Publications by authors named "Leslie J Baier"

90 Publications

Next generation sequencing for HLA loci in full heritage Pima Indians of Arizona, Part II: HLA-A, -B, and -C with selected non-classical loci at 4-field resolution from whole genome sequences.

Hum Immunol 2021 Apr 16. Epub 2021 Apr 16.

Phoenix Epidemiology and Clinical Research Branch, NIH, NIDDK, Phoenix 85014, AZ, United States.

While the samples and data from the Pima Indians of the Gila River Indian Community have been included in many international HLA workshops and conferences and have been the focus of numerous population reports and the source of novel alleles at the classical HLA loci, they have not been studied for the non-classical loci. In order to expand our HLA-disease association studies, we typed over 300 whole genome sequences from full Pima heritage members, controlled for first degree relationship, and employed recently developed computer algorithms to resolve HLA alleles. Both classical-HLA-A, -B, and -C- and non-classical- HLA-E, -F, -G, -J, -L, -W, -Y, -DPA2, -DPB2, -DMA, -DMB, -DOA, -DRB2, -DRB9, TAP1- loci were typed at the 4-field level of resolution. We present allele and selected haplotype frequencies, test the genotype distributions for population structure, discuss the issues that are created for tests of Hardy-Weinberg equilibrium over the four sample spaces of high resolution HLA typing, and address the implications for the evolution of non-classical pseudogenes that are no longer expressed in a phenotype subject to natural selection.
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http://dx.doi.org/10.1016/j.humimm.2021.03.013DOI Listing
April 2021

Exome Sequencing of 21 Bardet-Biedl Syndrome (BBS) Genes to Identify Obesity Variants in 6,851 American Indians.

Obesity (Silver Spring) 2021 Apr 22;29(4):748-754. Epub 2021 Feb 22.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.

Objective: In an ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet-Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling.

Methods: Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole-exome sequence data from 6,851 American Indians informative for BMI. Common variants (detected in ≥ 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers. Functional assessment of variants' effect on signal transducer and activator of transcription 3 (STAT3) activity was performed in vitro.

Results: One common variant, rs59252892 (Thr549Ile) in BBS9, was associated with BMI (P = 0.0008, β = 25% increase per risk allele). Among rare variants for which carriers had severe obesity (mean BMI > 40 kg/m ), four were in BBS9. In vitro analysis of BBS9 found the Ile allele at Thr549Ile had a 20% increase in STAT3 activity compared with the Thr allele (P = 0.01). Western blot analysis showed the Ile allele had a 15% increase in STAT3 phosphorylation (P = 0.006). Comparable functional results were observed with Ser545Gly and Val209Leu but not Leu665Phe and Lys810Glu.

Conclusions: Potentially functional variants in BBS genes in American Indians are reported. However, functional evidence supporting a causal role for BBS9 in obesity is inconclusive.
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http://dx.doi.org/10.1002/oby.23115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048836PMC
April 2021

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

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

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

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

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

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

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Assessment of the potential role of natural selection in type 2 diabetes and related traits across human continental ancestry groups: comparison of phenotypic with genotypic divergence.

Diabetologia 2020 12 4;63(12):2616-2627. Epub 2020 Sep 4.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.

Aims/hypothesis: Prevalence of type 2 diabetes differs among human ancestry groups, and many hypotheses invoke differential natural selection to account for these differences. We sought to assess the potential role of differential natural selection across major continental ancestry groups for diabetes and related traits, by comparison of genetic and phenotypic differences.

Methods: This was a cross-sectional comparison among 734 individuals from an urban sample (none of whom was more closely related to another than third-degree relatives), including 83 African Americans, 523 American Indians and 128 European Americans. Participants were not recruited based on diabetes status or other traits. BMI was calculated, and diabetes was diagnosed by a 75 g oral glucose tolerance test. In those with normal glucose tolerance (n = 434), fasting insulin and 30 min post-load insulin, adjusted for 30 min glucose, were taken as measures of insulin resistance and secretion, respectively. Whole exome sequencing was performed, resulting in 97,388 common (minor allele frequency ≥ 5%) variants; the coancestry coefficient (F) was calculated across all markers as a measure of genetic divergence among ancestry groups. The phenotypic divergence index (P) was also calculated from the phenotypic differences and heritability (which was estimated from genetic relatedness calculated empirically across all markers in 761 American Indian participants prior to the exclusion of close relatives). Under evolutionary neutrality, the expectation is P = F, while for traits under differential selection P is expected to be significantly greater than F A bootstrap procedure was used to test the hypothesis P = F RESULTS: With adjustment for age and sex, prevalence of type 2 diabetes was 34.0% in American Indians, 12.4% in African Americans and 10.4% in European Americans (p = 2.9 × 10 for difference among groups). Mean BMI was 36.3, 33.4 and 33.0 kg/m, respectively (p = 1.9 × 10). Mean fasting insulin was 63.8, 48.4 and 45.2 pmol/l (p = 9.2 × 10), while mean 30 min insulin was 559.8, 553.5 and 358.8 pmol/l, respectively (p = 5.7 × 10). F across all markers was 0.130, while P for liability to diabetes, adjusted for age and sex, was 0.149 (p = 0.35 for difference with F). P was 0.094 for BMI (p = 0.54), 0.095 for fasting insulin (p = 0.54) and 0.216 (p = 0.18) for 30 min insulin. For type 2 diabetes and BMI, the maximum divergence between populations was observed between American Indians and European Americans (P = 0.22, p = 0.37, and P = 0.14, p = 0.61), which suggests that a relatively modest 22% or 14% of the genetic variance, respectively, can potentially be explained by differential selection (assuming the absence of neutral drift).

Conclusions/interpretation: These analyses suggest that while type 2 diabetes and related traits differ significantly among continental ancestry groups, the differences are consistent with neutral expectations based on heritability and genetic distances. While these analyses do not exclude a modest role for natural selection, they do not support the hypothesis that differential natural selection is necessary to explain the phenotypic differences among these ancestry groups. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05272-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642101PMC
December 2020

Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians.

J Clin Endocrinol Metab 2020 11;105(11)

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona.

Background: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity.

Methods: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized.

Results: Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE.

Conclusion: Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity.

Clinical Trial Registration Number: NCT00340132.
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http://dx.doi.org/10.1210/clinem/dgaa548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501742PMC
November 2020

Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US.

Am J Hum Genet 2020 08 7;107(2):251-264. Epub 2020 Jul 7.

Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. Electronic address:

Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413855PMC
August 2020

Weight tracking in childhood and adolescence and type 2 diabetes risk.

Diabetologia 2020 09 18;63(9):1753-1763. Epub 2020 May 18.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ, 85014, USA.

Aims/hypothesis: The aim of this work was to examine the associations of average weight and weight velocity in three growth periods from birth through adolescence with type 2 diabetes incidence.

Methods: Child participants were selected from a 43 year longitudinal study of American Indians to represent three growth periods: pre-adolescence (birth to ~8 years); early adolescence (~8 to ~13 years); and late adolescence (~13 to ~18 years). Age-, sex- and height-standardised weight z score mean and weight z score velocity (change/year) were computed for each period. Participants were followed for up to 25 years from the end of each growth period until they developed diabetes. Associations of weight z score mean or weight z score velocity with diabetes incidence were determined with sex-, birth date- and maternal diabetes-adjusted Poisson regression models.

Results: Among 2100 participants representing the pre-adolescence growth period, 1558 representing the early adolescence period and 1418 representing the late adolescence period, there were 290, 315 and 380 incident diabetes cases, respectively. During the first 10 years of follow-up, the diabetes incidence rate ratio (95% CI) was 1.72 (1.40, 2.11)/SD of log weight z score mean in pre-adolescence, 2.09 (1.68, 2.60)/SD of log weight z score mean in early adolescence and 1.85 (1.58, 2.17)/SD of log weight z score mean in late adolescence. The diabetes incidence rate ratio (95% CI) was 1.79 (1.49, 2.17)/SD of log weight z score velocity in pre-adolescence, 1.13 (0.91, 1.41)/SD of log weight z score velocity in early adolescence and 1.29 (1.09, 1.51)/SD of log weight z score velocity in late adolescence. There were strong correlations in the weight z score means and weak correlations in the weight z score velocities between successive periods.

Conclusions/interpretation: Higher weight and accelerated weight gain in all growth periods associate with increased type 2 diabetes risk. Importantly, higher weight and greater weight velocity during pre-adolescence jointly associate with the highest type 2 diabetes risk. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05165-wDOI Listing
September 2020

Assessing established BMI variants for a role in nighttime eating behavior in robustly phenotyped Southwestern American Indians.

Eur J Clin Nutr 2020 12 12;74(12):1718-1724. Epub 2020 May 12.

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.

Background/objectives: Nighttime eating (NE) behavior has a genetic component and predicts weight gain. We hypothesized that some genetic variants, which affect NE would also show an effect on body mass index (BMI). We aimed to determine which known BMI variants associate with NE in Southwestern American Indians (SWAIs), who are at elevated risk for obesity.

Methods: Known BMI variants from the GIANT-UK Biobank meta-analysis (N = 700,000) were analysed in SWAIs characterized for NE during an inpatient 3-day protocol. Variants were analysed for association with NE using whole-genome sequence data from 50 SWAIs (23 cases and 27 controls) and selected variants were genotyped in an additional 32 SWAIs (13 NE cases and 19 controls). Variants associated with NE in a meta-analysis of the two SWAI samples were further analysed for association with nightly caloric intake and functionality in hypothalamus, pituitary, and adrenal tissues.

Results: Variants were identified where the allele that associated with increased BMI in the GIANT-UK Biobank meta-analysis (P ≤ 1 × 10) also had a P < 0.01 for increased NE in the SWAI meta-analysis. These variants were captured by six tagSNPs. Comparison of the nightly calorie intake by genotype and eQTL data from relevant tissues highlighted rs3753612 upstream of HCRTR1.

Conclusions: Our strategy led to the HCRTR1 locus, which has previously been linked to sleep regulation and feeding. Although this is an intriguing candidate gene for NE, further studies in larger samples and different populations are required to validate the role of HCRTR1 in NE.
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http://dx.doi.org/10.1038/s41430-020-0654-zDOI Listing
December 2020

Low Serum Insulinlike Growth Factor II Levels Correlate with High BMI in American Indian Adults.

Obesity (Silver Spring) 2020 03 6;28(3):676-682. Epub 2020 Feb 6.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.

Objective: Insulinlike growth factor II (IGF-II) regulates metabolism and growth. In humans, both positive and negative relationships have been reported between serum IGF-II levels and obesity. This study assessed the relationship between serum IGF-II levels and BMI and determined whether IGF-II levels predict weight gain.

Methods: Serum samples were available from 911 American Indians with a recorded BMI. IGF-II was measured using enzyme-linked immunosorbent assay.

Results: Serum IGF-II levels were negatively correlated with BMI (r = -0.17, P = 4.4 × 10 , adjusted for age, sex, and storage time). The strongest correlation was in participants aged ≥ 30 years (r = -0.28, P = 3.4 × 10 , N = 349), a modest correlation was in participants aged 20 to 29 years (r = -0.15, P = 7.6 × 10 , N = 322), and participants aged 15 to 19 years had no correlation (r = 0.05, P = 0.48, N = 240). IGF-II levels did not predict weight gain. However, among individuals who had genotypes for 64 established obesity variants (age ≥ 20 years, N = 671), a genetic risk score for high BMI was associated with lower IGF-II (β = -0.08 SD of IGF-II per SD of the genetic risk score, P = 0.025).

Conclusions: There is a negative relationship between IGF-II levels and BMI, in which the correlation is stronger at older ages. The association between genetic risk for BMI and IGF-II levels suggests that this correlation may be due to an effect of obesity on IGF-II.
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http://dx.doi.org/10.1002/oby.22741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192225PMC
March 2020

Identification and functional validation of genetic variants in potential miRNA target sites of established BMI genes.

Int J Obes (Lond) 2020 05 19;44(5):1191-1195. Epub 2019 Nov 19.

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.

Objective: MicroRNAs (miRNAs) play an important role in posttranscriptional regulation by binding to target sites in the 3'UTR of protein-coding genes. Genetic variation within target sites may potentially disrupt the binding activity of miRNAs, thereby impacting this regulation. In the current study, we investigated whether any established BMI-associated genetic variants potentially function by altering a miRNA target site.

Methods: The genomic positions of all predicted miRNA target site seed regions were identified, and these positions were queried in the T2D Knowledge Portal for variants that associated with BMI in the GIANT UK Biobank. This in silico analysis identified ten target site variants that associated with BMI with a P value ≤ 5 × 10. These ten variants mapped to nine genes, FAIM2, CCDC171, ADPGK, ZNF654, MLXIP, NT5C2, SHISA4, SLC25A22, and CTNNB1.

Results: In vitro functional analyses showed that five of these target site variants, rs7132908 (FAIM2), rs4963153 (SLC25A22), rs9460 (ADPGK), rs11191548 (NT5C2), and rs3008747 (CCDC171), disrupted the binding activity of miRNAs to their target in an allele-specific manner.

Conclusion: In conclusion, our study suggests that some established variants for BMI may function by altering miRNA binding to a 3'UTR target site.
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http://dx.doi.org/10.1038/s41366-019-0488-8DOI Listing
May 2020

Next generation sequencing and the classical HLA loci in full heritage Pima Indians of Arizona: Defining the core HLA variation for North American Paleo-Indians.

Hum Immunol 2019 Dec 6;80(12):955-965. Epub 2019 Nov 6.

Phoenix Epidemiology and Clinical Research Branch, NIH, NIDDK, Phoenix, AZ 85014, United States.

The Pima Indians of the Gila River Indian Community in Arizona have participated in a long-range study of type 2 diabetes mellitus since 1965 and have been the subject of HLA typing and population studies since the early days of serological assays. These data have been in numerous HLA workshops and conferences and have been the source of at least five novel alleles at the classical HLA loci. In recent time nearly the entire study group was subject to next generation sequencing by whole genome or exome technologies, which has allowed us to HLA type over 3000 full heritage persons with recently developed computer algorithms. We present here the results for the classical HLA Loci: HLA-A, B, C, DRA, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1, DQA1, and DQB1 to the third field of resolution for synonymous alleles and type the likely four field resolution alleles from the subset of whole genome sequences. Allele frequencies, and haplotype frequencies at up to five loci, are presented as well as measures of population structure and heterozygosity. We define a core set of HLA variation that approximates the distribution for the Paleo-Indians and impute nine-locus, 4-field haplotypes that are expected to be common in full heritage peoples.
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http://dx.doi.org/10.1016/j.humimm.2019.10.002DOI Listing
December 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21.

Cell Rep 2019 Sep;28(10):2567-2580.e6

Department of Integrative Biology and Physiology, University of Minnesota, 2231 6(th) St. SE, Minneapolis, MN, USA. Electronic address:

Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). After having characterized the TLQP-21/C3aR1 lipolytic mechanism, a homology modeling and molecular dynamics simulation identified the TLQP-21 binding motif and C3aR1 binding site for the human (h) and mouse (m) molecules. mTLQP-21 showed enhanced binding affinity and potency for hC3aR1 compared with hTLQP-21. Consistently, mTLQP-21, but not hTLQP-21, potentiates lipolysis in human adipocytes. These findings led us to uncover five mutations in the C3aR1 binding pocket of the rodent Murinae subfamily that are causal for enhanced calculated affinity and measured potency of TLQP-21. Identifying functionally relevant peptide/receptor co-evolution mechanisms can facilitate the development of innovative pharmacotherapies for obesity and other diseases implicating GPCRs.
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http://dx.doi.org/10.1016/j.celrep.2019.07.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753381PMC
September 2019

Association of CREBRF variants with obesity and diabetes in Pacific Islanders from Guam and Saipan.

Diabetologia 2019 09 6;62(9):1647-1652. Epub 2019 Jul 6.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 E. Indian School Road, Phoenix, AZ, 85014, USA.

Aims/hypothesis: Variants in CREBRF (rs12513649 and rs373863828) have been strongly associated with increased BMI and decreased risk of type 2 diabetes in Polynesian populations; the A allele at rs373863828 is common in Polynesians but rare in most other global populations. The aim of the present study was to assess the association of CREBRF variants with obesity and diabetes in Pacific Islander (largely Marianas and Micronesian) populations from Guam and Saipan.

Methods: CREBRF rs12513649 and rs373863828 were genotyped in 2022 participants in a community-based cross-sectional study designed to identify determinants of diabetes and end-stage renal disease (ESRD). Associations were analysed with adjustment for age, sex, ESRD and the first four genetic principal components from a genome-wide association study (to account for population stratification); a genomic control procedure was used to account for residual stratification.

Results: The G allele at rs12513649 had an overall frequency of 7.7%, which varied from 2.2% to 20.7% across different Marianas and Micronesian populations; overall frequency of the A allele at rs373863828 was 4.2% (range: 1.1-5.4%). The G allele at rs12513649 was associated with higher BMI (β = 1.55 kg/m per copy; p = 0.0026) as was the A allele at rs373863828 (β = 1.48 kg/m, p = 0.033). The same alleles were associated with lower risk of diabetes (OR per copy: 0.63 [p = 0.0063] and 0.49 [p = 0.0022], respectively). Meta-analyses combining the current results with previous results in Polynesians showed a strong association between the A allele at rs373863828 and BMI (β = 1.38 kg/m; p = 2.5 × 10) and diabetes (OR 0.65, p = 1.5 × 10).

Conclusions/interpretation: These results confirm the associations of CREBRF variants with higher BMI and lower risk of diabetes and, importantly, they suggest that these variants contribute to the risk of obesity and diabetes in Oceanic populations.
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http://dx.doi.org/10.1007/s00125-019-4932-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721609PMC
September 2019

Birthweight and early-onset type 2 diabetes in American Indians: differential effects in adolescents and young adults and additive effects of genotype, BMI and maternal diabetes.

Diabetologia 2019 09 20;62(9):1628-1637. Epub 2019 May 20.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ, 85014, USA.

Aims/hypothesis: The aim of this work was to estimate the impact of birthweight on early-onset (age <40 years) type 2 diabetes.

Methods: A longitudinal study of American Indians, aged ≥5 years, was conducted from 1965 to 2007. Participants who had a recorded birthweight were followed until they developed diabetes or their last examination before the age of 40 years, whichever came first. Age- and sex-adjusted diabetes incidence rates were computed and Poisson regression was used to model the effect of birthweight on diabetes incidence, adjusted for sex, BMI, a type 2 diabetes susceptibility genetic risk score (GRS) and maternal covariates.

Results: Among 3039 participants, there were 652 incident diabetes cases over a median follow-up of 14.3 years. Diabetes incidence increased with age and was greater in the lowest and highest quintiles of birthweight. Adjusted for covariates, the effect of birthweight on diabetes varied over time, with a non-linear effect at 10-19 years (p < 0.001) and a negative linear effect at older age intervals (20-29 years, p < 0.001; 30-39 years, p = 0.003). Higher GRS, greater BMI and maternal diabetes had additive but not interactive effects on the association between birthweight and diabetes incidence.

Conclusions/interpretation: In this high-risk population, both low and high birthweights were associated with increased type 2 diabetes risk in adolescence (age 10-19 years) but only low birthweight was associated with increased risk in young adulthood (20-39 years). Higher type 2 diabetes GRS, greater BMI and maternal diabetes added to the risk of early-onset diabetes.
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http://dx.doi.org/10.1007/s00125-019-4899-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679754PMC
September 2019

Assessing the Role of 98 Established Loci for BMI in American Indians.

Obesity (Silver Spring) 2019 05 18;27(5):845-854. Epub 2019 Mar 18.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.

Objective: Meta-analyses of genome-wide association studies in Europeans have identified > 98 loci for BMI. Transferability of these established associations in Pima Indians was analyzed.

Methods: Among 98 lead single nucleotide polymorphisms (SNPs), 82 had minor allele frequency ≥ 0.01 in Pima Indians and were analyzed for association with the maximum BMI in adulthood (n = 3,491) and BMI z score in childhood (n = 1,958). Common tag SNPs across 98 loci were also analyzed for additional signals.

Results: Among the lead SNPs, 13 (TMEM18, TCF7L2, MRPS33P4, PRKD1, ZFP64, FTO, TAL1, CALCR, GNPDA2, CREB1, LMX1B, ADCY9, NLRC3) were associated with BMI (P  ≤ 0.05) in Pima adults. A multi-allelic genetic risk score (GRS), which summed the risk alleles for 82 lead SNPs, showed a significant trend for a positive relationship between GRS and BMI in adulthood (beta = 0.48% per risk allele; P = 1.6 × 10 ) and BMI z score in childhood (beta = 0.024 SD; P = 1.7 × 10 ). GRS was significantly associated with BMI across all age groups ≥ 5 years, except for those ≥ 50 years. The strongest association was seen in adolescence (age 14-16 years; P = 1.84 × 10 ).

Conclusions: In aggregate, European-derived lead SNPs had a notable effect on BMI in Pima Indians. Polygenic obesity in this population manifests strongly in childhood and adolescence and persists throughout much of adult life.
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http://dx.doi.org/10.1002/oby.22433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478540PMC
May 2019

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

Ann Hum Genet 2018 09 17;82(5):287-299. Epub 2018 May 17.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.
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http://dx.doi.org/10.1111/ahg.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105364PMC
September 2018

HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults.

Diabetes 2018 05 26;67(5):861-871. Epub 2018 Feb 26.

HLA Laboratory, Kunming Blood Center, Kunming, Yunnan, China.

Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI ( = 6.89 × 10, 1.32 × 10, 1.52 × 10, and 4.45 × 10, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects ( = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of , , and with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.
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http://dx.doi.org/10.2337/db17-0852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463754PMC
May 2018

Identification and functional analysis of a novel G310D variant in the insulin-like growth factor 1 receptor (IGF1R) gene associated with type 2 diabetes in American Indians.

Diabetes Metab Res Rev 2018 05 25;34(4):e2994. Epub 2018 Mar 25.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA.

Aims: Insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and glucose homeostasis. In the current study, the IGF1R locus was analysed as a candidate gene for type 2 diabetes (T2D) in American Indians.

Materials And Methods: Whole genome sequence data from 335 American Indians identified 3 novel missense variants in IGF1R. The associations of IGF1R variants with T2D, age of T2D onset and birth weight were analysed in a population-based sample of 7701 American Indians.

Results: A novel glycine-to-aspartic acid substitution (G310D) in IGF1R was identified, which associated with T2D in a sex-specific manner (P interaction = 0.02). In women, the aspartic acid (D) allele (frequency = 0.034) was associated with increased risk for T2D (n = 4292, P = 2.0 × 10 adjusted for age, birth year, and the first 5 genetic principal components; odds ratio [OR] = 2.23 [1.54-3.23] per risk allele) and an earlier age of T2D onset (n = 4292, P = 2 × 10 , hazard rate ratio = 1.45 [1.20-1.75], P interaction = 0.05). Female carriers of the D-allele also had lower birth weight (n = 1313, β = -163 g, P = .006, P interaction = 0.008). Among 85 siblings discordant for G310D, carriers of the D-allele had shorter stature as compared with carriers of the G-allele (β = -1.6 cm, P = .001, within family model). The G310D variant was functionally studied in vitro, where the D-allele had a 22% increase (P = .0005) in FOXO1-induced transcriptional activity, due to decreased activation of the PI3K/AKT pathway mediated through reduced IGF1R activity.

Conclusion: A unique G310D variant in IGF1R, which occurs in 6% American Indians, may impair IGF1R signalling pathways, thereby increasing the risk of T2D.
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http://dx.doi.org/10.1002/dmrr.2994DOI Listing
May 2018

Using Luciferase Reporter Assays to Identify Functional Variants at Disease-Associated Loci.

Methods Mol Biol 2018 ;1706:303-319

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 N 5th Street, Phoenix, AZ, 85004, USA.

The genomic era, highlighted by large scale, genome-wide association studies (GWAS) for both common and rare diseases, have identified hundreds of disease-associated variants. However, most of these variants are not disease causing, but instead only provide information about a potential proximal functional variant through linkage disequilibrium. It is critical that these functional variants be identified, so that their role in disease risk can be ascertained. Luciferase assays are an invaluable tool for identifying and characterizing functional variants, allowing investigations of gene expression, intracellular signaling, transcription factors, receptor activity, and protein folding. In this chapter, we provide an overview of the different ways that luciferase assays can be used to validate functionality of a variant.
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http://dx.doi.org/10.1007/978-1-4939-7471-9_17DOI Listing
October 2018

Functional and association analysis of an Amerindian-derived population-specific p.(Thr280Met) variant in RBPJL, a component of the PTF1 complex.

Eur J Hum Genet 2018 02 4;26(2):238-246. Epub 2018 Jan 4.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445N 5th Street, Phoenix, AZ, 85004, USA.

PTF1 complex is critical for pancreatic development and maintenance of adult exocrine pancreas. As a part of our ongoing studies to identify genetic variation that contributes to type 2 diabetes (T2D) in American Indians, we analyzed variation in genes that form this complex, namely PTF1A, RBPJ, and its paralogue RBPJL. A c.839C>T (p.(Thr280Met)) variant (rs200998587:C>T, risk allele frequency = 0.03) in RBPJL, identified only in Amerindian-derived populations, associated with T2D (OR = 1.60[1.21-2.13] per Met allele, P = 0.001) and age of diabetes onset (HR = 1.40[1.14-1.72], P = 0.001). Knockdown of Rbpjl in mouse pancreatic acinar cells resulted in a significant decrease in the mRNA expression of genes encoding exocrine enzymes including Ctrb. CTRB1/2 is an established T2D locus where the protective allele associates with increased GLP-1-stimulated insulin secretion and higher expression of CTRB1/2. In vitro studies show that cells expressing the Met280 allele had lower RBPJL protein levels than cells expressing the Thr280 allele, despite having comparable levels of RNA, suggesting that the Met280 RBPJL is less stable. Additionally, luciferase assays in HEK293 cells which examined two different RBPJL responsive promoters, including the promoter for CTRB1, also identified reduced transactivation by the Met280 RBPJL. Similarly, overexpression of both Met280 and Thr280 RBPJL in mouse pancreatic acinar cells identified a significant impairment in the expression of Cel when transactivated by the Met280 RBPJL. In summary, we identified a functional, Amerindian-derived population-specific c.839C>T (p.(Thr280Met)) variant in the pancreas specific RBPJL that may modify T2D risk by regulating exocrine enzyme expression.
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http://dx.doi.org/10.1038/s41431-017-0062-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839029PMC
February 2018

Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an Founder Mutation.

Circ Cardiovasc Genet 2017 Dec;10(6)

From the Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, AZ (W.-C.H., A.K.N., S.K., P.C., A.M., W.C.K., L.J.B., R.L.H.); South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, San Antonio (H.H.H.G.); Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore (T.I.P.); and Illumina Inc, San Diego, CA (A.M.).

Background: Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization.

Methods And Results: Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; =3.5×10 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in (rs147210663) and 3 established functional SNPs in . The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=-0.92±0.059 SD unit; =9.6×10 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null.

Conclusions: constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.
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http://dx.doi.org/10.1161/CIRCGENETICS.117.001809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736502PMC
December 2017

Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits.

PLoS One 2017 20;12(11):e0188400. Epub 2017 Nov 20.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States of America.

Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), and pulse pressure (PP), in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian), for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP) and 0.04 (SBP) in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001) in a targeted association study of Blood Pressure (BP) traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695820PMC
December 2017

A Loss-of-Function Splice Acceptor Variant in Is Protective for Type 2 Diabetes.

Diabetes 2017 11 24;66(11):2903-2914. Epub 2017 Aug 24.

Department of Genetics, Harvard Medical School, Boston, MA.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of isoform 2. In individuals who do not carry the protective allele, expression of isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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http://dx.doi.org/10.2337/db17-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652606PMC
November 2017

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Nat Commun 2017 07 19;8(1):80. Epub 2017 Jul 19.

Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10) or suggestively genome wide (p < 2.3 × 10). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
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http://dx.doi.org/10.1038/s41467-017-00031-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517526PMC
July 2017

A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in Associated With Reduced Energy Expenditure in American Indians.

Diabetes 2017 08 5;66(8):2284-2295. Epub 2017 May 5.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians. Genotypic data from 491,265 variants were analyzed for association with resting metabolic rate (RMR) and 24-h EE assessed in a whole-room calorimeter in 507 and 419 Pima Indians, respectively. Variants associated with both measures of EE were analyzed for association with maximum BMI and percent body fat (PFAT) in 5,870 and 912 Pima Indians, respectively. rs11014566 nominally associated with both measures of EE and both measures of adiposity in Pima Indians, where the G allele (frequency: Pima Indians = 0.60, Europeans <0.01) associated with lower 24-h EE (β = -33 kcal/day per copy), lower RMR (β = -31 kcal/day), higher BMI (β = +0.6 kg/m), and higher PFAT (β = +0.9%). However, the association of rs11014566 with BMI did not directionally replicate when assessed in other ethnic groups. rs11014566 tags rs144895904, which affected promoter function in an in vitro luciferase assay. These variants map to , which is highly expressed in the brain and interacts with two other genes ( and ) known to affect obesity in knockout mice. Our results suggest that common ethnic-specific variation in may influence EE; however, its role in weight gain remains controversial, as it either had no association with BMI or associated with BMI but in the opposite direction in other ethnic groups.
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http://dx.doi.org/10.2337/db16-1565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521859PMC
August 2017

Admixture Mapping Identifies an Amerindian Ancestry Locus Associated with Albuminuria in Hispanics in the United States.

J Am Soc Nephrol 2017 Jul 30;28(7):2211-2220. Epub 2017 Jan 30.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina

Increased urine albumin excretion is highly prevalent in Hispanics/Latinos. Previous studies have found an association between urine albumin excretion and Amerindian ancestry in Hispanic/Latino populations. Admixture between racial/ethnic groups creates long-range linkage disequilibrium between variants with different allelic frequencies in the founding populations and it can be used to localize genes. Hispanic/Latino genomes are an admixture of European, African, and Amerindian ancestries. We leveraged this admixture to identify associations between urine albumin excretion (urine albumin-to-creatinine ratio [UACR]) and genomic regions harboring variants with highly differentiated allele frequencies among the ancestral populations. Admixture mapping analysis of 12,212 Hispanic Community Health Study/Study of Latinos participants, using a linear mixed model, identified three novel genome-wide significant signals on chromosomes 2, 11, and 16. The admixture mapping signal identified on chromosome 2, spanning q11.2-14.1 and not previously reported for UACR, is driven by a difference between Amerindian ancestry and the other two ancestries (<5.7 × 10). Within this locus, two common variants located at the proapoptotic gene associated with UACR: rs116907128 (allele frequency =0.14; =1.5 × 10) and rs586283 (C allele frequency =0.35; =4.2 × 10). In a secondary analysis, rs116907128 accounted for most of the admixture mapping signal observed in the region. The rs116907128 variant is common among full-heritage Pima Indians (A allele frequency =0.54) but is monomorphic in the 1000 Genomes European and African populations. In a replication analysis using a sample of full-heritage Pima Indians, rs116907128 significantly associated with UACR (=0.01; =1568). Our findings provide evidence for the presence of Amerindian-specific variants influencing the variation of urine albumin excretion in Hispanics/Latinos.
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http://dx.doi.org/10.1681/ASN.2016091010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491288PMC
July 2017

Differential methylation of genes in individuals exposed to maternal diabetes in utero.

Diabetologia 2017 04 26;60(4):645-655. Epub 2017 Jan 26.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 E. Indian School Rd, Phoenix, AZ, 85014, USA.

Aims/hypothesis: Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND).

Methods: DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed.

Results: Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10; PCDHGA4: 2.8% lower, p = 3.0 × 10; STC1: 2.9% lower, p = 1.6 × 10) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways.

Conclusions/interpretation: Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-016-4203-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194355PMC
April 2017

Assessing variation across 8 established East Asian loci for type 2 diabetes mellitus in American Indians: Suggestive evidence for new sex-specific diabetes signals in GLIS3 and ZFAND3.

Diabetes Metab Res Rev 2017 05 28;33(4). Epub 2016 Dec 28.

Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.

Background: Eight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genome-wide association study meta-analysis. We assess tag SNPs across these loci for associations with T2DM in American Indians.

Methods: A total of 435 SNPs that tag (R  ≥ .85) common variation across the 8 loci were analyzed for association with T2DM (n = 7710), early onset T2DM (n = 1060), body mass index (n = 6839), insulin sensitivity (n = 555), and insulin secretion (n = 298).

Results: Tag SNPs within FITM2-R3HDML-HNF4A, GLIS3, KCNK16, and ZFAND3 associated with T2DM after accounting for locus-wide multiple testing. The T2DM association in FITM2-R3HDML-HNF4A (rs3212183; P = .0002; OR = 1.19 [1.09-1.30]) was independent from the East Asian lead SNP (rs6017317), which did not associate with T2DM in American Indians. The top signals in GLIS3 (rs7875253; P = .0004; OR = 1.23 [1.10-1.38]) and KCNK16 (rs1544050; P = .002; OR = 1.16 [1.06-1.27]) were attenuated after adjustment for the East Asian lead SNPs (rs7041847 in GLIS3; rs1535500 in KCNK16), both of which also associated with T2DM in American Indians (P = .02; OR = 1.11 [1.01-1.21]; P = .007; OR = 1.19 [1.05-1.36] respectively). The top SNP in ZFAND3 (rs9470794; P = .002; OR = 1.43 [1.14-1.80]) was the identical East Asian lead SNP. Additional SNPs in GLIS3 (rs180867004) and ZFAND3 (rs4714120 and rs9470701) had significant genotype × sex interactions (P ≤ .008). The GLIS3 SNP (rs180867004) associated with T2DM only in men (P = .00006, OR = 1.94 [1.40-2.68]). The ZFAND3 SNPs (rs4714120 and rs9470701) associated with T2DM only in women (P = .0002, OR = 1.35 [1.16-1.59]; P = .0003, OR = 1.37 [1.16-1.63] respectively).

Conclusions: Replication of lead T2DM SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified.
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http://dx.doi.org/10.1002/dmrr.2869DOI Listing
May 2017