Publications by authors named "Deepti Jain"

104 Publications

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.

Hum Mol Genet 2021 Sep 6. Epub 2021 Sep 6.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
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http://dx.doi.org/10.1093/hmg/ddab252DOI Listing
September 2021

BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Framingham Heart Study, Framingham, MA, USA.

Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.
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http://dx.doi.org/10.1016/j.xhgg.2021.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321319PMC
July 2021

Hybrid Symmetry Epitaxy of the Superconducting Fe(Te,Se) Film on a Topological Insulator.

Nano Lett 2021 Aug 28;21(15):6518-6524. Epub 2021 Jul 28.

Center for Quantum Materials Synthesis and Department of Physics & Astronomy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.

It is challenging to grow an epitaxial 4-fold compound superconductor (SC) on a 6-fold topological insulator (TI) platform due to the stringent lattice-matching requirement. Here, we demonstrate that Fe(Te,Se) can grow epitaxially on a TI (BiTe) layer due to accidental, uniaxial lattice match, which is dubbed as "hybrid symmetry epitaxy". This new growth mode is critical to stabilizing robust superconductivity with as high as 13 K. Furthermore, the superconductivity in this FeTeSe/BiTe system survives in the Te-rich phase with Se content as low as = 0.03 but vanishes at Se content above = 0.56, exhibiting a phase diagram that is quite different from that of the conventional Fe(Te,Se) systems. This unique heterostructure platform that can be formed in both TI-on-SC and SC-on-TI sequences opens a route to unprecedented topological heterostructures.
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http://dx.doi.org/10.1021/acs.nanolett.1c01703DOI Listing
August 2021

Molecular and structural facets of c-di-GMP signalling associated with biofilm formation in Pseudomonas aeruginosa.

Mol Aspects Med 2021 Jul 23:101001. Epub 2021 Jul 23.

Transcription Regulation Lab, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, India. Electronic address:

Pseudomonas aeruginosa is an opportunistic human pathogen and is the primary cause of nosocomial infections. Biofilm formation by this organism results in chronic and hard to eradicate infections. The intracellular signalling molecule bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a secondary messenger in bacterial cells crucial for motile to sessile transition. The signalling pathway components encompass two classes of enzymes with antagonistic activities, the diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) that regulate the cellular levels of c-di-GMP at distinct stages of biofilm initiation, maturation and dispersion. This review summarizes the structural analysis and functional studies of the DGCs and PDEs involved in biofilm regulation in P. aeruginosa. In addition, we also describe the effector proteins that sense the perturbations in c-di-GMP levels to elicit a functional output. Finally, we discuss possible mechanisms that allow the dynamic levels of c-di-GMP to regulate cognate cellular response. Uncovering the details of the regulation of the c-di-GMP signalling pathway is vital for understanding the behaviour of the pathogen and characterization of novel targets for anti-biofilm interventions.
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http://dx.doi.org/10.1016/j.mam.2021.101001DOI Listing
July 2021

Spacer-Layer-Tunable Magnetism and High-Field Topological Hall Effect in Topological Insulator Heterostructures.

Nano Lett 2021 Jul 15;21(14):5914-5919. Epub 2021 Jul 15.

Center for Quantum Materials Synthesis and Department of Physics & Astronomy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.

Controlling magnetic order in magnetic topological insulators (MTIs) is a key to developing spintronic applications with MTIs and is commonly achieved by changing the magnetic doping concentration, which inevitably affects the spin-orbit coupling strength and the topological properties. Here, we demonstrate tunable magnetic properties in topological heterostructures over a wide range, from a ferromagnetic phase with a Curie temperature of around 100 K all the way to a paramagnetic phase, while keeping the overall chemical composition the same, by controlling the thickness of nonmagnetic spacer layers between two atomically thin magnetic layers. This work showcases that spacer-layer control is a powerful tool to manipulate magneto-topological functionalities in MTI heterostructures. Furthermore, the interaction between the MTI and the CrO buffer layers also leads to a robust topological Hall effect surviving up to a record-high 6 T of magnetic field, shedding light on the critical role of interfacial layers in thin-film topological materials.
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http://dx.doi.org/10.1021/acs.nanolett.1c00668DOI Listing
July 2021

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

PLoS One 2021 2;16(7):e0253611. Epub 2021 Jul 2.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253404PMC
July 2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Am J Hum Genet 2021 05 21;108(5):874-893. Epub 2021 Apr 21.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206199PMC
May 2021

The Medicago truncatula Sugar Transport Protein 13 and its Lr67res-like Variant Confer Powdery Mildew Resistance in Legumes via Defense Modulation.

Plant Cell Physiol 2021 02 8. Epub 2021 Feb 8.

Laboratory of Plant-Microbe Interactions, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad 121001, Haryana India.

Obligate biotrophic pathogens like the pea powdery mildew (PM) Erysiphe pisi establish long-term feeding relationships with their host, during which they siphon sugars from host cells through haustoria. Plants in turn deploy sugar transporters to restrict carbon allocation towards pathogens, as a defense mechanism. Studies in Arabidopsis have shown that sugar transport protein 13 (STP13), a proton-hexose symporter involved in apoplasmic hexose retrieval, contributes to bacterial and necrotrophic fungal resistance by limiting sugar flux towards these pathogens. By contrast, expression of Lr67res, a transport-deficient wheat STP13 variant harboring two amino acid substitutions (G144R and V387L), conferred resistance against biotrophic fungi in wheat and barley, indicating its broad applicability in disease management. Here we investigated the role of STP13 and STP13G144Rin legume-PM interactions. We show that Medicago truncatula STP13.1 is a proton-hexose symporter involved in basal resistance against PM, and indirectly show that Lr67res-mediated PM resistance, so far reported only in monocots, is transferable to legumes. Among the 30 MtSTPs, STP13.1 exhibited the highest fold-induction in PM-challenged leaves, and was also responsive to chitosan, ABA and sugar treatment. Functional assays in yeast showed that introduction of the G144R mutation but not V388L abolished MtSTP13.1's hexose uptake ability. Virus-induced gene silencing of MtSTP13 repressed PR gene expression and enhanced PM susceptibility in M. truncatula whereas transient overexpression of MtSTP13.1 or MtSTP13.1G144R in pea induced PR and isoflavonoid pathway genes and enhanced PM resistance. We propose a model in which STP13.1-mediated sugar signaling triggers defense responses against PM in legumes.
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http://dx.doi.org/10.1093/pcp/pcab021DOI Listing
February 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

Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program.

Transfusion 2021 02 24;61(2):603-616. Epub 2020 Nov 24.

Institute of Tropical Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Background: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data.

Study Design And Methods: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program.

Results: In SLC14A1, variants included four encoding a weak Jk phenotype and five null alleles (JK ). JKA*01N.09 was the most common JK . One possible JK mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fy (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting K phenotype, all in heterozygosity.

Conclusions: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.
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http://dx.doi.org/10.1111/trf.16204DOI Listing
February 2021

Complete Pathological Response Noted in Explanted Liver After Y90-SIR-Spheres Therapy for Hepatocellular Carcinoma.

Indian J Nucl Med 2020 Jul-Sep;35(3):267-268. Epub 2020 Jul 1.

Department of Pathology, MIOT International, Chennai, Tamil Nadu, India.

In the treatment of hepatocellular carcinoma, achieving complete pathological response (CPR) in explanted liver specimens following any locoregional treatments is associated with reduced recurrence rates and better posttransplant survival compared to the incomplete response. Here, we present the imaging findings of a patient who achieved CPR in the explanted liver following Y-90 SIR-Spheres® therapy.
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http://dx.doi.org/10.4103/ijnm.IJNM_23_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537917PMC
July 2020

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

JEM: A joint test to estimate the effect of multiple genetic variants on DNA methylation.

Genet Epidemiol 2021 Apr 10;45(3):280-292. Epub 2020 Oct 10.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

Multiple methods have been proposed to aggregate genetic variants in a gene or a region and jointly test their association with a trait of interest. However, these joint tests do not provide estimates of the individual effect of each variant. Moreover, few methods have evaluated the joint association of multiple variants with DNA methylation. We propose a method based on linear mixed models to estimate the joint and individual effect of multiple genetic variants on DNA methylation leveraging genomic annotations. Our approach is flexible, can incorporate covariates and annotation features, and takes into account relatedness and linkage disequilibrium (LD). Our method had correct Type-I error and overall high power for different simulated scenarios where we varied the number and specificity of functional annotations, number of causal and total genetic variants, frequency of genetic variants, LD, and genetic variant effect. Our method outperformed the family Sequence Kernel Association Test and had more stable estimations of effects than a classical single-variant linear mixed-effect model. Applied genome-wide to the Framingham Heart Study data, our method identified 921 DNA methylation sites influenced by at least one rare or low-frequency genetic variant located within 50 kilobases (kb) of the DNA methylation site.
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http://dx.doi.org/10.1002/gepi.22369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005415PMC
April 2021

Müllerianosis of the urinary bladder with unilateral complete renal agenesis: a rare coincidental finding causing delayed presentation.

BMJ Case Rep 2020 Jul 16;13(7). Epub 2020 Jul 16.

Department of Pathology, MIOT International, Chennai, India.

Müllerianosis is a rare benign lesion of the urinary bladder, which is constituted by two or more of the Müllerian-duct-derived tissues. We report a 45-year-old perimenopausal multiparous woman presenting with occasional episodes of dysuria and lower abdominal discomfort of recent duration. Ultrasound examination revealed a well-defined lesion in urinary bladder and the absence of left kidney. Contrast-enhanced CT of the abdomen confirmed the findings. During diagnostic cystoscopy, haemorrhagic polypoidal lesions were noted in the left side of the posterolateral wall and dome of urinary bladder along with the absence of left ureteric orifice. Transurethral resection of the bladder lesions was done and histology examination confirmed the diagnosis of Müllerianosis. She was administered Luteinizing hormone-releasing hormone (LHRH) agonist monthly. At 1 year of follow-up, cystoscopy showed only scar tissue. The case was reported for the rarity of Müllerianosis noted in a patient with unilateral agenesis of kidney, a possible cause of delayed presentation.
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http://dx.doi.org/10.1136/bcr-2020-235217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368546PMC
July 2020

Whole-Genome Sequencing Identifies Novel Functional Loci Associated with Lung Function in Puerto Rican Youth.

Am J Respir Crit Care Med 2020 10;202(7):962-972

Department of Bioengineering and Therapeutic Sciences and.

Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain. In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island ( = 836). We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data. We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07;  = 6.62 × 10) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of in nasal airway epithelial cells and in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21;  = 5.03 × 10). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function. We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.
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http://dx.doi.org/10.1164/rccm.202002-0351OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528787PMC
October 2020

Intrinsic Stability Study and Forced Degradation Profiling of Olopatadine Hydrochloride by RP-HPLC-DAD-HRMS Method.

Turk J Pharm Sci 2019 Dec 11;16(4):392-400. Epub 2019 Nov 11.

School of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal, Madhya Pradesh, India.

Objectives: Forced degradation determines the intrinsic stability of a molecule by establishing degradation pathways in order to identify the likely degradation products (DPs). The objective of the present research was to establish intrinsic stability and forced degradation profiling of olopatadine hydrochloride.

Materials And Methods: The intrinsic stability of olopatadine hydrochloride was evaluated by RP-HPLC, where a mixture of 0.1% formic acid and organic phase (methanol:acetonitrile; 50:50 % v/v) was used as mobile phase at 1.0 mL/min in gradient mode. Different stress conditions were employed to explore the intrinsic stability of olopatadine hydrochloride.

Results: In acidic condition, five DPs, i.e. OLO1, OLO2, OLO3, OLO4, and OLO5, were observed. OLO5 was the major DP that increased with time and the peak area of OLO was decreased. In addition to OLO3 and OLO5, two more DPs were observed in alkaline condition, i.e. OLO6 and OLO7. OLO5 and OLO6 were two major DPs; OLO5 increased with time while OLO6 had a zigzag pattern of peak area with time. All DPs of neutral condition were also found in acidic condition while OLO3 and OLO5 were common in all three types of hydrolytic degradation.

Conclusion: Thus, OLO has similar pattern of degradation profiling in all hydrolytic conditions (acidic, alkaline, and neutral). No degradation was found in thermal, ultraviolet light, or oxidative conditions over 10 days. OLO-Imp was recognized as an analogue structure of OLO and proposed as 11-[(3-dimethylamino)-propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-propanoic acid in standard drug. OLO1 was identified as (2-(4-(dimethylamino) butyl) phenyl)methanol, which may be formed by cleavage of the tricyclic ring in neutral condition.
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http://dx.doi.org/10.4274/tjps.galenos.2018.83007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227878PMC
December 2019

Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.

Genetics 2020 07 23;215(3):869-886. Epub 2020 Apr 23.

Department of Medicine, University of California, San Francisco, California 94143.

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 × 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.
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http://dx.doi.org/10.1534/genetics.120.303231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337089PMC
July 2020

Primary Retroperitoneal Transitional Cell Carcinoma Identified on 18F-Fludeoxyglucose Positron Emission Tomography/Computed Tomography: An Exceedingly Rare Radio-Pathological Entity.

Indian J Nucl Med 2020 Jan-Mar;35(1):63-65. Epub 2019 Dec 31.

Department of Pathology, MIOT International Hospital, Chennai, Tamil Nadu, India.

We report here initial staging and follow-up imaging findings of a case of primary retroperitoneal transitional cell carcinoma, one of the rarest nonurological tumors of the retroperitoneal space, to highlight the importance of F-fludeoxyglucose positron emission tomography/computed tomography in this infrequently encountered pathology.
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http://dx.doi.org/10.4103/ijnm.IJNM_129_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958964PMC
December 2019

Evaluation of Diagnostic Accuracy and Impact of Preoperative Positron Emission Tomography/Computed Tomography in the Management of Early Operable Breast Cancers.

Indian J Nucl Med 2020 Jan-Mar;35(1):40-47. Epub 2019 Dec 31.

Department of Nuclear Medicine, MIOT International, Chennai, Tamil Nadu, India.

Aim: Our aim of this study was to evaluate the diagnostic accuracy of staging positron emission tomography/computed tomography (PET/CT) in early breast cancers (EBCs) and to assess its impact on disease management.

Patients And Methods: We retrospectively reviewed preoperative PET/CT scans of patients from January 2015 to December 2018 with Stage I/II, clinically T1-T2 N0-N1 breast cancers. The diagnostic performance of PET/CT for nodal (N) and distant metastases (M), its correlation with patient/tumor-specific factors, and its impact on disease management were analyzed using histopathology/clinical follow-up as standards of reference.

Results: Of 158 patients evaluated, 14% of patients were Stage I (T1N0), 60% were Stage IIA (T1N1, T2N0), and 26% were Stage IIB (T2N1). Sensitivity, specificity, and the diagnostic accuracy of PET/CT for axillary staging were 76%, 97%, and 84% and for distant metastasis evaluation were 100%, 98%, and 99%, respectively. The diagnostic accuracy of PET/CT for axillary staging was lower for low-grade, T1 tumors, postmenopausal group, and luminal A pathological subtype (77%, 84%, 81%, and 73%, respectively) compared to high-grade, T2 tumors, premenopausal group, and nonluminal A subtype (88%, 88%, 94%, and 87%, respectively). Distant metastases were detected on PET/CT in overall 16% ( = 25) of the patients (9% in Stage IIA and 27% in Stage IIB). PET/CT also incidentally identified clinically occult internal mammary nodes in 5% ( = 8) and organ-confined synchronous second malignancies in 5% ( = 8) of the patients.

Conclusion: Preoperative PET/CT should be considered in all EBCs> 2 cm as it upstages the disease and alters management in about 24% of these patients. Given its high specificity for axillary staging PET/CT, patients with PET-positive axilla can be subjected to axillary dissection and those with PET-negative axilla to sentinel lymph node biopsy. The yield and diagnostic accuracy of PET/CT is less for low-grade tumors <2 cm and with luminal A subtype.
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http://dx.doi.org/10.4103/ijnm.IJNM_140_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958947PMC
December 2019

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

Am J Hum Genet 2020 01 26;106(1):112-120. Epub 2019 Dec 26.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042494PMC
January 2020

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

PLoS Genet 2019 12 23;15(12):e1008500. Epub 2019 Dec 23.

Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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http://dx.doi.org/10.1371/journal.pgen.1008500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953885PMC
December 2019

Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico.

Pediatr Pulmonol 2020 02 30;55(2):533-540. Epub 2019 Oct 30.

Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico.

Background: In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico.

Methods: CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than ​​​​60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools.

Results: Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.

Conclusions: In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.
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http://dx.doi.org/10.1002/ppul.24549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571374PMC
February 2020

Transfusion-Related Acute Lung Injury due to Iatrogenic IVIG Overdose in Guillain-Barre Syndrome.

J Pediatr Neurosci 2019 Jul-Sep;14(3):140-142. Epub 2019 Sep 27.

Department of Paediatrics, Dr. Baba Saheb Ambedkar Medical College and Hospital, Rohini, New Delhi, India.

Transfusion-related acute lung injury (TRALI) is a transfusion-related adverse effect associated with high mortality, manifesting with acute respiratory distress and with features of non-cardiogenic pulmonary edema. It is rarely reported following intravenous immunoglobulin (IVIG) infusion and is even rarer in pediatric population. We here present a 12-year-old female child who presented as a case of acute flaccid paralysis and was diagnosed clinically as Guillain-Barre syndrome. As per protocol, she was given IVIG for 4 of the 5 days therapy at the dose of 0.4mg/kg/day before the patient went to another hospital. Subsequently in the next 1 week, she received two more courses of IVIG in two different hospitals following which she developed respiratory distress and was again admitted in our hospital. A diagnosis of TRALI was leveled on clinical ground because of IVIG overdose. Patient subsequently improved on high-flow oxygen therapy and conservative management. This unfortunate case of iatrogenic IVIG overdose just reinforces the fact of proper documentation of treatment to avoid such mishap and also prompt diagnosis and management of this least recognized entity of TRALI.
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http://dx.doi.org/10.4103/jpn.JPN_47_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798284PMC
September 2019

Complete hydatidiform mole with a twin pregnancy at 26 weeks: a rare obstetric complication.

Authors:
Jain Deepti

Autops Case Rep 2019 Oct-Dec;9(4):e2019108. Epub 2019 Sep 27.

Chhotu Ram Hospital, Obstetrics and Gynecology Department. Rohtak, Haryana, India.

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http://dx.doi.org/10.4322/acr.2019.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771451PMC
September 2019

Tetramerization at Low pH Licenses DNA Methylation Activity of M.HpyAXI in the Presence of Acid Stress.

J Mol Biol 2020 01 16;432(2):324-342. Epub 2019 Oct 16.

Laboratory of Genomic Integrity & Evolution, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad 121001, Haryana, India. Electronic address:

Methylation of genomic DNA can influence the transcription profile of an organism and may generate phenotypic diversity for rapid adaptation in a dynamic environment. M.HpyAXI is a Type III DNA methyltransferase present in Helicobacter pylori and is upregulated at low pH. This enzyme may alter the expression of critical genes to ensure the survival of this pathogen at low pH inside the human stomach. M.HpyAXI methylates the adenine in the target sequence (5'-GCAG-3') and shows maximal activity at pH 5.5. Type III DNA methyltransferases are found to form an inverted dimer in the functional form. We observe that M.HpyAXI forms a nonfunctional dimer at pH 8.0 that is incapable of DNA binding and methylation activity. However, at pH 5.5, two such dimers associate to form a tetramer that now includes two functional dimers that can bind and methylate the target DNA sequence. Overall, we observe that the pH-dependent tetramerization of M.HpyAXI ensures that the enzyme is licensed to act only in the presence of acid stress.
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http://dx.doi.org/10.1016/j.jmb.2019.10.001DOI Listing
January 2020

Transcriptional Fidelity of Mitochondrial RNA Polymerase RpoTm from Arabidopsis thaliana.

J Mol Biol 2019 12 15;431(24):4767-4783. Epub 2019 Oct 15.

Transcription Regulation Lab, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad, 121001, India. Electronic address:

Fidelity of RNA synthesis is essential for the faithful transfer of information from DNA to RNA. A comprehensive analysis of the nucleotide selectivity by the mitochondrial RNA polymerase (RNAP) RpoTm, from Arabidopsis thaliana, has been carried out. The kinetic parameters for the incorporation of cognate, noncognate, and oxidized bases have been determined. The results establish high fidelity of mitochondrial transcription resembling those of replicative polymerases in the absence of repair. In addition, RpoTm incorporates oxidized nucleotides with similar efficiency compared with mismatches and is capable of extending the RNA beyond the insertion of the oxidized base. Furthermore, lesion bypass study on RpoTm demonstrates that the enzyme bypasses 8-oxo-guanine by insertion of adenine leading to C to A mutations in RNA. Homology modeling of RpoTm elongation complex allows delineation of the residues necessary for stabilizing the incoming NTP substrate and for posing the template nucleotide residue. Substitution of these residues leads to compromise in the activity of the enzyme corroborating their importance in RNA synthesis. Comparison of the data with T7 RNAPs indicates that low efficiency of misincorporation is a universal strategy used by single-subunit RNAPs for maintaining high fidelity in the absence of proofreading and repair activity in mitochondria.
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http://dx.doi.org/10.1016/j.jmb.2019.08.022DOI Listing
December 2019

Effector mining from the Erysiphe pisi haustorial transcriptome identifies novel candidates involved in pea powdery mildew pathogenesis.

Mol Plant Pathol 2019 11 11;20(11):1506-1522. Epub 2019 Oct 11.

Laboratory of Plant-Microbe Interactions, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India.

Pea powdery mildew (PM) is an important fungal disease caused by an obligate biotroph, Erysiphe pisi (Ep), which significantly impacts pea production worldwide. The phytopathogen secretes a plethora of effectors, primarily through specialized infection structures termed haustoria, to establish a dynamic relationship with its host. To identify Ep effector candidates, a cDNA library of enriched haustoria from Ep-infected pea leaves was sequenced. The Ep transcriptome encodes 622 Ep candidate secreted proteins (CSPs), of which 167 were predicted to be candidate secreted effector proteins (CSEPs). Phylogenetic analysis indicates that Ep CSEPs are highly diverse, but, unlike cereal PM CSEPs, exhibit extensive sequence similarity with effectors from other PMs. Quantitative real-time PCR of a subset of EpCSEP/CSPs revealed that the majority are preferentially expressed in haustoria and exhibit infection stage-specific expression patterns. The functional roles of EpCSEP001, EpCSEP009 and EpCSP083 were probed by host-induced gene silencing (HIGS) via a double-stranded (ds) RNA-mediated RNAi approach. Foliar application of individual EpCSEP/CSP dsRNAs resulted in a marked reduction in PM disease symptoms. These findings were consistent with microscopic and molecular studies, suggesting that these Ep CSEP/CSPs play important roles in pea PM pathogenesis. Homology modelling revealed that EpCSEP001 and EpCSEP009 are analogous to fungal ribonucleases and belong to the RALPH family of effectors. This is the first study to identify and functionally validate candidate effectors from the agriculturally relevant pea PM, and highlights the utility of transcriptomics and HIGS to elucidate the key proteins associated with Ep pathogenesis.
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http://dx.doi.org/10.1111/mpp.12862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804345PMC
November 2019

Pancreatitis, Cholangitis, and Gastritis: The Triumvirate of Immunoglobulin G4-Related Disease Identified Simultaneously on F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

Indian J Nucl Med 2019 Oct-Dec;34(4):335-337

Department of Pathology, MIOT International, Chennai, Tamil Nadu, India.

Immunoglobulin G4-related disease (IgG4) is an immune-mediated fibro-inflammatory entity which affects multiple organs, most frequently the pancreas. Although extrapancreatic inflammations are commonly seen in F-fluorodeoxyglucose positron emission tomography/computed tomography of majority of these patients at follow-up, simultaneous involvement of the gastric/biliary tract at presentation is rare. Here, we present imaging findings of a patient who presented with obstructive jaundice and initially thought to be due to cholangiocarcinoma, but was subsequently diagnosed as an IgG4-related inflammation.
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http://dx.doi.org/10.4103/ijnm.IJNM_110_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771203PMC
October 2019

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Am J Hum Genet 2019 10 26;105(4):706-718. Epub 2019 Sep 26.

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817529PMC
October 2019
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