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1.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443469

RESUMO

The classical genetic code maps nucleotide triplets to amino acids. The associated sequence composition is complex, representing many elaborations during evolution of form and function. Other genomic elements code for the expression and processing of RNA transcripts. However, over 50% of the human genome consists of widely dispersed repetitive sequences. Among these are simple sequence repeats (SSRs), representing a class of flipons, that under physiological conditions, form alternative nucleic acid conformations such as Z-DNA, G4 quartets, I-motifs, and triplexes. Proteins that bind in a structure-specific manner enable the seeding of condensates with the potential to regulate a wide range of biological processes. SSRs also encode the low complexity peptide repeats to patch condensates together, increasing the number of combinations possible. In situations where SSRs are transcribed, SSR-specific, single-stranded binding proteins may further impact condensate formation. Jointly, flipons and patches speed evolution by enhancing the functionality of condensates. Here, the focus is on the selection of SSR flipons and peptide patches that solve for survival under a wide range of environmental contexts, generating complexity with simple parts.


Assuntos
DNA Forma Z/química , DNA Forma Z/genética , Evolução Molecular , Conformação de Ácido Nucleico , Proteínas/química , Proteínas/genética , Animais , Códon , DNA Forma Z/metabolismo , Genética , Humanos , Repetições de Microssatélites/genética , Proteínas/metabolismo
2.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299306

RESUMO

It is now difficult to believe that a biological function for the left-handed Z-DNA and Z-RNA conformations was once controversial. The papers in this Special Issue, "Z-DNA and Z-RNA: from Physical Structure to Biological Function", are based on presentations at the ABZ2021 meeting that was held virtually on 19 May 2021 and provide evidence for several biological functions of these structures. The first of its kind, this international conference gathered over 200 scientists from many disciplines to specifically address progress in research involving Z-DNA and Z-RNA. These high-energy left-handed conformers of B-DNA and A-RNA are associated with biological functions and disease outcomes, as evidenced from both mouse and human genetic studies. These alternative structures, referred to as "flipons", form under physiological conditions, regulate type I interferon responses and induce necroptosis during viral infection. They can also stimulate genetic instability, resulting in adaptive evolution and diseases such as cancer. The meeting featured cutting-edge science that was, for the most part, unpublished. We plan for the ABZ meeting to reconvene in 2022.


Assuntos
DNA Forma Z/química , Conformação de Ácido Nucleico , RNA/química , Animais , DNA Forma Z/genética , DNA Forma Z/metabolismo , Humanos , Camundongos , RNA/genética , RNA/metabolismo
4.
PLoS Genet ; 17(5): e1009513, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983939

RESUMO

Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation-associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell's repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.


Assuntos
Helicase IFIH1 Induzida por Interferon/metabolismo , Conformação de Ácido Nucleico , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/metabolismo , Adenosina Desaminase/química , Adenosina Desaminase/metabolismo , Animais , RNA Helicases DEAD-box/metabolismo , Doença , Edição de Genes , Humanos , Proteínas de Neoplasias/metabolismo , RNA Helicases/metabolismo , RNA de Cadeia Dupla/genética , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Especificidade por Substrato , Vírus
5.
J Immunother Cancer ; 8(2)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33323465

RESUMO

The synapses between immune cells and their targets are 150 Å wide. They regulate immune cell responses (IRs) to cognate antigens. Here, I outline a potential mechanism for self-nonself discrimination based on the C3d and iC3b proteolytic fragments of complement protein C3. The proposed C3 checkpoint works through complement receptor 3 (CR3), which binds both C3d and iC3b. The CR3 conformations involved differ; the bent, cis-acting CR3 engages C3d, activating the immune cell expressing CR3; the extended, transacting CR3 conformer binds iC3b on another cell, inhibiting IRs. The CR3 complexes formed with iC3b and C3d vary greatly in size. Only bound C3d is small enough to fit within the synapse. It stimulates IRs by countering the inhibitory signals that iC3b generates at the synapse edge. The competition between C3d and iC3b dynamically determines whether or not an immune cell activates. Host cells use regulators of complement activation (RCA) to coat themselves with iC3b, silencing IRs against self by preventing synapse formation. Tumors exploit this process by overexpressing C3 and RCA to masquerade as 'super-self', with iC3b masking neoantigens. Enhancing synapse formation by specifically labeling cancer cells as nonself with targeted C3d therapeutics offers a new strategy for boosting tumor-specific immunity.


Assuntos
Complemento C3/fisiologia , Imunoterapia/métodos , Neoplasias/metabolismo , Sinapses/metabolismo , Humanos
6.
R Soc Open Sci ; 7(6): 200222, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32742689

RESUMO

ALUs contribute to genetic diversity by altering DNA's linear sequence through retrotransposition, recombination and repair. ALUs also have the potential to form alternative non-B-DNA conformations such as Z-DNA, triplexes and quadruplexes that alter the read-out of information from the genome. I suggest here these structures enable the rapid reprogramming of cellular pathways to offset DNA damage and regulate inflammation. The experimental data supporting this form of genetic encoding is presented. ALU sequence motifs that form non-B-DNA conformations under physiological conditions are called flipons. Flipons are binary switches. They are dissipative structures that trade energy for information. By efficiently targeting cellular machines to active genes, flipons expand the repertoire of RNAs compiled from a gene. Their action greatly increases the informational capacity of linearly encoded genomes. Flipons are programmable by epigenetic modification, synchronizing cellular events by altering both chromatin state and nucleosome phasing. Different classes of flipon exist. Z-flipons are based on Z-DNA and modify the transcripts compiled from a gene. T-flipons are based on triplexes and localize non-coding RNAs that direct the assembly of cellular machines. G-flipons are based on G-quadruplexes and sense DNA damage, then trigger the appropriate protective responses. Flipon conformation is dynamic, changing with context. When frozen in one state, flipons often cause disease. The propagation of flipons throughout the genome by ALU elements represents a novel evolutionary innovation that allows for rapid change. Each ALU insertion creates variability by extracting a different set of information from the neighbourhood in which it lands. By elaborating on already successful adaptations, the newly compiled transcripts work with the old to enhance survival. Systems that optimize flipon settings through learning can adapt faster than with other forms of evolution. They avoid the risk of relying on random and irreversible codon rewrites.

7.
Trends Genet ; 36(10): 739-750, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32690316

RESUMO

Processing of RNA involves heterogeneous nuclear ribonucleoproteins. The simple sequence repeats (SSRs) they bind can also adopt alternative DNA structures, like Z DNA, triplexes, G quadruplexes, and I motifs. Those SSRs capable of switching conformation under physiological conditions (called flipons) are genetic elements that can encode alternative RNA processing by their effects on RNA processivity, most likely as DNA:RNA hybrids. Flipons are elements of a binary, instructive genetic code directing how genomic sequences are compiled into transcripts. The combinatorial nature of this code provides a rich set of options for creating genetic computers able to reproduce themselves and use a heritable and evolvable code to optimize survival. The underlying computational logic potentiates a diverse set of genetic programs that modify cis-mediated heritability and disease risk.


Assuntos
DNA/genética , Quadruplex G , Código Genético , Genoma , Repetições de Microssatélites , RNA/genética , Animais , DNA/química , Genômica , Humanos , RNA/química
8.
Eur J Hum Genet ; 28(1): 114-117, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31320745

RESUMO

Variants in the human double-stranded RNA editing enzyme ADAR produce three well-characterized rare Mendelian Diseases: Dyschromatosis Symmetrica Hereditaria (OMIM: 127400), Aicardi-Goutières syndrome (OMIM: 615010) and Bilateral Striatal Necrosis/Dystonia. ADAR encodes p150 and p110 protein isoforms. p150 incorporates the Zα domain that binds left-handed Z-DNA and Z-RNA with high affinity through contact of highly conserved residues with the DNA and RNA double helix. In certain individuals, frameshift variants on one parental chromosome in the second exon of ADAR produce haploinsufficiency of p150 while maintaining normal expression of p110. In other individuals, loss of p150 expression from one chromosome allows mapping of Zα p150 variants from the other parental chromosome directly to phenotype. The analysis reveals that loss of function Zα variants cause dysregulation of innate interferon responses to double-stranded RNA. This approach confirms a biological role for the left-handed conformation in human disease, further validating the power of Mendelian genetics to deliver unambiguous answers to difficult questions. The findings reveal that the human genome encodes genetic information using both shape and sequence.


Assuntos
Adenosina Desaminase/genética , Alelos , Doenças Genéticas Inatas/genética , Doenças do Sistema Imunitário/genética , Proteínas de Ligação a RNA/genética , Adenosina Desaminase/química , Adenosina Desaminase/metabolismo , Sítios de Ligação , Sequência Conservada , DNA Forma Z/metabolismo , Mutação da Fase de Leitura , Humanos , Interferons/metabolismo , Mutação com Perda de Função , Fenótipo , Ligação Proteica , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo
9.
Trends Genet ; 35(12): 887-890, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31668857

RESUMO

Flipons are sequences capable of forming either right- or left-handed DNA under physiological conditions, forming a class of dissipative structures that trade metabolic energy for information by cycling DNA between different chromatin states. Flipons enhance the diversity of transcriptomes, increasing entropy while enabling the evolution of features both new and unexpected.


Assuntos
DNA/química , DNA/genética , Código Genético , Conformação de Ácido Nucleico , DNA Forma Z/química , Proteínas de Ligação a DNA/química , Entropia , Evolução Molecular , Humanos , Domínios e Motivos de Interação entre Proteínas
10.
Trends Cancer ; 5(5): 272-282, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31174840

RESUMO

The regulation of immune responses by tumors is central to their survival. By diminishing the production of interferon (IFN) and other inflammatory mediators, tumors enhance immune evasion. Responses initiated by nucleic acid sensors and triggered by dysregulated RNA transcription and cytoplasmic DNA undergo down-modulation in tumors. A protein hub that involves the double-stranded RNA (dsRNA) editing enzyme adenosine deaminase RNA specific (ADAR), the RNase DICER1, and the dsRNA-activated kinase protein activator of PKR (PACT) mediates many of these tumor-intrinsic responses, with in vitro ADAR dependency varying by tumor type (range 11-80%). The central role played by ADAR, both as an enzyme and as a scaffold, sets it as a target for cancer immunotherapy. Therapeutic approaches focusing on the ADAR p150 isoform and its Z-DNA- and Z-RNA-specific Zα domain find support from recent mouse and human studies.


Assuntos
Adenosina Desaminase/metabolismo , Suscetibilidade a Doenças , Neoplasias/etiologia , Neoplasias/metabolismo , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/metabolismo , Evasão Tumoral , Animais , DNA Forma Z/genética , Epigênese Genética , Humanos , Imunidade Inata , Interferons , Neoplasias/patologia , RNA de Cadeia Dupla/genética , Proteínas de Ligação a RNA/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Commun Biol ; 2: 7, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729177

RESUMO

Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-Goutières Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , DNA Forma Z/genética , DNA Forma Z/metabolismo , Malformações do Sistema Nervoso/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Elementos Alu/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , RNA Helicases DEAD-box/genética , DNA Forma Z/química , Humanos , Mutação com Perda de Função , Conformação de Ácido Nucleico , Ligação Proteica , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/genética
12.
Front Immunol ; 10: 2898, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921159

RESUMO

Winning the game "Rock, Scissors, Paper" depends on what others do. There is no guarantee that one choice will always win. Does the adaptive immune system use the same intransitive logic to select winners? Here I propose that specialized receptor-ligand pairs, called clicks, initiate contextual cell death to select the best adaptive immune response to a particular challenge. The outcome depends heavily on the phenotypic plasticity of the immune system and upon cell assemblies built from different lineages. These assemblies are self-organizing and use clicks to determine the combination of cells best equipped to defeat a threat. The arrangement is highly adaptive and capable of rapid evolution. Opportunities exist to re-engineer click-based assemblies to produce novel therapeutics.


Assuntos
Imunidade Adaptativa , Morte Celular/imunologia , Humanos
13.
PLoS One ; 12(7): e0180870, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28719615

RESUMO

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Sistema Imunitário/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Quimiocinas/biossíntese , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Fagócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Receptores Toll-Like/metabolismo , Transcriptoma/efeitos dos fármacos
14.
J Contam Hydrol ; 167: 1-22, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25147021

RESUMO

A safety case for the disposal of Intermediate Level (radioactive) Waste (ILW) in a deep geological disposal facility (GDF) requires consideration of the potential for waste-derived light non-aqueous phase liquid (LNAPL) to migrate under positive buoyancy from disposed waste packages. Were entrainment of waste-derived radionuclides in LNAPL to occur, such migration could result in a shorter overall travel time to environmental or human receptors than radionuclide migration solely associated with the movement of groundwater. This paper provides a contribution to the assessment of this issue through multiphase-flow numerical modelling underpinned by a review of the UK's ILW inventory and literature to define the nature of the associated ILW LNAPL source term. Examination has been at the waste package-local GDF environment scale to determine whether proposed disposal of ILW would lead to significant likelihood of LNAPL migration, both from waste packages and from a GDF vault into the local host rock. Our review and numerical modelling support the proposition that the release of a discrete free phase LNAPL from ILW would not present a significant challenge to the safety case even with conservative approximations. 'As-disposed' LNAPL emplaced with the waste is not expected to pose a significant issue. 'Secondary LNAPL' generated in situ within the disposed ILW, arising from the decomposition of plastics, in particular PVC (polyvinyl chloride), could form the predominant LNAPL source term. Released high molecular weight phthalate plasticizers are judged to be the primary LNAPL potentially generated. These are expected to have low buoyancy-based mobility due to their very low density contrast with water and high viscosity. Due to the inherent uncertainties, significant conservatisms were adopted within the numerical modelling approach, including: the simulation of a deliberately high organic material--PVC content wastestream (2D03) within an annular grouted waste package vulnerable to LNAPL release; upper bound inventory estimates of LNAPLs; incorporating the lack of any hydraulic resistance of the package vent; the lack of any degradation of dissolved LNAPL; and, significantly, the small threshold displacement pressure assumed at which LNAPL is able to enter initially water-saturated pores. Initial scoping calculations on the latter suggested that the rate at which LNAPL is able to migrate from a waste package is likely to be very small and insignificant for likely representative displacement pressure data: this represents a key result. Adopting a conservative displacement pressure, however, allowed the effect of other features and processes in the system to be assessed. High LNAPL viscosity together with low density contrast with water reduces LNAPL migration potential. Migration to the host rock is less likely if waste package vent fluxes are small, solubility limits are high and path lengths through the backfill are short. The capacity of the system to dissolve all of the free LNAPL will, however, depend on groundwater availability. Even with the conservatisms invoked, the overall conclusion of model simulations of intact and compromised (cracked or corroded) waste packages, for a range of realistic ILW LNAPL scenarios, is that it is unlikely that significant LNAPL would be able to migrate from the waste packages and even more unlikely it would be sufficiently persistent to reach the host rock immediately beyond the GDF.


Assuntos
Geologia , Modelos Teóricos , Resíduos Radioativos , Eliminação de Resíduos/métodos , Medição de Risco/métodos , Movimentos da Água , Simulação por Computador , Reino Unido
15.
PLoS One ; 7(9): e45112, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028791

RESUMO

The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.


Assuntos
Afro-Americanos/genética , Loci Gênicos/genética , Testes de Função Renal , Rim/fisiologia , Feminino , Genealogia e Heráldica , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
16.
BMC Med Genet ; 13: 88, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22994408

RESUMO

BACKGROUND: A recent, large genome-wide association study (GWAS) of European ancestry individuals has identified multiple genetic variants influencing serum lipids. Studies of the transferability of these associations to African Americans remain few, an important limitation given interethnic differences in serum lipids and the disproportionate burden of lipid-associated metabolic diseases among African Americans. METHODS: We attempted to evaluate the transferability of 95 lipid-associated loci recently identified in European ancestry individuals to 887 non-diabetic, unrelated African Americans from a population-based sample in the Washington, DC area. Additionally, we took advantage of the generally reduced linkage disequilibrium among African ancestry populations in comparison to European ancestry populations to fine-map replicated GWAS signals. RESULTS: We successfully replicated reported associations for 10 loci (CILP2/SF4, STARD3, LPL, CYP7A1, DOCK7/ANGPTL3, APOE, SORT1, IRS1, CETP, and UBASH3B). Through trans-ethnic fine-mapping, we were able to reduce associated regions around 75% of the loci that replicated. CONCLUSIONS: Between this study and previous work in African Americans, 40 of the 95 loci reported in a large GWAS of European ancestry individuals also influence lipid levels in African Americans. While there is now evidence that the lipid-influencing role of a number of genetic variants is observed in both European and African ancestry populations, the still considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of these traits.


Assuntos
Afro-Americanos/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Loci Gênicos , Triglicerídeos/sangue , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Doenças Metabólicas/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
17.
Hum Mol Genet ; 21(20): 4530-6, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22791750

RESUMO

Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/etnologia , Resistência à Insulina/genética , Insulina/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Adulto , Afro-Americanos , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Jejum/metabolismo , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
18.
Eur J Hum Genet ; 20(4): 463-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22085899

RESUMO

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10(-8). The lowest P-value was 1.7 × 10(-22) for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10(-11); this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r(2)≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.


Assuntos
Afro-Americanos , Bilirrubina/sangue , Glucuronosiltransferase/genética , Adulto , Bilirrubina/genética , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
19.
Immunogenetics ; 64(5): 351-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22205395

RESUMO

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 × 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10(-6) to 1.75 × 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 × 10(-6) to 1.63 × 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.


Assuntos
Afro-Americanos/genética , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Proteínas 14-3-3/genética , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fenômenos Imunogenéticos , Interleucina-1/genética , Masculino , Pessoa de Meia-Idade , Família Multigênica , Proteínas MutL , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras da Sinalização de Citocina/genética
20.
BMC Med Genomics ; 4: 17, 2011 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-21294900

RESUMO

BACKGROUND: Uric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI), sex, and multiple complex diseases including gout, hypertension (HTN), renal disease, and type 2 diabetes (T2D). Multiple genome-wide association studies (GWAS) in individuals of European ancestry (EA) have reported associations between serum uric acid levels (SUAL) and specific genomic loci. The purposes of this study were: 1) to replicate major signals reported in EA populations; and 2) to use the weak LD pattern in African ancestry population to better localize (fine-map) reported loci and 3) to explore the identification of novel findings cognizant of the moderate sample size. METHODS: African American (AA) participants (n = 1,017) from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix® Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs) were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification. RESULTS: Four variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 × 10(-9) to 1.38 × 10(-9)). Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples. CONCLUSIONS: The most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA populations GWAS signals in African-ancestry populations with weaker linkage disequilibrium.


Assuntos
Afro-Americanos/genética , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/genética , Ácido Úrico/sangue , Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Africano/genética , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Gota/genética , Humanos , Hipertensão/genética , Desequilíbrio de Ligação , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único
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