Publications by authors named "Yii-Der I Chen"

122 Publications

Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease.

Mol Metab 2021 Sep 24;54:101342. Epub 2021 Sep 24.

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

Objective: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine.

Methods: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data.

Results: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (P <2.02 × 10). Trait associations were replicated in IRASFS African Americans (P < 1.12 × 10). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (S), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (P = 9.00 × 10, P = 2.31 × 10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (P = 6.64 × 10).

Conclusions: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.
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http://dx.doi.org/10.1016/j.molmet.2021.101342DOI Listing
September 2021

Sequencing of 640,000 exomes identifies variants associated with protection from obesity.

Science 2021 07;373(6550)

Geisinger Obesity Institute, Geisinger Health System, Danville, PA 17882, USA.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (, , , , and ). Protein-truncating variants in were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
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http://dx.doi.org/10.1126/science.abf8683DOI Listing
July 2021

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Metabolites 2021 Jun 26;11(7). Epub 2021 Jun 26.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.
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http://dx.doi.org/10.3390/metabo11070420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304591PMC
June 2021

Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.

PLoS One 2021 20;16(5):e0251423. Epub 2021 May 20.

Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136717PMC
October 2021

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Hum Mol Genet 2021 Jul;30(15):1443-1456

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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http://dx.doi.org/10.1093/hmg/ddab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283205PMC
July 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Multi-omics analysis identifies CpGs near G6PC2 mediating the effects of genetic variants on fasting glucose.

Diabetologia 2021 Jul 12;64(7):1613-1625. Epub 2021 Apr 12.

Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Aims/hypothesis: An elevated fasting glucose level in non-diabetic individuals is a key predictor of type 2 diabetes. Genome-wide association studies (GWAS) have identified hundreds of SNPs for fasting glucose but most of their functional roles in influencing the trait are unclear. This study aimed to identify the mediation effects of DNA methylation between SNPs identified as significant from GWAS and fasting glucose using Mendelian randomisation (MR) analyses.

Methods: We first performed GWAS analyses for three cohorts (Taiwan Biobank with 18,122 individuals, the Healthy Aging Longitudinal Study in Taiwan with 1989 individuals and the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance with 416 individuals) with individuals of Han Chinese ancestry in Taiwan, followed by a meta-analysis for combining the three GWAS analysis results to identify significant and independent SNPs for fasting glucose. We determined whether these SNPs were methylation quantitative trait loci (meQTLs) by testing their associations with DNA methylation levels at nearby CpG sites using a subsample of 1775 individuals from the Taiwan Biobank. The MR analysis was performed to identify DNA methylation with causal effects on fasting glucose using meQTLs as instrumental variables based on the 1775 individuals. We also used a two-sample MR strategy to perform replication analysis for CpG sites with significant MR effects based on literature data.

Results: Our meta-analysis identified 18 significant (p < 5 × 10) and independent SNPs for fasting glucose. Interestingly, all 18 SNPs were meQTLs. The MR analysis identified seven CpGs near the G6PC2 gene that mediated the effects of a significant SNP (rs2232326) in the gene on fasting glucose. The MR effects for two CpGs were replicated using summary data based on the European population, using an exonic SNP rs2232328 in G6PC2 as the instrument.

Conclusions/interpretation: Our analysis results suggest that rs2232326 and rs2232328 in G6PC2 may affect DNA methylation at CpGs near the gene and that the methylation may have downstream effects on fasting glucose. Therefore, SNPs in G6PC2 and CpGs near G6PC2 may reside along the pathway that influences fasting glucose levels. This is the first study to report CpGs near G6PC2, an important gene for regulating insulin secretion, mediating the effects of GWAS-significant SNPs on fasting glucose.
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http://dx.doi.org/10.1007/s00125-021-05449-9DOI Listing
July 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

Physical Activity Associations with Bone Mineral Density and Modification by Metabolic Traits.

J Endocr Soc 2020 Aug 7;4(8):bvaa092. Epub 2020 Jul 7.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Objective: To assess the relationship of physical activity with bone mineral density (BMD) at various sites and examine potential modifying metabolic factors.

Methods: Responses from physical activity questionnaires were used to determine total physical activity (PA), moderate physical activity (mod-PA), and sedentary time. Regression analyses were performed to evaluate association of activity traits with insulin sensitivity by euglycemic clamp, adiponectin, C-reactive protein (CRP), and plasminogen activator inhibitor-1 (PAI-1) in 741 healthy subjects.

Results: The cohort was relatively sedentary. Activity level was associated with arm, pelvis, and leg BMD in univariate analyses. In multivariate association analyses of arm BMD, only female sex (β = -0.73, < 0.0001) and adiponectin (β = -0.076, = 0.0091) were significant. Multivariate analyses of pelvis BMD found independent associations with body mass index (BMI) (β = 0.33, < 0.0001), adiponectin (β = -0.10, = 0.013), female sex (β = -0.18, < 0.0001), sedentary time (β = -0.088, = 0.034), PA (β = 0.11, = 0.01), and mod-PA (β = 0.11, = 0.014). Age (β = -0.10, = 0.0087), female sex (β = -0.63, < 0.0001), BMI (β = 0.24, < 0.0001), and mod-PA (β = 0.10, = 0.0024) were independently associated with leg BMD.

Conclusions: These results suggest that BMD increases with physical activity in the arms, legs, and pelvis and is inversely related to sedentary time in the pelvis and legs; these associations may be modified by age, sex, BMI, and adiponectin, depending on the site, with physical activity being more important to pelvis and leg BMD than arm BMD and sedentary time being important for pelvis BMD. Moreover, we demonstrated that CRP, PAI-1, and insulin sensitivity play a minor role in BMD.
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http://dx.doi.org/10.1210/jendso/bvaa092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417873PMC
August 2020

Genetic variants modulate gene expression statin response in human lymphoblastoid cell lines.

BMC Genomics 2020 Aug 12;21(1):555. Epub 2020 Aug 12.

Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.

Background: Statins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene's transcription start site.

Results: From the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone.

Conclusions: Several of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.
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http://dx.doi.org/10.1186/s12864-020-06966-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430882PMC
August 2020

Rationale, design and baseline characteristics of the Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Diabetes Obes Metab 2020 11 20;22(11):1976-1984. Epub 2020 Aug 20.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Aim: To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D).

Materials And Methods: The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline.

Results: After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance.

Conclusions: The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.
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http://dx.doi.org/10.1111/dom.14145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444996PMC
November 2020

Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

J Clin Endocrinol Metab 2020 04;105(4)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, US.

Context: Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D).

Objective: To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans.

Design, Setting, And Participants: A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans.

Results: Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method.

Conclusions: Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.
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http://dx.doi.org/10.1210/clinem/dgz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059988PMC
April 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

Association of severity of primary open-angle glaucoma with serum vitamin D levels in patients of African descent.

Mol Vis 2019 9;25:438-445. Epub 2019 Aug 9.

Viterbi Family Department of Ophthalmology, Shiley Eye Institute, Hamilton Glaucoma Center, UC San Diego, La Jolla, CA.

Purpose: To study the relationship between primary open-angle glaucoma (POAG) in a cohort of patients of African descent (AD) and serum vitamin D levels.

Methods: A subset of the AD and glaucoma evaluation study III (ADAGES III) cohort, consisting of 357 patients with a diagnosis of POAG and 178 normal controls of self-reported AD, were included in this analysis. Demographic information, family history, and blood samples were collected from all the participants. All the subjects underwent clinical evaluation, including visual field (VF) mean deviation (MD), central cornea thickness (CCT), intraocular pressure (IOP), and height and weight measurements. POAG patients were classified into early and advanced phenotypes based on the severity of their visual field damage, and they were matched for age, gender, and history of hypertension and diabetes. Serum 25-Hydroxy (25-OH) vitamin D levels were measured by enzyme-linked immunosorbent assay (ELISA). The association of serum vitamin D levels with the development and severity of POAG was tested by analysis of variance (ANOVA) and the paired -test.

Results: The 178 early POAG subjects had a visual field MD of better than -4.0 dB, and the 179 advanced glaucoma subjects had a visual field MD of worse than -10 dB. The mean (95% confidence interval [CI]) levels of vitamin D of the subjects in the control (8.02 ± 6.19 pg/ml) and early phenotype (7.56 ± 5.74 pg/ml) groups were significantly or marginally significantly different from the levels observed in subjects with the advanced phenotype (6.35 ± 4.76 pg/ml; p = 0.0117 and 0.0543, respectively). In contrast, the mean serum vitamin D level in controls was not significantly different from that of the subjects with the early glaucoma phenotype (p = 0.8508).

Conclusions: In this AD cohort, patients with advanced glaucoma had lower serum levels of vitamin D compared with early glaucoma and normal subjects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707754PMC
April 2020

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes.

Hepatol Commun 2019 Jul 18;3(7):894-907. Epub 2019 Apr 18.

Division of Statistical Genomics, Department of Genetics Washington University School of Medicine St. Louis MO.

The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 () gene, the glucokinase regulatory protein () gene, the neurocan/transmembrane 6 superfamily member 2 () gene and the lysophospholipase-like 1 () gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, -rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the -rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying rs738409-G may preferentially decrease hepatic steatosis.
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http://dx.doi.org/10.1002/hep4.1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601321PMC
July 2019

Genetic Risk Score in Diabetes Associated With Chronic Pancreatitis Versus Type 2 Diabetes Mellitus.

Clin Transl Gastroenterol 2019 07;10(7):e00057

Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM.

Methods: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin.

Results: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM.

Discussion: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.
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http://dx.doi.org/10.14309/ctg.0000000000000057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708663PMC
July 2019

Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium.

Obesity (Silver Spring) 2019 08 20;27(8):1331-1337. Epub 2019 Jun 20.

Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA.

Objective: Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.

Methods: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.

Results: In the PNPLA3 gene, rs4823173 (P = 3.44 × 10 ), rs2896019 (P = 7.29 × 10 ), and rs2281135 (P = 8.73 × 10 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10 , P = 1.98 × 10 , and P = 1.81 × 10 , respectively). The strong correlation (r  = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.

Conclusions: PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
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http://dx.doi.org/10.1002/oby.22527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656610PMC
August 2019

Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.

Sleep 2019 08;42(8)

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Study Objectives: Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS).

Methods: We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.

Results: In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations.

Conclusions: We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.
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http://dx.doi.org/10.1093/sleep/zsz101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685317PMC
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

Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Mice and Humans.

Obesity (Silver Spring) 2019 03;27(3):434-443

Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, California, USA.

Objective: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.

Methods: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps.

Results: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.

Conclusions: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.
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http://dx.doi.org/10.1002/oby.22418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474357PMC
March 2019

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance, β-cell function, and diabetes in Hispanics and African Americans.

J Diabetes Complications 2019 02 3;33(2):118-122. Epub 2018 Nov 3.

Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America; VA Eastern Colorado Health Care System, Denver, CO 80220, United States of America. Electronic address:

Objective: The TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians; however, there is limited data in other ethnic groups. We hypothesized that the TG/HDL-C ratio is associated with IR in Hispanics and African Americans (AA).

Research Design And Methods: Data from the Insulin Resistance Atherosclerosis Family Study was examined for associations between TG/HDL-C ratio and IR, β-cell function and incident diabetes in non-diabetic Hispanics (n = 872, 63% female) and AA (n = 371, 61% female). Insulin sensitivity index (S) and disposition index (DI) from frequently-sampled intravenous glucose tolerance tests were used as markers of IR and β-cell function respectively. Incident type 2 diabetes was determined by fasting glucose ≥ 126 mg/dl or initiation of anti-hyperglycemia agents over 5 year follow-up.

Results: Higher TG/HDL-C ratio was associated with IR in Hispanic and AA men and women (P < 0.0002), as well as β-cell function in Hispanic women and AA men and women (P < 0.02). TG/HDL-C predicted incident type 2 diabetes in women (area under the curves 0.703 and 0.795 for Hispanics and AA respectively).

Conclusions: Similar to Caucasians, the TG/HDL-C ratio can be used to identify IR in Hispanics and AA, and may predict type 2 diabetes in women.
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http://dx.doi.org/10.1016/j.jdiacomp.2018.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331279PMC
February 2019

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

Acta Ophthalmol 2018 Nov 4;96(7):e811-e819. Epub 2018 Sep 4.

Singapore Eye Research Institute, Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore.

Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.

Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.

Results: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10 and 1.23 × 10 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).

Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
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http://dx.doi.org/10.1111/aos.13769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263819PMC
November 2018

ZNF542P is a pseudogene associated with LDL response to simvastatin treatment.

Sci Rep 2018 08 20;8(1):12443. Epub 2018 Aug 20.

Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA, 94609, USA.

Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 "signature" gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.
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http://dx.doi.org/10.1038/s41598-018-30859-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102286PMC
August 2018

Gene Is Associated With Triglyceride Levels In Subjects With Family History Of Hypertension From The SAPPHIRe And TWB Projects.

Int J Med Sci 2018 14;15(10):1035-1042. Epub 2018 Jun 14.

Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Taiwan.

Chromosome 12q23-q24 has been linked to triglyceride (TG) levels by previous linkage studies, and it contains the () gene. We investigated the association between and TG levels using two independent samples collected in Taiwan. First, based on 954 siblings in 397 families from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe), we found that rs978458 was associated with TG levels ( = -0.049, = 0.0043) under a recessive genetic model. Specifically, subjects carrying the homozygous genotype of the minor allele had lower TG levels, compared with other subjects. Then, a series of stratification analyses in a large sample of 13,193 unrelated subjects from the Taiwan biobank (TWB) project showed that this association appeared in subjects with a family history (FH) of hypertension ( = -0.045, = 0.0000034), but not in subjects without such an FH. A re-examination of the SAPPHIRe sample confirmed that this association appeared in subjects with an FH of hypertension ( = -0.068, = 0.0025), but not in subjects without an FH. The successful replication in two independent samples indicated that is associated with TG levels in subjects with an FH of hypertension in Taiwan.
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http://dx.doi.org/10.7150/ijms.25742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036157PMC
January 2019

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.

Nat Commun 2018 06 13;9(1):2252. Epub 2018 Jun 13.

Geisinger, Danville, 17822, PA, USA.

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
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http://dx.doi.org/10.1038/s41467-018-04611-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997992PMC
June 2018

Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.

Genet Epidemiol 2018 Sep 24;42(6):559-570. Epub 2018 Apr 24.

Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P = 1.43 × 10 ; P = 4.70 × 10 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.
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http://dx.doi.org/10.1002/gepi.22126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160319PMC
September 2018

Association between site-specific bone mineral density and glucose homeostasis and anthropometric traits in healthy men and women.

Clin Endocrinol (Oxf) 2018 06 14;88(6):848-855. Epub 2018 Apr 14.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Objective: Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits.

Design/patients/measurements: In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD.

Results: Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (β = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (β = .22, P < .0001) and legs (β = .17, P = .001) in women and pelvis (β = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes.

Conclusion: Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass.
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http://dx.doi.org/10.1111/cen.13602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980742PMC
June 2018
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