Publications by authors named "Amit Patki"

34 Publications

Mendelian randomization in the multivariate general linear model framework.

Genet Epidemiol 2021 Oct 21. Epub 2021 Oct 21.

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Mendelian randomization (MR) is an application of instrumental variable (IV) methods to observational data in which the IV is a genetic variant. MR methods applicable to the general exponential family of distributions are currently not well characterized. We adapt a general linear model framework to the IV setting and propose a general MR method applicable to any full-rank distribution from the exponential family. Empirical bias and coverage are estimated via simulations. The proposed method is compared to several existing MR methods. Real data analyses are performed using data from the REGARDS study to estimate the potential causal effect of smoking frequency on stroke risk in African Americans. In simulations with binary variates and very weak instruments the proposed method had the lowest median [Q , Q ] bias (0.10 [-3.68 to 3.62]); compared with 2SPS (0.27 [-3.74 to 4.26]) and the Wald method (-0.69 [-1.72 to 0.35]). Low bias was observed throughout other simulation scenarios; as well as more than 90% coverage for the proposed method. In simulations with count variates, the proposed method performed comparably to 2SPS; the Wald method maintained the most consistent low bias; and 2SRI was biased towards the null. Real data analyses find no evidence for a causal effect of smoking frequency on stroke risk. The proposed MR method has low bias and acceptable coverage across a wide range of distributional scenarios and instrument strengths; and provides a more parsimonious framework for asymptotic hypothesis testing compared to existing two-stage procedures.
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http://dx.doi.org/10.1002/gepi.22435DOI Listing
October 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

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

Genome Med 2021 Apr 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-Exome Sequencing and hiPSC Cardiomyocyte Models Identify , , and of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population.

Front Genet 2021 19;12:588452. Epub 2021 Feb 19.

College of Public Health, University of Kentucky, Lexington, KY, United States.

: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. We conducted an exome-wide association study of LV mass (LVM) adjusted to height, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (), trafficking protein particle complex 11 (), and solute carrier family 27 member 6 ()] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. knockdowns showed a significant decrease in atrial natriuretic factor () and brain natriuretic peptide () expression. Knockdowns of the heart long chain fatty acid (FA) transporter resulted in downregulated caveolin 3 () expression, which has been linked to hypertrophic phenotypes in animal models. Finally, knockdown was linked to deficient calcium handling. : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.
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http://dx.doi.org/10.3389/fgene.2021.588452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933688PMC
February 2021

Neighborhood Walkability as a Predictor of Incident Hypertension in a National Cohort Study.

Front Public Health 2021 1;9:611895. Epub 2021 Feb 1.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.

The built environment (BE) has been associated with health outcomes in prior studies. Few have investigated the association between neighborhood walkability, a component of BE, and hypertension. We examined the association between neighborhood walkability and incident hypertension in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Walkability was measured using Street Smart Walk Score based on participants' residential information at baseline (collected between 2003 and 2007) and was dichotomized as more (score ≥70) and less (score <70) walkable. The primary outcome was incident hypertension defined at the second visit (collected between 2013 and 2017). We derived risk ratios (RR) using modified Poisson regression adjusting for age, race, sex, geographic region, income, alcohol use, smoking, exercise, BMI, dyslipidemia, diabetes, and baseline blood pressure (BP). We further stratified by race, age, and geographic region. Among 6,894 participants, 6.8% lived in more walkable areas and 38% ( = 2,515) had incident hypertension. In adjusted analysis, neighborhood walkability (Walk Score ≥70) was associated with a lower risk of incident hypertension (RR [95%CI]: 0.85[0.74, 0.98], = 0.02), with similar but non-significant trends in race and age strata. In secondary analyses, living in a more walkable neighborhood was protective against being hypertensive at both study visits (OR [95%CI]: 0.70[0.59, 0.84], < 0.001). Neighborhood walkability was associated with incident hypertension in the REGARDS cohort, with the relationship consistent across race groups. The results of this study suggest increased neighborhood walkability may be protective for high blood pressure in black and white adults from the general US population.
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http://dx.doi.org/10.3389/fpubh.2021.611895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882902PMC
May 2021

Correction to: Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2020 Feb 10;20(1):111. Epub 2020 Feb 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

After publication of the original article [1], we were notified that Fig. 3 has "Fig. 1" posted on the top of it and Figs. 4 and 5 have "Genomic Position" in a different spot.
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http://dx.doi.org/10.1186/s12879-020-4766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008528PMC
February 2020

Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2019 Dec 10;19(1):1046. Epub 2019 Dec 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

Background: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and a leading cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Despite extensive research, clinical or laboratory markers to identify CMV infected children with increased risk for disease have not been identified. This study utilizes viral whole-genome next generation-sequencing (NGS) of specimens from congenitally infected infants to explore viral diversity and specific viral variants that may be associated with symptomatic infection and SNHL.

Methods: CMV DNA from urine specimens of 30 infants (17 asymptomatic, 13 symptomatic) was target enriched and next generation sequenced resulting in 93% coverage of the CMV genome allowing analysis of viral diversity.

Results: Variant frequency distribution was compared between children with symptomatic and asymptomatic cCMV and those with (n = 13) and without (n = 17) hearing loss. The CMV genes UL48A, UL88, US19 and US22 were found to have an increase in nucleotide diversity in symptomatic children; while UL57, UL20, UL104, US14, UL115, and UL35 had an increase in diversity in children with hearing loss. An analysis of single variant differences between symptomatic and asymptomatic children found UL55 to have the highest number, while the most variants associated with SNHL were in the RL11 gene family. In asymptomatic infants with SNHL, mutations were observed more frequently in UL33 and UL20.

Conclusion: CMV genomes from infected newborns can be mapped to 93% of the genome at a depth allowing accurate and reproducible analysis of polymorphisms for variant and gene discovery that may be linked to symptomatic and hearing loss outcomes.
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http://dx.doi.org/10.1186/s12879-019-4681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905059PMC
December 2019

Changes in Bone Mass After Discontinuation of Preexposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine in Young Men Who Have Sex With Men: Extension Phase Results of Adolescent Trials Network Protocols 110 and 113.

Clin Infect Dis 2020 02;70(4):687-691

Department of Medicine, University of California at San Francisco, Zuckerberg San Francisco General Hospital.

Human immunodeficiency virus-seronegative men aged 15-22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15-19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113).
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http://dx.doi.org/10.1093/cid/ciz486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319267PMC
February 2020

Brief Report: Role of Sociobehavioral Factors in Subprotective TFV-DP Levels Among YMSM Enrolled in 2 PrEP Trials.

J Acquir Immune Defic Syndr 2019 02;80(2):160-165

Department of Psychiatry, Stroger Hospital of Cook County, Chicago, IL.

Background: Young men who have sex with men (YMSM) experience disparities in HIV acquisition more than any other group. Daily oral pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine has been shown to effectively prevent HIV transmission in YMSM; however, recent studies suggest that young Black men who have sex with men experience subprotective levels of tenofovir diphosphate more frequently than other groups.

Setting: Combined data from Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 110/113, 2 open-label PrEP studies that provided PrEP and evidence-based behavioral interventions to YMSM aged 15-22 years.

Methods: Bivariate and logistic regression analyses were used to examine sociodemographic and behavioral factors associated with protective tenofovir diphosphate levels (defined as ≥700 fmol/punch) in ATN 110/113 data.

Results: In bivariate analysis, self-identified Black participants, residential displacement due to sexual orientation, low perceived risk, and stigma with the medication were associated with subprotective levels. Hispanic ethnicity was associated with protective levels. In the final models, Black males were less likely to have subprotective levels than non-Black males at 4, 8, and 12 weeks. Self-reported displacement due to sexual orientation was associated with subprotective levels, whereas older age was as associated with protective levels.

Conclusions: These findings highlight how future behavioral research and biomedical prevention efforts in YMSM will need to address PrEP disparities that may occur in young Black men who have sex with men, perception of risk, and lack of key supportive housing during this period that may be critical factors that contribute to HIV acquisition.
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http://dx.doi.org/10.1097/QAI.0000000000001901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486465PMC
February 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019

Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

Obesity (Silver Spring) 2018 11;26(11):1733-1739

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice.

Methods: In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a "normal" or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression.

Results: Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding.

Conclusions: Weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.
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http://dx.doi.org/10.1002/oby.22290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221135PMC
November 2018

Epigenome-wide association study of metabolic syndrome in African-American adults.

Clin Epigenetics 2018 10;10:49. Epub 2018 Apr 10.

2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL USA.

Background: The high prevalence of obesity among US adults has resulted in significant increases in associated metabolic disorders such as diabetes, dyslipidemia, and high blood pressure. Together, these disorders constitute metabolic syndrome, a clinically defined condition highly prevalent among African-Americans. Identifying epigenetic alterations associated with metabolic syndrome may provide additional information regarding etiology beyond current evidence from genome-wide association studies.

Methods: Data on metabolic syndrome and DNA methylation was assessed on 614 African-Americans from the Hypertension Genetic Epidemiology Network (HyperGEN) study. Metabolic syndrome was defined using the joint harmonized criteria, and DNA methylation was assessed using the Illumina HumanMethylation450K Bead Chip assay on DNA extracted from buffy coat. Linear mixed effects regression models were used to examine the association between CpG methylation at > 450,000 CpG sites and metabolic syndrome adjusted for study covariates. Replication using DNA from a separate sample of 69 African-Americans, as well as meta-analysis combining both cohorts, was conducted.

Results: Two differentially methylated CpG sites in the gene on chromosome 17 (cg06638433; value = 3.10 × 10) and the gene on chromosome 21 (cg06500161; value = 2.60 × 10) were identified. Results for the gene remained statistically significant in the replication dataset and meta-analysis.

Conclusion: Metabolic syndrome was consistently associated with increased methylation in the gene in the discovery and replication datasets, a gene that encodes a protein in the ATP-binding cassette transporter family and is involved in intra- and extra-cellular signaling and lipid transport.
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http://dx.doi.org/10.1186/s13148-018-0483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891946PMC
February 2019

No Significant Effect of Maternal Perception of the Food Environment on Reproductive Success or Pup Outcomes in C57BL/6J Mice.

Obesity (Silver Spring) 2018 04 24;26(4):723-729. Epub 2018 Feb 24.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: Prior work concerning maternal perception of the food environment suggests that perceived disparities in food resources resulted in reduced pup mass and dam reproductive success. This study attempted to replicate this result with increased sample size and additional measures.

Methods: Female C57BL/6J mice (n = 160; 3 weeks old) were randomly assigned to either subject or peer and were pair housed in partitioned cages with olfactory and visual contact. After a 6-week maturation period on an energy-rich cafeteria diet, cages were randomly assigned to Control (subject and peer fed pelleted diet) or Treatment (subject fed pellets, peer fed cafeteria diet), and subjects were bred. After weaning, one pup from each sex per litter was reared to 5 months.

Results: Treatment did not affect the number of births, pup size at birth, or the proportion of pups surviving to weaning (P > 0.09). Treatment did not affect dam body or fat mass at parturition (P > 0.22), but these measures were higher in some Treatment dams at weaning (P < 0.05). Smaller female pups were weaned from Treatment dams pregnant on the first breeding attempt (P = 0.01), but no other pup effects were observed (P > 0.07).

Conclusions: Exposure to food-environment disparity in this study did not replicate previous findings or affect pup growth after weaning.
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http://dx.doi.org/10.1002/oby.22141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866215PMC
April 2018

Adiposity and Reproductive Cycling Status in Zoo African Elephants.

Obesity (Silver Spring) 2018 01;26(1):103-110

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objective: The majority of zoo African elephants exhibit abnormal reproductive cycles, but it is unclear why. Acyclicity has been positively associated with body condition scores. The objective of this study was to measure body composition and examine the relationship between adiposity and cyclicity status, mediated by glucose, insulin, leptin, and inflammation.

Methods: Body composition was assessed by deuterium dilution in 22 African elephants. Each elephant was weighed and given deuterated water orally (0.05 mL/kg), and blood was collected from the ear prior to and five times after deuterium administration. Glucose, insulin, leptin, and proinflammatory biomarker concentrations in serum were determined.

Results: Body fat percentage ranged from 5.24% to 15.97%. Fat adjusted for fat free mass (FFM) and age was not significantly associated with cyclicity status (P = 0.332). Age was the strongest predictor of cyclicity status (P = 0.040). Fat was correlated with weight (ρ = 0.455, P = 0.044) and when adjusted for FFM with circulating glucose (ρ = 0.520, P = 0.022) and showed a trend for association with leptin (unadjusted: ρ = 0.384, P = 0.095; adjusted for FFM: ρ = 0.403, P = 0.087).

Conclusions: Deuterium dilution appears to be an available technique to measure body composition in African elephants. In this sample, fat was not associated with cyclicity status, and age may be more important to cyclicity status.
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http://dx.doi.org/10.1002/oby.22046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744898PMC
January 2018

Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array.

Pharmacogenomics 2017 Jul 7;18(11):1059-1073. Epub 2017 Jul 7.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Aim: We conducted a genome-wide association study using the Illumina Exome Array to identify coding SNPs that may explain additional warfarin dose variability.

Patients & Methods: Analysis was performed after adjustment for clinical variables and genetic factors known to influence warfarin dose among 1680 warfarin users (838 European-Americans and 842 African-Americans). Replication was performed in an independent sample.

Results: We confirmed the influence of known genetic variants on warfarin dose variability. Our study is the first to show the association between rs12772169 and warfarin dose in African-Americans. In addition, genes COX15 and FGF5 showed significant association in European-Americans.

Conclusion: We identified some novel genes/SNPs that underpin warfarin dose response. Further replication is needed to confirm our findings.
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http://dx.doi.org/10.2217/pgs-2017-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619051PMC
July 2017

Longevity is impacted by growth hormone action during early postnatal period.

Elife 2017 07 4;6. Epub 2017 Jul 4.

Department of Internal Medicine, Southern Illinois University, School of Medicine, Springfield, United States.

Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease.
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http://dx.doi.org/10.7554/eLife.24059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515575PMC
July 2017

Sex-dependent Differences in Liver and Gut Metabolomic Profiles With Acarbose and Calorie Restriction in C57BL/6 Mice.

J Gerontol A Biol Sci Med Sci 2018 01;73(2):157-165

Department of Nutrition Sciences, University of Alabama at Birmingham.

Acarbose, an alpha-glucosidase inhibitor used in treating type 2 diabetes, impairs complex carbohydrate digestion and absorption and extends life span in mice (without a requisite reduction in food intake). To assess sex-differential effects coincident with calorie restriction versus a nonrestricted longevity enhancing intervention, we evaluated the metabolite profiles (by liquid chromatography-mass spectroscopy) from livers and cecal contents of C57BL/6J mice (n = 4/sex/group), which were maintained for 10 months under one of the three diet treatments: ad libitum control diet (CON), ad libitum control diet containing 0.1% acarbose (ACA), or 40% calorie restriction using the control diet (CR). Principal component analysis revealed sex-differential profiles with ACA in livers. Of the identified metabolites (n = 621) in liver, CR significantly altered ~44% (males:187↑/131↓, females:74↑/148↓) compared with CON, in contrast with ACA (M:165↑/61↓, F:52↑/60↓). Dissimilarity in ACA-F liver metabolites was observed for ~50% of common metabolites from ACA-M and CR-M/F. CR resulted in fewer significant cecal metabolite differences (n = 615 metabolites; M:86↑/66↓, F:51↑/48↓ vs CON), relative to ACA treatment (M:32↑/189↓, F:36↑/137↓). Metabolomic profiling identifies sex-differential and tissue-specific effects with amino acid metabolism sub-pathways including those involving tryptophan, branch-chain and sulfur amino acids, and the urea cycle, as well as bile acid, porphyrin, and cofactor metabolism pathways.
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http://dx.doi.org/10.1093/gerona/glx127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861978PMC
January 2018

Observational research rigour alone does not justify causal inference.

Eur J Clin Invest 2016 Dec 28;46(12):985-993. Epub 2016 Oct 28.

Office of Energetics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Differing opinions exist on whether associations obtained in observational studies can be reliable indicators of a causal effect if the observational study is sufficiently well controlled and executed.

Materials And Methods: To test this, we conducted two animal observational studies that were rigorously controlled and executed beyond what is achieved in studies of humans. In study 1, we randomized 332 genetically identical C57BL/6J mice into three diet groups with differing food energy allotments and recorded individual self-selected daily energy intake and lifespan. In study 2, 60 male mice (CD1) were paired and divided into two groups for a 2-week feeding regimen. We evaluated the association between weight gain and food consumption. Within each pair, one animal was randomly assigned to an S group in which the animals had free access to food. The second paired animal (R group) was provided exactly the same diet that their S partner ate the day before.

Results: In study 1, across all three groups, we found a significant negative effect of energy intake on lifespan. However, we found a positive association between food intake and lifespan among the ad libitum feeding group: 29·99 (95% CI: 8·2-51·7) days per daily kcal. In study 2, we found a significant (P = 0·003) group (randomized vs. self-selected)-by-food consumption interaction effect on weight gain.

Conclusion: At least in nutrition research, associations derived from observational studies may not be reliable indicators of causal effects, even with the most rigorous study designs achievable.
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http://dx.doi.org/10.1111/eci.12681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118066PMC
December 2016

Longevity and plasticity of CFTR provide an argument for noncanonical SNP organization in hominid DNA.

PLoS One 2014 28;9(10):e109186. Epub 2014 Oct 28.

Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Like many other ancient genes, the cystic fibrosis transmembrane conductance regulator (CFTR) has survived for hundreds of millions of years. In this report, we consider whether such prodigious longevity of an individual gene--as opposed to an entire genome or species--should be considered surprising in the face of eons of relentless DNA replication errors, mutagenesis, and other causes of sequence polymorphism. The conventions that modern human SNP patterns result either from purifying selection or random (neutral) drift were not well supported, since extant models account rather poorly for the known plasticity and function (or the established SNP distributions) found in a multitude of genes such as CFTR. Instead, our analysis can be taken as a polemic indicating that SNPs in CFTR and many other mammalian genes may have been generated--and continue to accrue--in a fundamentally more organized manner than would otherwise have been expected. The resulting viewpoint contradicts earlier claims of 'directional' or 'intelligent design-type' SNP formation, and has important implications regarding the pace of DNA adaptation, the genesis of conserved non-coding DNA, and the extent to which eukaryotic SNP formation should be viewed as adaptive.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211684PMC
June 2015

Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.

Circ Cardiovasc Genet 2013 Feb 28;6(1):37-46. Epub 2012 Dec 28.

Department of Medicine, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA.

Background: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

Methods And Results: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

Conclusions: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
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http://dx.doi.org/10.1161/CIRCGENETICS.111.962365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591479PMC
February 2013

Subclinical, hemodynamic, and echocardiographic abnormalities of high pulse pressure in hypertensive and non-hypertensive adults.

Am J Cardiovasc Dis 2012 25;2(4):309-17. Epub 2012 Oct 25.

University of Alabama at Birmingham AL.

Background: High pulse pressure (PP) is associated with cardiovascular events, but subclinical abnormalities in cardiac structure and function in relation to high pulse pressure are not well described.

Methods And Results: 2225 hypertensive and 1380 non-hypertensive participants with adequate echocardiographic left ventricular measurements were evaluated. Non-hypertensives in the highest PP tertile (compared to the lower tertiles) were older (44 years vs. 40 years, p<0.009), had higher systolic pressure [(SBP) 136 mmHg vs. 108 mmHg] and lower diastolic pressure [(DBP) 54 vs. 71 mmHg (p=.0001)], greater BMI (27 vs. 25 kg/m2, p<.001) and more diabetes (4% vs. 2.25%, p<.001). In the hypertensive group, subjects in the highest PP tertile were older (52 vs 42 years), had higher SBP (157 vs. 116 mmHg) but lower DBP (65 vs. 83 mmHg). In the non-hypertensive group, higher PP (>60 mmHG) was associated with a higher frequency of echocardiographic structural and functional abnormalities, specifically, greater posterior and relative wall thickness, longer isovolumic relaxation time, and concentric left ventricular (LV) hypertrophy.

Conclusion: In a population-based sample of hypertensive and non-hypertensive participants, higher PP was associated with subclinical abnormalities of cardiac structure and function, which exist even in the absence of hypertension and/or the use of antihypertensive treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499939PMC
November 2012

Controlling Population Structure in Human Genetic Association Studies with Samples of Unrelated Individuals.

Stat Interface 2011 ;4(3):317-326

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294.

In genetic studies, associations between genotypes and phenotypes may be confounded by unrecognized population structure and/or admixture. Studies have shown that even in European populations, which are thought to be relatively homogeneous, population stratification exists and can affect the validity of association studies. A number of methods have been proposed to address this issue in recent years. Among them, the mixed-model based approach and the principal component-based approach have several advantages over other methods. However, these approaches have not been thoroughly evaluated on large human datasets. The objectives of this study are to (1) evaluate and compare the performance of the mixed-model approach and the principal component-based approach for genetic association mapping using human data consisting of unrelated individuals, and (2) understand the relationship between these two approaches. To achieve these goals, we simulate datasets based on the HapMap data under various scenarios. Our results indicate that the mixed-model approach performs well in controlling for population structure/admixture. It has similar performance as that based on principal component analysis. However, the approach combining mixed-model and principal component analysis does not perform as well as either method itself.
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http://dx.doi.org/10.4310/sii.2011.v4.n3.a6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269890PMC
January 2011

Real data examples in statistical methods papers: Tremendously valuable, and also tremendously misvalued.

Stat Interface 2011 ;4(3):267-272

Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

When a statistical methods paper is submitted to a journal for publication, examples in which the method is applied to real data are highly encouraged by many journals and in some cases are explicitly demanded. In this commentary, we argue that real data examples serve several useful purposes. However, we also argue that in many cases, particularly in the fields of genetics and genomics, there is an implicit or explicit expectation for examples to support purposes for which they are ill-suited and furthermore that these inappropriate expectations have negative consequences for the field. We conclude by noting that real data examples can be tremendously valuable and should continue to be used where appropriate, but that the demands for, expectations of, and conclusions drawn from them need to be scaled back.
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http://dx.doi.org/10.4310/sii.2011.v4.n3.a1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225256PMC
January 2011

Association of Allelic Variation in Genes Mediating Aspects of Energy Homeostasis with Weight Gain during Administration of Antipsychotic Drugs (CATIE Study).

Front Genet 2011 1;2:56. Epub 2011 Sep 1.

Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham Birmingham, AL, USA.

Antipsychotic drugs are widely used in treating schizophrenia, bipolar disorder, and other psychiatric disorders. Many of these drugs, despite their therapeutic advantages, substantially increase body weight. We assessed the association of alleles of 31 genes implicated in body weight regulation with weight gain among patients being treated with specific antipsychotic medications in the clinical antipsychotic trials in intervention effectiveness study, we found that rs2237988 in Potassium Channel Inwardly Rectifying Subfamily J Member 11 (KCNJ11), rs13269119 in Solute carrier family 30 member 8 (SLC30A8), and rs9922047 in fat mass and obesity associated (FTO) were associated with percent weight gain. We also observed the significant interaction of rs11643744 by treatment effect on the weight gain.
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http://dx.doi.org/10.3389/fgene.2011.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202977PMC
April 2013

Accurate and flexible power calculations on the spot: Applications to genomic research.

Stat Interface 2011 ;4(3):353-358

Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA,

Often investigators need to calculate power to demonstrate feasibility of proposed genetic studies for grant proposals or simply to aid in their own study planning. Frequently, power can be easily calculated using a closed form formula. However, in some situations such formulae for calculating power have not been derived and derivation on demand may be difficult if not impossible. In these situations investigators typically perform simulations specific to the study. Yet such simulations can be computationally extensive and take weeks to months depending on the circumstances. Here, we provide a simple method to rapidly estimate power when one has power estimates available for corresponding situations that differ from the situation of interest only in sample size and/or alpha (type I error) level desired. We show by application to multiple published results from the genomics field that these methods are generally very accurate and applicable to a broad range of genomic studies.
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http://dx.doi.org/10.4310/sii.2011.v4.n3.a9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196559PMC
January 2011

Genome-wide joint SNP and CNV analysis of aortic root diameter in African Americans: the HyperGEN study.

BMC Med Genomics 2011 Jan 11;4. Epub 2011 Jan 11.

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

Background: Aortic root diameter is a clinically relevant trait due to its known relationship with the pathogenesis of aortic regurgitation and risk for aortic dissection. African Americans are an understudied population despite a particularly high burden of cardiovascular diseases. We report a genome-wide association study on aortic root diameter among African Americans enrolled in the HyperGEN study. We invoked a two-stage, mixed model procedure to jointly identify SNP allele and copy number variation effects.

Results: Results suggest novel genetic contributors along a large region between the CRCP and KCTD7 genes on chromosome 7 (p = 4.26 × 10(-7)); and the SIRPA and PDYN genes on chromosome 20 (p = 3.28 × 10(-8)).

Conclusions: The regions we discovered are candidates for future studies on cardiovascular outcomes, particularly in African Americans. The methods we employed can also provide an outline for genetic researchers interested in jointly testing SNP and CNV effects and/or applying mixed model procedures on a genome-wide scale.
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http://dx.doi.org/10.1186/1755-8794-4-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027088PMC
January 2011

Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families.

Circ Res 2011 Feb 6;108(3):279-83. Epub 2011 Jan 6.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, RPHB 220E, 1530 3rd Ave South, Birmingham, AL 35294-0022, USA.

Rationale: Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals.

Objective: Identify genetic predictors of echocardiographic phenotypes in hypertensive families.

Methods And Results: A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestry: in stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had P≤10(-6). In stage II, 1 SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In stage III, rs1436109 was associated with RWT (P=5.47×10(-4)) and LVID (P=1.86×10(-4)). Fisher combined probability value for all stages was RWT=3.80×10(-9), PWT=3.12×10(-7), IVST=8.69×10(-7), LV mass=2.52×10(-3), and LVID=4.80×10(-4).

Conclusions: This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt-sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.
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http://dx.doi.org/10.1161/CIRCRESAHA.110.239210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328104PMC
February 2011

Genes and biochemical pathways in human skeletal muscle affecting resting energy expenditure and fuel partitioning.

J Appl Physiol (1985) 2011 Mar 25;110(3):746-55. Epub 2010 Nov 25.

Dept. of Nutrition Sciences, The Univ. of Alabama at Birmingham, 1675 University Blvd., Birmingham, AL 35294-3360, USA.

Genes influencing resting energy expenditure (REE) and respiratory quotient (RQ) represent candidate genes for obesity and the metabolic syndrome because of the involvement of these traits in energy balance and substrate oxidation. We aim to explore the molecular basis for individual variation in REE and fuel partitioning as reflected by RQ. We performed microarray studies in human vastus lateralis muscle biopsies from 40 healthy subjects with measured REE and RQ values. We identified 2,392 and 1,115 genes significantly correlated with REE and RQ, respectively. Genes correlated with REE and RQ encompass a broad array of functions, including carbohydrate and lipid metabolism, gene expression, mitochondrial processes, and membrane transport. Microarray pathway analysis revealed that REE was positively correlated with upregulation of G protein-coupled receptor signaling (meet criteria/total genes: 65 of 283) involved in autonomic nervous system functions, including those receptors mediating adrenergic, dopamine, γ-aminobutyric acid (GABA), neuropeptide Y (NPY), and serotonin action (meet criteria/total genes: 46 of 176). Reduced REE was associated with an increase in genes participating in ubiquitin-proteasome-dependent proteolytic pathways (58 of 232). Serine-type peptidase activity (9 of 76) was positively correlated with RQ, while genes involved in the protein phosphatase type 2A complex (4 of 9), mitochondrial function and cellular respiration (38 of 315), and unfolded protein binding (19 of 97) were associated with reduced RQ values and a preference for lipid fuel metabolism. Individual variations in whole body REE and RQ are regulated by differential expressions of specific genes and pathways intrinsic to skeletal muscle.
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http://dx.doi.org/10.1152/japplphysiol.00293.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070475PMC
March 2011

Within-Cluster Resampling for Analysis of Family Data: Ready for Prime-Time?

Stat Interface 2010 Apr;3(2):169-176

Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294.

Hoffman et al. [1] proposed an elegant resampling method for analyzing clustered binary data. The focus of their paper was to perform association tests on clustered binary data using within-cluster-resampling (WCR) method. Follmann et al. [2] extended Hoffman et al.'s procedure more generally with applicability to angular data, combining of p-values, testing of vectors of parameters, and Bayesian inference. Follmann et al. [2] termed their procedure multiple outputation because all "excess" data within each cluster is thrown out multiple times. Herein, we refer to this procedure as WCR-MO. For any statistical test to be useful for a particular design, it must be robust, have adequate power, and be easy to implement and flexible. WCR-MO can be easily extended to continuous data and is a computationally intensive but simple and highly flexible method. Considering family as a cluster, one can apply WCR to familial data in genetic studies. Using simulations, we evaluated WCR-MO's robustness for analysis of a continuous trait in terms of type I error rates in genetic research. WCR-MO performed well at the 5% α-level. However, it provided inflated type I error rates for α-levels less than 5% implying the procedure is liberal and may not be ready for application to genetic studies where α levels used are typically much less than 0.05.
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http://dx.doi.org/10.4310/sii.2010.v3.n2.a4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907179PMC
April 2010
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