP25 and β-actin, but only the latter interaction was time-dependent (p < 0.05). Finally, Scgn siRNA-treated cells demonstrated significantly blunted GLP-1 secretion (p < 0.01) in response to stimulation at the peak time point only.

Conclusions: These data demonstrate, for the first time, that mice display a circadian pattern in GLP-1 secretion, which is impaired in Bmal1 knockout mice, and that Bmal1 regulation of Scgn expression plays an essential role in the circadian release of the incretin hormone GLP-1.
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http://dx.doi.org/10.1016/j.molmet.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920326PMC
January 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 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.
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http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

Association of breast milk gamma-linolenic acid with infant anthropometric outcomes in urban, low-income Bangladeshi families: a prospective, birth cohort study.

Eur J Clin Nutr 2020 05 9;74(5):698-707. Epub 2019 Sep 9.

Division of Infectious Diseases and International Health, Department of Medicine, Charlottesville, VA, 22908, USA.

Background/objectives: Infant linear-growth faltering remains a major public health issue in low- and middle-income countries and suboptimal breast milk composition may be a local, population-specific risk factor. The relationship between early post-natal breast milk fatty acid (FA) composition and infant growth at 1 and 2 years of age was investigated prospectively in 563 families in Dhaka, Bangladesh.

Subjects/methods: A maternal breast milk sample drawn before infant age 6 weeks was analyzed for percentage composition of 26 FAs, and infant length for age Z score (LAZ) was measured longitudinally to infant age 2 years. Individual FAs were tested as predictors of the infant growth outcomes.

Results: Of 26 tested FAs, %gamma-linolenic acid (%GLA) was mostly significantly associated with increase in LAZ from 6 to 52 weeks (ΔLAZ(52-6w)), and also to 104 weeks. The association was consistent over all breast milk stages with estimated effect size of +0.05 ΔLAZ(52-6w) per 20% change in %GLA (p value = 3 × 10), and stronger for ΔLAZ(104-6w) at +0.06 (p value = 8 × 10), explaining 1% of the outcome variance. Infant serum zinc measurements at 6 and 18 weeks of age were included in adjusted analyses, suggesting at least partial independence of infant zinc levels. The association was strongest in 417/563 (74.1%) families with %GLA <0.2%. Breast milk arachidonic acid fraction was within normal range with weaker evidence of association in early breast milk stages.

Conclusions: This study found that %GLA in breast milk was independently associated with infant linear growth, albeit with small effect size, in a predominantly slum-dwelling, low-income, Bangladeshi cohort.
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http://dx.doi.org/10.1038/s41430-019-0498-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214250PMC
May 2020

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

A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies.

Diabetes 2019 08 24;68(8):1649-1662. Epub 2019 May 24.

Research Division, Joslin Diabetes Center, Boston, MA

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance ( < 5 × 10) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55-0.74, = 1.9 × 10). This effect was not influenced by ACCORD treatment assignments ( for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42-0.80, = 9 × 10; summary = 7.9 × 10). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene () coding for human voltage-gated sodium channel NaV1.2 ( = 9 × 10). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions.
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http://dx.doi.org/10.2337/db19-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692816PMC
August 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.
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http://dx.doi.org/10.1186/s40246-019-0205-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521376PMC
May 2019

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Nat Commun 2019 01 3;10(1):29. Epub 2019 Jan 3.

Department of Pathology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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http://dx.doi.org/10.1038/s41467-018-07867-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318312PMC
January 2019

Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy.

Diabetes Care 2019 01 19;42(1):93-101. Epub 2018 Nov 19.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts.

Research Design And Methods: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD.

Results: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, = 0.003) and lowest in Steno (HR 0.54, < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes.

Conclusions: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.
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http://dx.doi.org/10.2337/dc18-1369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300701PMC
January 2019

Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes.

Clin J Am Soc Nephrol 2018 11 25;13(11):1693-1702. Epub 2018 Oct 25.

Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background And Objectives: In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (<5 years) kidney outcomes. We aimed to determine the long-term kidney effects of these interventions.

Design, Setting, Participants, & Measurements: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a multifactorial intervention study in people with type 2 diabetes at high risk for cardiovascular disease (=10,251), to examine the effects of intensive glycemic control (hemoglobin A1c <6.0% versus 7%-7.9%), BP control (systolic BP <120 mm Hg versus <140 mm Hg) or fenofibrate versus placebo added to simvastatin on cardiovascular events and death. The glycemia trial lasted 3.7 years and participants were followed for another 6.5 years in ACCORDION, the ACCORD Follow-On Study. The primary composite kidney outcome was defined as incident macroalbuminuria, creatinine doubling, need for dialysis, or death by any cause. Cox proportional hazards regression estimated the effect of each intervention on the composite outcome and individual components. In secondary outcome analyses, competing risk regression was used to account for the risk of death in incident kidney outcomes. Analyses were adjusted for sociodemographics, randomization groups, and clinical factors.

Results: There were 988 cases of incident macroalbuminuria, 954 with doubling of creatinine, 351 requiring dialysis, and 1905 deaths. Hazard ratios (HRs) for the composite outcome with intensive glycemic, BP control, and fenofibrate use compared with standard therapy were 0.92 (95% confidence interval [95% CI], 0.86 to 0.98), 1.16 (95% CI, 1.05 to 1.28), and 1.16 (95% CI, 1.06 to 1.27). Multivariable, secondary outcome analyses showed that in the glycemia trial, only macroalbuminuria was significantly decreased (HR, 0.68; 95% CI, 0.59 to 0.77). In the BP and lipid trials, only creatinine doubling was affected (HR, 1.64; 95% CI, 1.30 to 2.06 and HR, 2.00; 95% CI, 1.61 to 2.49, respectively).

Conclusions: In people with type 2 diabetes at high risk for cardiovascular disease, intensive glycemic control may result in a long-term reduction in macroalbuminuria; however, intensive BP control and fenofibrates may increase the risk for adverse kidney events.
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http://dx.doi.org/10.2215/CJN.06200518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237052PMC
November 2018

Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial.

Diabetes Care 2018 Nov 27;41(11):2404-2413. Epub 2018 Sep 27.

Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA

Objective: We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk.

Research Design And Methods: A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression.

Results: The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, = 4 × 10, and HR per SD 1.35, 95% CI 1.16-1.58, = 2 × 10, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, = 7 × 10). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years.

Conclusions: When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.
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http://dx.doi.org/10.2337/dc18-0709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196830PMC
November 2018

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Wellcome Open Res 2018 12;3. Epub 2018 Jan 12.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27514, USA.

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
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http://dx.doi.org/10.12688/wellcomeopenres.12583.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081985PMC
January 2018

Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of variants to arachidonic acid, a critical infant micronutrient.

J Med Genet 2018 07 7;55(7):459-468. Epub 2018 Mar 7.

Division of Infectious Diseases and International Health, Department of Medicine, Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.

Background: Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition.

Methods: We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE.

Results: After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the region were also associated with breast milk FA composition (experiment-wise significance threshold 4.2×10). Hypothesis-neutral comparison of the 33 fractions showed that the most significant genetic association at the locus was with fraction of arachidonic acid (AA) at SNP rs174556, with a very large per major allele effect size of 17% higher breast milk AA level. There was no evidence of independent association at with any other FA or SNP after conditioning on AA and rs174556. We also found novel significant experiment-wise SNP associations with: polyunsaturated fatty acid (PUFA) 6/PUFA3 ratio (sorting nexin ), eicosenoic (intergenic) and capric (component of oligomeric Golgi complex 3) acids; and six additional loci at genomewide significance (<5×10).

Conclusions: AA is the primary FA in breast milk influenced by genetic variation at the locus, extending the potential phenotypes under genetic selection to include breast milk composition, thereby possibly affecting infant growth or cognition. Breast milk FA composition is influenced by maternal genetics in addition to diet and body composition.
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http://dx.doi.org/10.1136/jmedgenet-2017-105134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047159PMC
July 2018

Rotavirus-Specific Immunoglobulin A Responses Are Impaired and Serve as a Suboptimal Correlate of Protection Among Infants in Bangladesh.

Clin Infect Dis 2018 07;67(2):186-192

Department of Medicine, Vaccine Testing Center, University of Vermont Larner College of Medicine, Burlington.

Background: Rotavirus (RV)-specific immunoglobulin A (IgA) responses following oral RV vaccination are impaired in low-income countries, where the utility of RV-IgA as a correlate of protection (CoP) remains unclear. In a monovalent oral RV vaccine (Rotarix) efficacy trial among infants in Dhaka, Bangladesh, we identified factors associated with poor RV-IgA responses and explored the utility of RV-IgA as a CoP.

Methods: Infants were randomized to receive Rotarix or no Rotarix at 10 and 17 weeks of life and followed with active diarrheal surveillance. RV-IgA concentration, seroconversion, and seropositivity were determined at 18 weeks of life and analyzed for correlation(s) with rotavirus diarrhea (RVD) and for contribution to Rotarix vaccine effect.

Results: Among vaccinated infants, overall RV-IgA geometric mean concentration was 21 U/mL; only 27% seroconverted and 32% were seropositive after vaccination. Increased RV-specific maternal antibodies significantly impaired immunogenicity. Seroconversion was associated with reduced risk of RVD through 1 year of life, but RV-IgA seropositivity only explained 7.8% of the vaccine effect demonstrated by the clinical endpoint (RVD).

Conclusions: RV-IgA responses were low among infants in Bangladesh and were significantly impaired by maternal antibodies. RV-IgA is a suboptimal CoP in this setting; an improved CoP for RV in low-income countries is needed.

Clinical Trials Registration: NCT01375647.
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http://dx.doi.org/10.1093/cid/ciy076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030840PMC
July 2018

Histo-Blood Group Antigen Phenotype Determines Susceptibility to Genotype-Specific Rotavirus Infections and Impacts Measures of Rotavirus Vaccine Efficacy.

J Infect Dis 2018 04;217(9):1399-1407

Department of Medicine, University of Vermont Larner College of Medicine, Burlington.

Background: Lewis and secretor histo-blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE.

Methods: In infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD.

Results: A vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36-.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort.

Conclusions: Host HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status.

Clinical Trials Registration: NCT01375647.
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http://dx.doi.org/10.1093/infdis/jiy054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894073PMC
April 2018

Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD.

Diabetes Care 2018 02 28;41(2):348-355. Epub 2017 Nov 28.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants.

Research Design And Methods: Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy ( = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data ( = 351) stratified by intervention arm.

Results: A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm ( = 3 × 10). This effect was driven by rs57922 ( = 5 × 10). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm.

Conclusions: Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.
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http://dx.doi.org/10.2337/dc17-1638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780047PMC
February 2018

Association of Mitochondrial DNA Copy Number With Cardiovascular Disease.

JAMA Cardiol 2017 11;2(11):1247-1255

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Mitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.

Objective: To determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.

Design, Setting, And Participants: Prospective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.

Exposures: Mitochondrial DNA-CN measured from buffy coat/circulating leukocytes.

Main Outcomes And Measures: Incident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.

Results: Of the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P < .001). Mitochondrial DNA-CN further improved sensitivity and specificity for the 2013 American College of Cardiology/American Heart Association recommendations on initiating statin therapy for primary prevention of ASCVD (net 221 individuals appropriately downclassified and net 15 individuals appropriately upclassified).

Conclusions And Relevance: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.
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http://dx.doi.org/10.1001/jamacardio.2017.3683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710361PMC
November 2017

Influence of maternal and socioeconomic factors on breast milk fatty acid composition in urban, low-income families.

Matern Child Nutr 2017 10 15;13(4). Epub 2017 Feb 15.

Center for Public Health Genomics, University of Virginia, Charlottesville, 22908, Virginia, USA.

The lipid composition of breast milk may have a significant impact on early infant growth and cognitive development. Comprehensive breast milk data is lacking from low-income populations in the Indian subcontinent impeding assessment of deficiencies and limiting development of maternal nutritional interventions. A single breast milk specimen was collected within 6 weeks postpartum from two low-income maternal cohorts of exclusively breastfed infants, from Dhaka, Bangladesh (n = 683) and Kolkata, India (n = 372) and assayed for percentage composition of 26 fatty acids. Mature milk (>15 days) in Dhaka (n = 99) compared to Kolkata (n = 372) was higher in total saturated fatty acid (SFA; mean 48% vs. 44%) and disproportionately lower in ω3-polyunsaturated fatty acid (PUFA), hence the ω6- and ω3-PUFA ratio in Dhaka were almost double the value in Kolkata. In both sites, after adjusting for days of lactation, increased maternal education was associated with decreased SFA and PUFA, and increasing birth order or total pregnancies was associated with decreasing ω6-PUFA or ω3-PUFA by a factor of 0.95 for each birth and pregnancy. In Dhaka, household prosperity was associated with decreased SFA and PUFA and increased ω6- and ω3-PUFA. Maternal height was associated with increased SFA and PUFA in Kolkata (1% increase per 1 cm), but body mass index showed no independent association with either ratio in either cohort. In summary, the socioeconomic factors of maternal education and household prosperity were associated with breast milk composition, although prosperity may only be important in higher cost of living communities. Associated maternal biological factors were height and infant birth order, but not adiposity. Further study is needed to elucidate the underlying mechanisms of these effects.
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http://dx.doi.org/10.1111/mcn.12423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638057PMC
October 2017

Genome-Wide Analysis in Brazilians Reveals Highly Differentiated Native American Genome Regions.

Mol Biol Evol 2017 03;34(3):559-574

Center for Global Health, University of Virginia, Charlottesville, VA.

Despite its population, geographic size, and emerging economic importance, disproportionately little genome-scale research exists into genetic factors that predispose Brazilians to disease, or the population genetics of risk. After identification of suitable proxy populations and careful analysis of tri-continental admixture in 1,538 North-Eastern Brazilians to estimate individual ancestry and ancestral allele frequencies, we computed 400,000 genome-wide locus-specific branch length (LSBL) Fst statistics of Brazilian Amerindian ancestry compared to European and African; and a similar set of differentiation statistics for their Amerindian component compared with the closest Asian 1000 Genomes population (surprisingly, Bengalis in Bangladesh). After ranking SNPs by these statistics, we identified the top 10 highly differentiated SNPs in five genome regions in the LSBL tests of Brazilian Amerindian ancestry compared to European and African; and the top 10 SNPs in eight regions comparing their Amerindian component to the closest Asian 1000 Genomes population. We found SNPs within or proximal to the genes CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch, while SNPs in the genes ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) were most highly differentiated in the Asian comparison. These genes are known to influence immune function, metabolic and anthropometry traits, and embryonic development. These analyses have identified candidate genes for selection within Amerindian ancestry, and by comparison of the two analyses, those for which the differentiation may have arisen during the migration from Asia to the Americas.
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http://dx.doi.org/10.1093/molbev/msw249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430616PMC
March 2017

Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.

Diabetes Care 2016 Nov 15;39(11):1915-1924. Epub 2016 Aug 15.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Research Design And Methods: A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality.

Results: Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10 and P = 2 × 10, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029).

Conclusions: Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.
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http://dx.doi.org/10.2337/dc16-0285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079609PMC
November 2016
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