Alan Herbert - Academia.edu (original) (raw)
Papers by Alan Herbert
Proceedings of the National Academy of Sciences of the United States of America, Oct 9, 2001
International Journal of Molecular Sciences
The classical view of gene regulation draws from prokaryotic models, where responses to environme... more The classical view of gene regulation draws from prokaryotic models, where responses to environmental changes involve operons regulated by sequence-specific protein interactions with DNA, although it is now known that operons are also modulated by small RNAs. In eukaryotes, pathways based on microRNAs (miR) regulate the readout of genomic information from transcripts, while alternative nucleic acid structures encoded by flipons influence the readout of genetic programs from DNA. Here, we provide evidence that miR- and flipon-based mechanisms are deeply connected. We analyze the connection between flipon conformation and the 211 highly conserved human miR that are shared with other placental and other bilateral species. The direct interaction between conserved miR (c-miR) and flipons is supported by sequence alignments and the engagement of argonaute proteins by experimentally validated flipons as well as their enrichment in promoters of coding transcripts important in multicellular ...
Deep learning methods have been successfully applied to the tasks of predicting functional genomi... more Deep learning methods have been successfully applied to the tasks of predicting functional genomic elements such as histone marks, transcriptions factor binding sites, non-B DNA structures, and regulatory variants. Initially convolutional neural networks (CNN) and recurrent neural networks (RNN) or hybrid CNN-RNN models appeared to be the methods of choice for genomic studies. With the advance of machine learning algorithms other deep learning architectures started to outperform CNN and RNN in various applications. Thus, graph neural network (GNN) applications improved the prediction of drug effects, disease associations, protein-protein interactions, protein structures and their functions. The performance of GNN is yet to be fully explored in genomics. Earlier we developed DeepZ approach in which deep learning model is trained on information both from sequence and omics data. Initially this approach was implemented with CNN and RNN but is not limited to these classes of neural netw...
We present evidence that the severe acute respiratory syndrome coronavirus (SARS) non-structural ... more We present evidence that the severe acute respiratory syndrome coronavirus (SARS) non-structural protein 13 (Nsp13) modulates the Z-RNA dependent regulated cell death pathway of necroptosis (1). We show that Z-prone sequences (called flipons (2)) exist in coronavirus and provide a signature that enables identification of the animal viruses which have become human pathogens. We also identify a potential RHIM in Nsp13. These two observations allow us to suggest a model in which Nsp13 may regulate Z-RNA-initiated RHIM-dependent cell death outcomes at two steps. The first step involves possible new ATP-independent Z-flipon helicase activity in Nsp13, which is distinct from the activity of the canonical A-RNA helicase. This activity unwinds/quenches nascent Z-RNAs, preventing their sensing by ZBP1. The second step involves RHIM-dependent inhibition of ZBP1, RIPK3 and/or RIPK1, preventing cell death downstream of Z-RNA sensing. Together the RHIM and Z-flipon helicase have the potential to...
Z-Scores were determined using ZHUNT3 Champ, P. C., S. Maurice, et al. (2004). "Distribution... more Z-Scores were determined using ZHUNT3 Champ, P. C., S. Maurice, et al. (2004). "Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation." Nucleic acids research 32(22): 6501-6510. The input was from the hg19 build and only Z-Scores>250 are presen
1500 – Genetics, 2021
improvement of the gut barrier and growth inhibition of a translocating Lactobacillus strain. Thi... more improvement of the gut barrier and growth inhibition of a translocating Lactobacillus strain. This Lactobacillus sp. was shown to drive lupus-related pathology in mice via the type I interferon pathway, and its genus was also enriched in a subset of SLE patients. Whether diet enriched in RS have similar effects in patients is unknown. We aimed to understand how dietary RS content influences gut microbial community structures in SLE and SLE-related antiphospholipid syndrome (APS) patients with well-defined microbiomes. 3,4 Methods Stools and dietary information were collected from 12 SLE (n=28), 15 APS (n=44) patients and 20 control subjects (n=48) for up to 3 visits (0, 4 and 8 weeks) as previously described (3,4). Microbiota composition was defined by 16S rRNA V4 region sequencing. The FDA reference list was used to calculate the RS content. Patients' diets were classified as low RS content if less than 2.5 g per day, medium RS if 2.5 to 15 g, and high RS above 15 g. Results Lactobacillus spp. were significantly enriched in SLE patients (p=0.002) compared to non-disease controls. APS patients showed a similar trend (p=0.06), but SLE patients displayed higher relative abundance compared to APS (p=0.011). No significant association was observed between low-to-medium RS content and Lactobacillus. High RS content was not achieved in routine diets of SLE and APS patients in these cohorts. However, medium RS was associated with an outgrowth of Bifidobacterium in SLE patients (p=0.016). Also, medium RS correlated in APS patients with a reduction of cardiolipin-synthesizing bacteria from the Coriobacteriaceae family (p=0.011) including Collinsella (p=0.009) and Slackia genera (p=0.033), previously linked to APS. 5,6 Conclusions The content of RS in patients`regular diets has a distinct impact on the gut microbiota composition depending on the autoimmune disorder. Medium levels of dietary RS were associated in SLE with increased Bifidobacterium, shortchain fatty acid producing bacteria known to promote immune homeostasis, and with decreased cardiolipin-producing commensals in APS. It remains to be tested in an interventional trial if high RS content corrects the outgrowth of Lactobacillus in these patients, but moderate levels of RS may provide already beneficial effects on other taxa potentially involved in the pathogenesis of these disorders.
The Quarterly Review of Biology, 2004
Journal of Biological Chemistry, 1996
Immunogenetics, 2011
Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma leve... more 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 interindividual 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 thePMS1 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 SNP 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), 10 SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p=1.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2013
Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with ... more Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with numerous psychiatric disorders, most notably symptoms of depression. Twin studies have suggested that genetic influences partially underlie the variation seen for numerous sleep‐related traits across individuals. Recently, two Genome‐Wide Association Studies (GWAS) conducted for sleep traits have revealed new candidate genes for sleep‐related measures. We attempted to replicate the two most significant associations from these two studies, CACNA1C (a l‐type calcium channel) with sleep latency and quality and ABCC9 (an ATP‐sensitive potassium channel) with sleep duration, using the G1219 British population sample. We genotyped single‐nucleotide polymorphisms (SNPs) for each of the two different sleep GWAS loci. Linear regression analyses were conducted to assess main effects of these SNPs on their corresponding sleep measures, as well as for depressive symptoms. We successfully replicated ...
International Journal of Molecular Sciences
Cell responses are usually viewed as transitive events with fixed inputs and outputs that are reg... more Cell responses are usually viewed as transitive events with fixed inputs and outputs that are regulated by feedback loops. In contrast, directed cycles (DCs) have all nodes connected, and the flow is in a single direction. Consequently, DCs can regenerate themselves and implement intransitive logic. DCs are able to couple unrelated chemical reactions to each edge. The output depends upon which node is used as input. DCs can also undergo selection to minimize the loss of thermodynamic entropy while maximizing the gain of information entropy. The intransitive logic underlying DCs enhances their programmability and impacts their evolution. The natural selection of DCs favors the persistence, adaptability, and self-awareness of living organisms and does not depend solely on changes to coding sequences. Rather, the process can be RNA-directed. I use flipons, nucleic acid sequences that change conformation under physiological conditions, as a simple example and then describe more complex ...
Zebrafish larvae are able to track and capture prey five days post-fertilization, consistent with... more Zebrafish larvae are able to track and capture prey five days post-fertilization, consistent with a genetic specification of pattern recognition by the nervous system, yet inconsistent with a process that involves tweaking of individual neural connections by processes similar to those currently employed to train artificial neural nets (ANN). Biological neural networks appear extremely efficient and adaptable when compared to ANN. Here I describe self-calibrating randomly initiated binary encoders (SCRIBEs) that produce sparse output and are highly scalable. The self-calibrating nets (SCN) they generate are capable of classifying and tracking objects with high accuracy and fluency by a process based on selection of SCRIBE arrays optimizing survival. Calibration of SCRIBEs depends on array thresholds that vary with their size but can happen without external input during development and sleep. In neural systems, synchronization likely depends on neuromodulator and brainwave status.
PLoS ONE, 2012
The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans... more The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a twofold 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 populationbased 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.
Science, 2006
Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, ... more Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.
Science, 2007
Identification of genetic variants affecting complex traits such as obesity is confounded by many... more Identification of genetic variants affecting complex traits such as obesity is confounded by many types of bias, especially when effect sizes are small. Given our findings of a positive association between rs7566605 and body mass index in four out of five separate samples, a false positive finding cannot be ruled out with certainty but seems unlikely. Meta-analyses of multiple large studies will help refine the estimate of the effects of rs7566605 on body mass index.
Current Opinion in Clinical Nutrition and Metabolic Care, 2008
Purpose of review-Many genes affect pathways that predispose to and protect against obesity. We a... more Purpose of review-Many genes affect pathways that predispose to and protect against obesity. We ask how many different variants affect human obesity and how common are they? Recent findings-The current generation of genome-wide association scans is moderately powered to detect and replicate associations between single nucleotide polymorphisms, or common copy number variations and common diseases. They are not designed either to find rare germline variants or those somatic changes, unique to an individual, that arise with high frequency in adult stem cells. They do not directly assay the epigenetic reprogramming of outcomes related to maternal or environmental exposures. Summary-There are more gene variants, more gene-gene and gene-environmental interactions leading to obesity than current GWAS studies can validate. Those genetic associations that can be verified provide valuable insight into the pathways contributing to human obesity.
American Heart Journal, 2007
Background-Previous studies have suggested a positive association between phenotypes of fucosyltr... more Background-Previous studies have suggested a positive association between phenotypes of fucosyltransferase 3 (FUT3) gene (also known as Lewis gene) and coronary heart disease. Methods-We used data on 1,735 unrelated subjects in the Framingham Offspring Study to assess whether 3 functional single nucleotide polymorphisms (SNPs) of the FUT3 gene (T59G, T1067A, and T202C) were associated with prevalent atherothrombotic disease. Results-Contrary to T1067A and T202C SNPs, there was evidence for an association between T59G SNP and atherothrombotic disease prevalence. In a multivariable model controlling for age, sex, alcohol intake, pack-years of smoking, ratio of total-to-HDL-cholesterol, and diabetes mellitus, odds ratios (95% CI) for prevalent atherothrombotic disease were 1.0 (reference), 0.80 (0.46-1.41), and 6.70 (1.95-23.01) for TT, TG, and GG genotypes of the T59G SNP, respectively. Minor alleles of T202C and T1067A SNPs showed a modest and non-significant association with atherothrombotic disease. Overall, FUT3 polymorphism that influences the enzyme activity (GG genotype for T59G or ≥ 1 minor allele of T202C or T1067A) was associated with increased atherothrombotic disease prevalence [OR: 1.57 (1.05-2.34)] and this association was stronger among abstainers (2-fold increased odds) than among current drinkers (p for interaction 0.11). Conclusions-Our data suggest that functional mutations of the FUT3 gene may be associated with an increased atherothrombotic disease prevalence, especially among abstainers. Additional studies are warranted to confirm these findings.
International Journal of Molecular Sciences, 2022
Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory ... more Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory cell death (ICD), ZBP1 activates host defenses to destroy infectious threats. ZBP1 is also able to induce noninflammatory regulated cell death via apoptosis (RCD). ZBP1 senses the presence of left-handed Z-DNA and Z-RNA (ZNA), including that formed by expression of endogenous retroelements. Viruses such as the Epstein–Barr “kissing virus” inhibit ICD, RCD and other cell death signaling pathways to produce persistent infection. EBV undergoes lytic replication in plasma cells, which maintain detectable levels of basal ZBP1 expression, leading us to suggest a new role for ZBP1 in maintaining EBV latency, one of benefit for both host and virus. We provide an overview of the pathways that are involved in establishing latent infection, including those regulated by MYC and NF-κB. We describe and provide a synthesis of the evidence supporting a role for ZNA in these pathways, highlighting the po...
Proceedings of the National Academy of Sciences of the United States of America, Oct 9, 2001
International Journal of Molecular Sciences
The classical view of gene regulation draws from prokaryotic models, where responses to environme... more The classical view of gene regulation draws from prokaryotic models, where responses to environmental changes involve operons regulated by sequence-specific protein interactions with DNA, although it is now known that operons are also modulated by small RNAs. In eukaryotes, pathways based on microRNAs (miR) regulate the readout of genomic information from transcripts, while alternative nucleic acid structures encoded by flipons influence the readout of genetic programs from DNA. Here, we provide evidence that miR- and flipon-based mechanisms are deeply connected. We analyze the connection between flipon conformation and the 211 highly conserved human miR that are shared with other placental and other bilateral species. The direct interaction between conserved miR (c-miR) and flipons is supported by sequence alignments and the engagement of argonaute proteins by experimentally validated flipons as well as their enrichment in promoters of coding transcripts important in multicellular ...
Deep learning methods have been successfully applied to the tasks of predicting functional genomi... more Deep learning methods have been successfully applied to the tasks of predicting functional genomic elements such as histone marks, transcriptions factor binding sites, non-B DNA structures, and regulatory variants. Initially convolutional neural networks (CNN) and recurrent neural networks (RNN) or hybrid CNN-RNN models appeared to be the methods of choice for genomic studies. With the advance of machine learning algorithms other deep learning architectures started to outperform CNN and RNN in various applications. Thus, graph neural network (GNN) applications improved the prediction of drug effects, disease associations, protein-protein interactions, protein structures and their functions. The performance of GNN is yet to be fully explored in genomics. Earlier we developed DeepZ approach in which deep learning model is trained on information both from sequence and omics data. Initially this approach was implemented with CNN and RNN but is not limited to these classes of neural netw...
We present evidence that the severe acute respiratory syndrome coronavirus (SARS) non-structural ... more We present evidence that the severe acute respiratory syndrome coronavirus (SARS) non-structural protein 13 (Nsp13) modulates the Z-RNA dependent regulated cell death pathway of necroptosis (1). We show that Z-prone sequences (called flipons (2)) exist in coronavirus and provide a signature that enables identification of the animal viruses which have become human pathogens. We also identify a potential RHIM in Nsp13. These two observations allow us to suggest a model in which Nsp13 may regulate Z-RNA-initiated RHIM-dependent cell death outcomes at two steps. The first step involves possible new ATP-independent Z-flipon helicase activity in Nsp13, which is distinct from the activity of the canonical A-RNA helicase. This activity unwinds/quenches nascent Z-RNAs, preventing their sensing by ZBP1. The second step involves RHIM-dependent inhibition of ZBP1, RIPK3 and/or RIPK1, preventing cell death downstream of Z-RNA sensing. Together the RHIM and Z-flipon helicase have the potential to...
Z-Scores were determined using ZHUNT3 Champ, P. C., S. Maurice, et al. (2004). "Distribution... more Z-Scores were determined using ZHUNT3 Champ, P. C., S. Maurice, et al. (2004). "Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation." Nucleic acids research 32(22): 6501-6510. The input was from the hg19 build and only Z-Scores>250 are presen
1500 – Genetics, 2021
improvement of the gut barrier and growth inhibition of a translocating Lactobacillus strain. Thi... more improvement of the gut barrier and growth inhibition of a translocating Lactobacillus strain. This Lactobacillus sp. was shown to drive lupus-related pathology in mice via the type I interferon pathway, and its genus was also enriched in a subset of SLE patients. Whether diet enriched in RS have similar effects in patients is unknown. We aimed to understand how dietary RS content influences gut microbial community structures in SLE and SLE-related antiphospholipid syndrome (APS) patients with well-defined microbiomes. 3,4 Methods Stools and dietary information were collected from 12 SLE (n=28), 15 APS (n=44) patients and 20 control subjects (n=48) for up to 3 visits (0, 4 and 8 weeks) as previously described (3,4). Microbiota composition was defined by 16S rRNA V4 region sequencing. The FDA reference list was used to calculate the RS content. Patients' diets were classified as low RS content if less than 2.5 g per day, medium RS if 2.5 to 15 g, and high RS above 15 g. Results Lactobacillus spp. were significantly enriched in SLE patients (p=0.002) compared to non-disease controls. APS patients showed a similar trend (p=0.06), but SLE patients displayed higher relative abundance compared to APS (p=0.011). No significant association was observed between low-to-medium RS content and Lactobacillus. High RS content was not achieved in routine diets of SLE and APS patients in these cohorts. However, medium RS was associated with an outgrowth of Bifidobacterium in SLE patients (p=0.016). Also, medium RS correlated in APS patients with a reduction of cardiolipin-synthesizing bacteria from the Coriobacteriaceae family (p=0.011) including Collinsella (p=0.009) and Slackia genera (p=0.033), previously linked to APS. 5,6 Conclusions The content of RS in patients`regular diets has a distinct impact on the gut microbiota composition depending on the autoimmune disorder. Medium levels of dietary RS were associated in SLE with increased Bifidobacterium, shortchain fatty acid producing bacteria known to promote immune homeostasis, and with decreased cardiolipin-producing commensals in APS. It remains to be tested in an interventional trial if high RS content corrects the outgrowth of Lactobacillus in these patients, but moderate levels of RS may provide already beneficial effects on other taxa potentially involved in the pathogenesis of these disorders.
The Quarterly Review of Biology, 2004
Journal of Biological Chemistry, 1996
Immunogenetics, 2011
Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma leve... more 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 interindividual 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 thePMS1 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 SNP 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), 10 SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p=1.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2013
Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with ... more Sleep is a critical behavior shared by most higher animals. Sleep disturbances are comorbid with numerous psychiatric disorders, most notably symptoms of depression. Twin studies have suggested that genetic influences partially underlie the variation seen for numerous sleep‐related traits across individuals. Recently, two Genome‐Wide Association Studies (GWAS) conducted for sleep traits have revealed new candidate genes for sleep‐related measures. We attempted to replicate the two most significant associations from these two studies, CACNA1C (a l‐type calcium channel) with sleep latency and quality and ABCC9 (an ATP‐sensitive potassium channel) with sleep duration, using the G1219 British population sample. We genotyped single‐nucleotide polymorphisms (SNPs) for each of the two different sleep GWAS loci. Linear regression analyses were conducted to assess main effects of these SNPs on their corresponding sleep measures, as well as for depressive symptoms. We successfully replicated ...
International Journal of Molecular Sciences
Cell responses are usually viewed as transitive events with fixed inputs and outputs that are reg... more Cell responses are usually viewed as transitive events with fixed inputs and outputs that are regulated by feedback loops. In contrast, directed cycles (DCs) have all nodes connected, and the flow is in a single direction. Consequently, DCs can regenerate themselves and implement intransitive logic. DCs are able to couple unrelated chemical reactions to each edge. The output depends upon which node is used as input. DCs can also undergo selection to minimize the loss of thermodynamic entropy while maximizing the gain of information entropy. The intransitive logic underlying DCs enhances their programmability and impacts their evolution. The natural selection of DCs favors the persistence, adaptability, and self-awareness of living organisms and does not depend solely on changes to coding sequences. Rather, the process can be RNA-directed. I use flipons, nucleic acid sequences that change conformation under physiological conditions, as a simple example and then describe more complex ...
Zebrafish larvae are able to track and capture prey five days post-fertilization, consistent with... more Zebrafish larvae are able to track and capture prey five days post-fertilization, consistent with a genetic specification of pattern recognition by the nervous system, yet inconsistent with a process that involves tweaking of individual neural connections by processes similar to those currently employed to train artificial neural nets (ANN). Biological neural networks appear extremely efficient and adaptable when compared to ANN. Here I describe self-calibrating randomly initiated binary encoders (SCRIBEs) that produce sparse output and are highly scalable. The self-calibrating nets (SCN) they generate are capable of classifying and tracking objects with high accuracy and fluency by a process based on selection of SCRIBE arrays optimizing survival. Calibration of SCRIBEs depends on array thresholds that vary with their size but can happen without external input during development and sleep. In neural systems, synchronization likely depends on neuromodulator and brainwave status.
PLoS ONE, 2012
The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans... more The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a twofold 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 populationbased 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.
Science, 2006
Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, ... more Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.
Science, 2007
Identification of genetic variants affecting complex traits such as obesity is confounded by many... more Identification of genetic variants affecting complex traits such as obesity is confounded by many types of bias, especially when effect sizes are small. Given our findings of a positive association between rs7566605 and body mass index in four out of five separate samples, a false positive finding cannot be ruled out with certainty but seems unlikely. Meta-analyses of multiple large studies will help refine the estimate of the effects of rs7566605 on body mass index.
Current Opinion in Clinical Nutrition and Metabolic Care, 2008
Purpose of review-Many genes affect pathways that predispose to and protect against obesity. We a... more Purpose of review-Many genes affect pathways that predispose to and protect against obesity. We ask how many different variants affect human obesity and how common are they? Recent findings-The current generation of genome-wide association scans is moderately powered to detect and replicate associations between single nucleotide polymorphisms, or common copy number variations and common diseases. They are not designed either to find rare germline variants or those somatic changes, unique to an individual, that arise with high frequency in adult stem cells. They do not directly assay the epigenetic reprogramming of outcomes related to maternal or environmental exposures. Summary-There are more gene variants, more gene-gene and gene-environmental interactions leading to obesity than current GWAS studies can validate. Those genetic associations that can be verified provide valuable insight into the pathways contributing to human obesity.
American Heart Journal, 2007
Background-Previous studies have suggested a positive association between phenotypes of fucosyltr... more Background-Previous studies have suggested a positive association between phenotypes of fucosyltransferase 3 (FUT3) gene (also known as Lewis gene) and coronary heart disease. Methods-We used data on 1,735 unrelated subjects in the Framingham Offspring Study to assess whether 3 functional single nucleotide polymorphisms (SNPs) of the FUT3 gene (T59G, T1067A, and T202C) were associated with prevalent atherothrombotic disease. Results-Contrary to T1067A and T202C SNPs, there was evidence for an association between T59G SNP and atherothrombotic disease prevalence. In a multivariable model controlling for age, sex, alcohol intake, pack-years of smoking, ratio of total-to-HDL-cholesterol, and diabetes mellitus, odds ratios (95% CI) for prevalent atherothrombotic disease were 1.0 (reference), 0.80 (0.46-1.41), and 6.70 (1.95-23.01) for TT, TG, and GG genotypes of the T59G SNP, respectively. Minor alleles of T202C and T1067A SNPs showed a modest and non-significant association with atherothrombotic disease. Overall, FUT3 polymorphism that influences the enzyme activity (GG genotype for T59G or ≥ 1 minor allele of T202C or T1067A) was associated with increased atherothrombotic disease prevalence [OR: 1.57 (1.05-2.34)] and this association was stronger among abstainers (2-fold increased odds) than among current drinkers (p for interaction 0.11). Conclusions-Our data suggest that functional mutations of the FUT3 gene may be associated with an increased atherothrombotic disease prevalence, especially among abstainers. Additional studies are warranted to confirm these findings.
International Journal of Molecular Sciences, 2022
Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory ... more Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory cell death (ICD), ZBP1 activates host defenses to destroy infectious threats. ZBP1 is also able to induce noninflammatory regulated cell death via apoptosis (RCD). ZBP1 senses the presence of left-handed Z-DNA and Z-RNA (ZNA), including that formed by expression of endogenous retroelements. Viruses such as the Epstein–Barr “kissing virus” inhibit ICD, RCD and other cell death signaling pathways to produce persistent infection. EBV undergoes lytic replication in plasma cells, which maintain detectable levels of basal ZBP1 expression, leading us to suggest a new role for ZBP1 in maintaining EBV latency, one of benefit for both host and virus. We provide an overview of the pathways that are involved in establishing latent infection, including those regulated by MYC and NF-κB. We describe and provide a synthesis of the evidence supporting a role for ZNA in these pathways, highlighting the po...