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Article ; Online: Genetics of Type 2 Diabetes in African Americans.

Ng, Maggie C Y

2015 Volume 15, Issue 10, Page(s) 74

Abstract: Type 2 diabetes (T2D) is a global health problem showing substantial ethnic disparity in disease prevalence. African Americans have one of the highest prevalence of T2D in the USA but little is known about their genetic risks. This review summarizes the ... ...

Abstract	Type 2 diabetes (T2D) is a global health problem showing substantial ethnic disparity in disease prevalence. African Americans have one of the highest prevalence of T2D in the USA but little is known about their genetic risks. This review summarizes the findings of genetic regions and loci associated with T2D and related glycemic traits using linkage, admixture, and association approaches in populations of African ancestry. In particular, findings from genome-wide association and exome chip studies suggest the presence of both ancestry-specific and shared loci for T2D and glycemic traits. Among the European-identified loci that are transferable to individuals of African ancestry, allelic heterogeneity as well as differential linkage disequilibrium and risk allele frequencies pose challenges and opportunities for fine mapping and identification of causal variant(s) by trans-ancestry meta-analysis. More genetic research is needed in African ancestry populations including the next-generation sequencing to improve the understanding of genetic architecture of T2D.
MeSH term(s)	Black or African American/genetics ; Diabetes Mellitus, Type 2/genetics ; Genetic Heterogeneity ; Genome-Wide Association Study ; Humans ; Linkage Disequilibrium ; Risk Factors
Language	English
Publishing date	2015-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2065167-3
ISSN	1539-0829 ; 1534-4827
ISSN (online)	1539-0829
ISSN	1534-4827
DOI	10.1007/s11892-015-0651-0
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Article ; Online: Predicting diabetes risk in diverse populations: what next?

Mercader, Josep M / Ng, Maggie C Y / Manning, Alisa K / Rich, Stephen S

The lancet. Diabetes & endocrinology

2021 Volume 9, Issue 12, Page(s) 808–810

MeSH term(s)	Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/epidemiology ; Humans ; Risk Assessment ; Risk Factors
Language	English
Publishing date	2021-10-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2213-8595
ISSN (online)	2213-8595
DOI	10.1016/S2213-8587(21)00287-4
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Article ; Online: Methods for estimating insulin resistance from untargeted metabolomics data.

Hsu, Fang-Chi / Palmer, Nicholette D / Chen, Shyh-Huei / Ng, Maggie C Y / Goodarzi, Mark O / Rotter, Jerome I / Wagenknecht, Lynne E / Bancks, Michael P / Bergman, Richard N / Bowden, Donald W

Metabolomics : Official journal of the Metabolomic Society

2023 Volume 19, Issue 8, Page(s) 72

Abstract: Context: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming.: Objective: Develop estimation models for measures of insulin resistance, including ...

Abstract	Context: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. Objective: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. Design: Insulin Resistance Atherosclerosis Family Study (IRASFS). Setting: Community based. Participants: Mexican Americans (MA) and African Americans (AA). Main outcome: Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. Results: Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r Conclusions: We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.
MeSH term(s)	Humans ; Insulin Resistance ; Metabolomics ; Atherosclerosis/metabolism
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2250617-2
ISSN	1573-3890 ; 1573-3882
ISSN (online)	1573-3890
ISSN	1573-3882
DOI	10.1007/s11306-023-02035-5
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Article ; Online: Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS).

Okut, Hayrettin / Lu, Yingchang / Palmer, Nicholette D / Chen, Yii-Der Ida / Taylor, Kent D / Norris, Jill M / Lorenzo, Carlos / Rotter, Jerome I / Langefeld, Carl D / Wagenknecht, Lynne E / Bowden, Donald W / Ng, Maggie C Y

Metabolomics : Official journal of the Metabolomic Society

2023 Volume 19, Issue 4, Page(s) 35

Abstract: Introduction: African Americans are at increased risk for type 2 diabetes.: Objectives: This work aimed to examine metabolomic signature of glucose homeostasis in African Americans.: Methods: We used an untargeted liquid chromatography-mass ... ...

Abstract	Introduction: African Americans are at increased risk for type 2 diabetes. Objectives: This work aimed to examine metabolomic signature of glucose homeostasis in African Americans. Methods: We used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (S Results: We confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans. Conclusion: We extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.
MeSH term(s)	Humans ; Atherosclerosis/metabolism ; Black or African American ; Diabetes Mellitus, Type 2/metabolism ; Glucose ; Glutamates ; Homeostasis/physiology ; Insulin Resistance ; Metabolomics
Chemical Substances	Glucose (IY9XDZ35W2) ; Glutamates
Language	English
Publishing date	2023-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2250617-2
ISSN	1573-3890 ; 1573-3882
ISSN (online)	1573-3890
ISSN	1573-3882
DOI	10.1007/s11306-023-01984-1
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Article ; Online: Polygenic Risk for Type 2 Diabetes in African Americans.

Irvin, Marguerite R / Ge, Tian / Patki, Amit / Srinivasasainagendra, Vinodh / Armstrong, Nicole D / Davis, Brittney / Jones, Alana C / Perez, Emma / Stalbow, Lauren / Lebo, Matthew / Kenny, Eimear / Loos, Ruth J F / Ng, Maggie C Y / Smoller, Jordan W / Meigs, James B / Lange, Leslie A / Karlson, Elizabeth W / Limdi, Nita A / Tiwari, Hemant K

Diabetes

2024

Abstract: African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Herein, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an ... ...

Abstract	African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Herein, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method (PRS-CS). We further tested the score in three independent studies with a total of 7,275 AAs. We then compared the PRSAA to other published scores. Results show that a 1 standard deviation increase in the PRSAA was associated with 40%-60% increase in the odds of T2D (OR=1.60, 95% CI 1.37-1.88; OR=1.40, 95% CI 1.16-1.70; and OR=1.45, 95% CI 1.30-1.62) across three testing cohorts. These models captured 1.0%-2.6% of the variance (R2) in T2D on the liability scale. The positive predictive values (PPV) for three calculated score thresholds (the top 2%, 5% 10%) ranged from 14% to 35%. The PRSAA, in general, performed similarly to existing T2D PRS. Larger datasets remain needed to continue to evaluate the utility of within-ancestry scores in the AA population.
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db23-0232
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Article: Is genetic testing of value in predicting and treating obesity?

Ng, Maggie C Y / Bowden, Donald W

North Carolina medical journal

2013 Volume 74, Issue 6, Page(s) 530–533

Abstract: Obesity is a multifactorial disease resulting from the interaction between genetic factors and lifestyle. Identification of rare genetic variations with strong effects on obesity has been useful in diagnosing and designing personalized therapy for early- ... ...

Abstract	Obesity is a multifactorial disease resulting from the interaction between genetic factors and lifestyle. Identification of rare genetic variations with strong effects on obesity has been useful in diagnosing and designing personalized therapy for early-onset or syndromic obesity. However, common variants identified in recent genome-wide association studies have limited clinical value.
MeSH term(s)	Genetic Testing ; Humans ; Obesity/genetics ; Obesity/therapy ; Precision Medicine ; Predictive Value of Tests
Language	English
Publishing date	2013-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	422795-5
ISSN	0029-2559
ISSN	0029-2559
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Article ; Online: A novel TCF7L2 type 2 diabetes SNP identified from fine mapping in African American women.

Haddad, Stephen A / Palmer, Julie R / Lunetta, Kathryn L / Ng, Maggie C Y / Ruiz-Narváez, Edward A

PloS one

2017 Volume 12, Issue 3, Page(s) e0172577

Abstract: SNP rs7903146 in the Wnt pathway's TCF7L2 gene is the variant most significantly associated with type 2 diabetes to date, with associations observed across diverse populations. We sought to determine whether variants in other Wnt pathway genes are also ... ...

Abstract	SNP rs7903146 in the Wnt pathway's TCF7L2 gene is the variant most significantly associated with type 2 diabetes to date, with associations observed across diverse populations. We sought to determine whether variants in other Wnt pathway genes are also associated with this disease. We evaluated 69 genes involved in the Wnt pathway, including TCF7L2, for associations with type 2 diabetes in 2632 African American cases and 2596 controls from the Black Women's Health Study. Tag SNPs for each gene region were genotyped on a custom Affymetrix Axiom Array, and imputation was performed to 1000 Genomes Phase 3 data. Gene-based analyses were conducted using the adaptive rank truncated product (ARTP) statistic. The PSMD2 gene was significantly associated with type 2 diabetes after correction for multiple testing (corrected p = 0.016), based on the nine most significant single variants in the +/- 20 kb region surrounding the gene, which includes nearby genes EIF4G1, ECE2, and EIF2B5. Association data on four of the nine variants were available from an independent sample of 8284 African American cases and 15,543 controls; associations were in the same direction, but weak and not statistically significant. TCF7L2 was the only other gene associated with type 2 diabetes at nominal p <0.01 in our data. One of the three variants in the best gene-based model for TCF7L2, rs114770437, was not correlated with the GWAS index SNP rs7903146 and may represent an independent association signal seen only in African ancestry populations. Data on this SNP were not available in the replication sample.
MeSH term(s)	Adult ; African Americans/genetics ; Aged ; Chromosome Mapping ; Diabetes Mellitus, Type 2/genetics ; Female ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Transcription Factor 7-Like 2 Protein/genetics ; Young Adult
Chemical Substances	TCF7L2 protein, human ; Transcription Factor 7-Like 2 Protein
Language	English
Publishing date	2017-03-02
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0172577
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Article ; Online: Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease.

Das, Swapan K / Ainsworth, Hannah C / Dimitrov, Latchezar / Okut, Hayrettin / Comeau, Mary E / Sharma, Neeraj / Ng, Maggie C Y / Norris, Jill M / Chen, Yii-der I / Wagenknecht, Lynne E / Bowden, Donald W / Hsu, Fang-Chi / Taylor, Kent D / Langefeld, Carl D / Palmer, Nicholette D

Molecular metabolism

2021 Volume 54, Page(s) 101342

Abstract: 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 ... ...

Abstract	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 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.
MeSH term(s)	Adolescent ; Adult ; Cardiovascular Diseases/metabolism ; Female ; Humans ; Lactones/metabolism ; Male ; Middle Aged ; Obesity/metabolism ; Sulfates/metabolism ; Young Adult
Chemical Substances	Lactones ; Sulfates
Language	English
Publishing date	2021-09-24
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2021.101342
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Article ; Online: Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.

PloS one

2021 Volume 16, Issue 5, Page(s) e0251423

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	African Americans/genetics ; Aged ; Bone Density ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/physiopathology ; Female ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Vitamin D/genetics ; Vitamin D-Binding Protein/blood ; Vitamin D-Binding Protein/genetics
Chemical Substances	Vitamin D-Binding Protein ; Vitamin D (1406-16-2) ; 1,25-dihydroxyvitamin D (66772-14-3) ; 25-hydroxyvitamin D (A288AR3C9H)
Language	English
Publishing date	2021-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0251423
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Article ; Online: Role of DNA secondary structures in fragile site breakage along human chromosome 10.

Dillon, Laura W / Pierce, Levi C T / Ng, Maggie C Y / Wang, Yuh-Hwa

Human molecular genetics

2013 Volume 22, Issue 7, Page(s) 1443–1456

Abstract: The formation of alternative DNA secondary structures can result in DNA breakage leading to cancer and other diseases. Chromosomal fragile sites, which are regions of the genome that exhibit chromosomal breakage under conditions of mild replication ... ...

Abstract	The formation of alternative DNA secondary structures can result in DNA breakage leading to cancer and other diseases. Chromosomal fragile sites, which are regions of the genome that exhibit chromosomal breakage under conditions of mild replication stress, are predicted to form stable DNA secondary structures. DNA breakage at fragile sites is associated with regions that are deleted, amplified or rearranged in cancer. Despite the correlation, unbiased examination of the ability to form secondary structures has not been evaluated in fragile sites. Here, using the Mfold program, we predict potential DNA secondary structure formation on the human chromosome 10 sequence, and utilize this analysis to compare fragile and non-fragile DNA. We found that aphidicolin (APH)-induced common fragile sites contain more sequence segments with potential high secondary structure-forming ability, and these segments clustered more densely than those in non-fragile DNA. Additionally, using a threshold of secondary structure-forming ability, we refined legitimate fragile sites within the cytogenetically defined boundaries, and identified potential fragile regions within non-fragile DNA. In vitro detection of alternative DNA structure formation and a DNA breakage cell assay were used to validate the computational predictions. Many of the regions identified by our analysis coincide with genes mutated in various diseases and regions of copy number alteration in cancer. This study supports the role of DNA secondary structures in common fragile site instability, provides a systematic method for their identification and suggests a mechanism by which DNA secondary structures can lead to human disease.
MeSH term(s)	Chromosome Fragile Sites ; Chromosomes, Human, Pair 10/genetics ; Computer Simulation ; DNA/genetics ; DNA Cleavage ; Humans ; Models, Molecular ; Neoplasms/genetics ; Nucleic Acid Conformation ; Thermodynamics
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2013-01-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/dds561
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