17 results on '"Williams, Scott M."'
Search Results
2. Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.
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Chen, Jing, Bacelis, Jonas, Sole-Navais, Pol, Srivastava, Amit, Juodakis, Julius, Rouse, Amy, Hallman, Mikko, Teramo, Kari, Melbye, Mads, Feenstra, Bjarke, Freathy, Rachel M., Smith, George Davey, Lawlor, Deborah A., Murray, Jeffrey C., Williams, Scott M., Jacobsson, Bo, Muglia, Louis J., and Zhang, Ge
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WEIGHT in infancy ,FETAL growth disorders ,SINGLE nucleotide polymorphisms ,BIRTH weight ,BLOOD sugar ,BIRTH size ,FETAL development - Abstract
Background: Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved.Methods and Findings: Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10-4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10-17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10-4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10-3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10-2 and p = 4.5 × 10-3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10-6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10-3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10-3) and a stronger fetal effect (p = 1.3 × 10-5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10-4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10-2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits.Conclusions: We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes. [ABSTRACT FROM AUTHOR]- Published
- 2020
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3. Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: evidence for coevolution?
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McHenry, Michael L., Bartlett, Jacquelaine, Igo, Robert P., Wampande, Eddie M., Benchek, Penelope, Mayanja-Kizza, Harriet, Fluegge, Kyle, Hall, Noemi B., Gagneux, Sebastien, Tishkoff, Sarah A., Wejse, Christian, Sirugo, Giorgio, Boom, W. Henry, Joloba, Moses, Williams, Scott M., and Stein, Catherine M.
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MYCOBACTERIUM tuberculosis ,TUBERCULOSIS ,CONTACT tracing ,HUMAN genetic variation ,ANIMAL disease models ,SINGLE nucleotide polymorphisms ,HUMAN genetics - Abstract
Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB. Author summary: Susceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in the two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available. We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS.
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Manduchi, Elisabetta, Williams, Scott M., Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Grant, Struan F. A., and Moore, Jason H.
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EPIGENOMICS , *SINGLE nucleotide polymorphisms , *GENOMES , *TYPE 2 diabetes , *MEDICAL genetics - Abstract
Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait’s predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance. Each analyzed SNP pair consists of one SNP in a putative active enhancer and another SNP in a putative physically interacting gene promoter in a trait-relevant tissue. As a proof-of-principle case study, we used this approach to identify focused collections of SNP pairs that we analyzed in three independent Type 2 diabetes (T2D) GWAS. This approach led us to discover 35 significant SNP pairs, encompassing both novel signals and signals for which we have found orthogonal support from other sources. Nine of these pairs are consistent with eQTL results, two are consistent with our own capture C experiments, and seven involve signals supported by recent T2D literature. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Addressing Population-Specific Multiple Testing Burdens in Genetic Association Studies.
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Sobota, Rafal S., Shriner, Daniel, Kodaman, Nuri, Goodloe, Robert, Zheng, Wei, Gao, Yu‐Tang, Edwards, Todd L., Amos, Christopher I., and Williams, Scott M.
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POPULATION genetics ,GENOMES ,SINGLE nucleotide polymorphisms ,AUTOCORRELATION (Statistics) ,MELANOMA ,LINKAGE disequilibrium - Abstract
The number of effectively independent tests performed in genome-wide association studies (GWAS) varies by population, making a universal P-value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD-pruning function in PLINK, and (2) an autocorrelation-based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population-specific thresholds for genome-wide significance. African populations had the most stringent thresholds (1.49 × 10
-7 for YRI at r² = 0.3), East Asian populations the least (3.75 × 10-7 for JPT at r² = 0.3). We also assessed how using populationspecific significance thresholds compared to using a single multiple testing threshold at the conventional 5 × 10-8 cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome-wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations. [ABSTRACT FROM AUTHOR]- Published
- 2015
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6. SHBG Gene Polymorphism (rs1799941) Associates with Metabolic Syndrome in Children and Adolescents.
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White, Marquitta J., Eren, Fatih, Agirbasli, Deniz, Williams, Scott M., and Agirbasli, Mehmet
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METABOLIC syndrome ,GENETIC polymorphisms ,JUVENILE diseases ,INSULIN resistance ,SINGLE nucleotide polymorphisms - Abstract
Background: Metabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents. Methods: Genetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish pediatric cohort (37 cases, 323 controls). Results: Logistic regression analysis revealed a significant association between rs1799941, located in SHBG, and MetS (OR = 3.09, p-value = 0.006). The association with MetS remained after sequential adjustment for each CM factor included in the syndrome definition, indicating that the identified association is not being driven by any single trait. A relationship between rs1799941 and SHBG levels, was also discovered, but it was dependent on MetS status. In control subjects, the A allele of rs1799941 associated with a significant increase in SHBG levels (p = 0.012), while in cases there was no association between rs1799941 and SHBG levels (p = 0.963). Conclusions: The significant association between rs1799941 and MetS in children is not contingent on any single CM trait. Additionally, the presence of MetS may abrogate effect of rs1799941 polymorphism on SHBG levels in children. [ABSTRACT FROM AUTHOR]
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- 2015
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7. The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function.
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Wang, Ya-Juan, Tayo, Bamidele O., Bandyopadhyay, Anupam, Wang, Heming, Feng, Tao, Franceschini, Nora, Tang, Hua, Gao, Jianmin, Sung, Yun Ju, Elston, Robert C., Williams, Scott M., Cooper, Richard S., Mu, Ting-Wei, and Zhu, Xiaofeng
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HYPERTENSION genetics ,SINGLE nucleotide polymorphisms ,BLOOD pressure ,ENDOPLASMIC reticulum ,BLOOD plasma - Abstract
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism. [ABSTRACT FROM AUTHOR]
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- 2014
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8. A Simple and Computationally Efficient Approach to Multifactor Dimensionality Reduction Analysis of Gene-Gene Interactions for Quantitative Traits.
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Gui, Jiang, Moore, Jason H., Williams, Scott M., Andrews, Peter, Hillege, Hans L., van der Harst, Pim, Navis, Gerjan, Van Gilst, Wiek H., Asselbergs, Folkert W., and Gilbert-Diamond, Diane
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DIMENSION reduction (Statistics) ,QUANTITATIVE research ,SINGLE nucleotide polymorphisms ,CARDIOVASCULAR diseases ,CLINICAL epidemiology ,GENETIC polymorphisms ,POPULATION genetics - Abstract
We present an extension of the two-class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of a quantitative trait. The proposed Quantitative MDR (QMDR) method handles continuous data by modifying MDR’s constructive induction algorithm to use a T-test. QMDR replaces the balanced accuracy metric with a T-test statistic as the score to determine the best interaction model. We used a simulation to identify the empirical distribution of QMDR’s testing score. We then applied QMDR to genetic data from the ongoing prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. [ABSTRACT FROM AUTHOR]
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- 2013
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9. Multifactor dimensionality reduction reveals a three-locus epistatic interaction associated with susceptibility to pulmonary tuberculosis.
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Collins, Ryan L., Ting Hu, Wejse, Christian, Sirugo, Giorgio, Williams, Scott M., and Moore, Jason H.
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DIMENSION reduction (Statistics) ,TUBERCULOSIS ,MACHINE learning ,DATA mining ,SINGLE nucleotide polymorphisms ,COMPUTER algorithms ,COMPUTATIONAL complexity - Abstract
Background: Identifying high-order genetics associations with non-additive (i.e. epistatic) effects in population-based studies of common human diseases is a computational challenge. Multifactor dimensionality reduction (MDR) is a machine learning method that was designed specifically for this problem. The goal of the present study was to apply MDR to mining high-order epistatic interactions in a population-based genetic study of tuberculosis (TB). Results: The study used a previously published data set consisting of 19 candidate single-nucleotide polymorphisms (SNPs) in 321 pulmonary TB cases and 347 healthy controls from Guniea-Bissau in Africa. The ReliefF algorithm was applied first to generate a smaller set of the five most informative SNPs. MDR with 10-fold crossvalidation was then applied to look at all possible combinations of two, three, four and five SNPs. The MDR model with the best testing accuracy (TA) consisted of SNPs rs2305619, rs187084, and rs11465421 (TA = 0.588) in PTX3, TLR9 and DC-Sign, respectively. A general 1000-fold permutation test of the null hypothesis of no association confirmed the statistical significance of the model (p = 0.008). An additional 1000-fold permutation test designed specifically to test the linear null hypothesis that the association effects are only additive confirmed the presence of non-additive (i.e. nonlinear) or epistatic effects (p = 0.013). An independent information-gain measure corroborated these results with a third-order epistatic interaction that was stronger than any lower-order associations. Conclusions: We have identified statistically significant evidence for a three-way epistatic interaction that is associated with susceptibility to TB. This interaction is stronger than any previously described one-way or two-way associations. This study highlights the importance of using machine learning methods that are designed to embrace, rather than ignore, the complexity of common diseases such as TB. We recommend future studies of the genetics of TB take into account the possibility that high-order epistatic interactions might play an important role in disease susceptibility. [ABSTRACT FROM AUTHOR]
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- 2013
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10. A Small Number of Candidate Gene SNPs Reveal Continental Ancestry in African Americans.
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Kodaman, Nuri, Aldrich, Melinda C., Smith, Jeffrey R., Signorello, Lisa B., Bradley, Kevin, Breyer, Joan, Cohen, Sarah S., Long, Jirong, Cai, Qiuyin, Giles, Justin, Bush, William S., Blot, William J., Matthews, Charles E., and Williams, Scott M.
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GENETIC markers ,SINGLE nucleotide polymorphisms ,AFRICAN Americans ,EUROPEAN Americans ,GENETIC databases ,OBESITY ,GENETICS education ,GENEALOGY - Abstract
Using genetic data from an obesity candidate gene study of self-reported African Americans and European Americans, we investigated the number of Ancestry Informative Markers (AIMs) and candidate gene SNPs necessary to infer continental ancestry. Proportions of African and European ancestry were assessed with STRUCTURE ( K = 2), using 276 AIMs. These reference values were compared to estimates derived using 120, 60, 30, and 15 SNP subsets randomly chosen from the 276 AIMs and from 1144 SNPs in 44 candidate genes. All subsets generated estimates of ancestry consistent with the reference estimates, with mean correlations greater than 0.99 for all subsets of AIMs, and mean correlations of 0.99 ± 0.003; 0.98 ± 0.01; 0.93 ± 0.03; and 0.81 ± 0.11 for subsets of 120, 60, 30, and 15 candidate gene SNPs, respectively. Among African Americans, the median absolute difference from reference African ancestry values ranged from 0.01 to 0.03 for the four AIMs subsets and from 0.03 to 0.09 for the four candidate gene SNP subsets. Furthermore, YRI/CEU Fst values provided a metric to predict the performance of candidate gene SNPs. Our results demonstrate that a small number of SNPs randomly selected from candidate genes can be used to estimate admixture proportions in African Americans reliably. [ABSTRACT FROM AUTHOR]
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- 2013
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11. MCP1 SNPs and Pulmonary Tuberculosis in Cohorts from West Africa, the USA and Argentina: Lack of Association or Epistasis with IL12B Polymorphisms.
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Edwards, Digna R. Velez, Tacconelli, Alessandra, Wejse, Christian, Hill, Philip C., Morris, Gerard A. J., Edwards, Todd L., Gilbert, John R., Myers, Jamie L., Park, Yo Son, Stryjewski, Martin E., Abbate, Eduardo, Estevan, Rosa, Rabna, Paulo, Novelli, Giuseppe, Hamilton, Carol D., Adegbola, Richard, Østergaard, Lars, Williams, Scott M., Scott, William K., and Sirugo, Giorgio
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TUBERCULOSIS ,MONOCYTE chemotactic factor ,SINGLE nucleotide polymorphisms ,MULTICULTURALISM - Abstract
The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (-2581A/G), rs2857656 (-362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility. [ABSTRACT FROM AUTHOR]
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- 2012
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12. Interaction between M. tuberculosis Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB.
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McHenry, Michael L., Wampande, Eddie M., Joloba, Moses L., Malone, LaShaunda L., Mayanja-Kizza, Harriet, Bush, William S., Boom, W. Henry, Williams, Scott M., and Stein, Catherine M.
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GENETIC variation ,TUBERCULOSIS ,MYCOBACTERIUM tuberculosis ,SYMPTOMS ,SINGLE nucleotide polymorphisms ,BLOOD platelet aggregation ,CELL aggregation - Abstract
Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and Mycobacterium tuberculosis (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothesize that long-term coexistence between human genomes and MTBC lineages modulates disease to affect its severity. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which we identified three MTBC lineages, of which one, L4.6-Uganda, is clearly derived and hence recent. We quantified TB severity using the Bandim TBscore and examined the interaction between MTBC lineage and human single-nucleotide polymorphisms (SNPs) genome-wide, in two independent cohorts of TB cases (n = 149 and n = 127). We found a significant interaction between an SNP in PPIAP2 and the Uganda lineage (combined p = 4 × 10
−8 ). PPIAP2 is a pseudogene that is highly expressed in immune cells. Pathway and eQTL analyses indicated potential roles between coevolving SNPs and cellular replication and metabolism as well as platelet aggregation and coagulation. This finding provides further evidence that host–pathogen interactions affect clinical presentation differently than host and pathogen genetic variation independently, and that human–MTBC coevolution is likely to explain patterns of disease severity. [ABSTRACT FROM AUTHOR]- Published
- 2021
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13. Non-additive effects of ACVR2A in preeclampsia in a Philippine population.
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Amosco, Melissa D., Tavera, Gloria R., Villar, Van Anthony M., Naniong, Justin Michael A., David-Bustamante, Lara Marie G., Williams, Scott M., Jose, Pedro A., and Palmes-Saloma, Cynthia P.
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PREECLAMPSIA ,SINGLE nucleotide polymorphisms ,GENOTYPES ,BODY mass index ,FILIPINO women ,GENETIC polymorphisms ,AGE distribution ,CELL receptors ,DISEASE susceptibility ,DATA mining ,CASE-control method - Abstract
Background: Multiple interrelated pathways contribute to the pathogenesis of preeclampsia, and variants in susceptibility genes may play a role among Filipinos, an ethnically distinct group with high prevalence of the disease. The objective of this study was to examine the association between variants in maternal candidate genes and the development of preeclampsia in a Philippine population.Methods: A case-control study involving 29 single nucleotide polymorphisms (SNPs) in 21 candidate genes was conducted in 150 patients with preeclampsia (cases) and 175 women with uncomplicated normal pregnancies (controls). Genotyping for the GRK4 and DRD1 gene variants was carried out using the TaqMan Assay, and all other variants were assayed using the Sequenom MassARRAY Iplex Platform. PLINK was used for SNP association testing. Multilocus association analysis was performed using multifactor dimensionality reduction (MDR) analysis.Results: Among the clinical factors, older age (P < 1 × 10-4), higher BMI (P < 1 × 10-4), having a new partner (P = 0.006), and increased time interval from previous pregnancy (P = 0.018) associated with preeclampsia. The MDR algorithm identified the genetic variant ACVR2A rs1014064 as interacting with age and BMI in association with preeclampsia among Filipino women.Conclusions: The MDR algorithm identified an interaction between age, BMI and ACVR2A rs1014064, indicating that context among genetic variants and demographic/clinical factors may be crucial to understanding the pathogenesis of preeclampsia among Filipino women. [ABSTRACT FROM AUTHOR]- Published
- 2019
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14. 11: Use of evolutionary triangulation to refine genetic association studies of spontaneous preterm birth (SPTB).
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Manuck, Tracy A., Huang, Minjun, Muglia, Louis, and Williams, Scott M.
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PREMATURE labor ,DISEASE prevalence ,HISPANIC Americans ,SINGLE nucleotide polymorphisms ,GENE frequency - Published
- 2017
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15. A Systems Genetics Approach to Dyslipidemia in Children and Adolescents.
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White, Marquitta J., Eren, Fatih, Ağırbaşlı, Deniz, Chen, Jane, Hu, Ting, Moore, Jason H., Williams, Scott M., and Ağırbaşlı, Mehmet
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DYSLIPIDEMIA , *BLOOD diseases , *JUVENILE diseases , *DISEASES in teenagers , *SINGLE nucleotide polymorphisms , *PATIENTS - Abstract
Elevated triglycerides (TG) or low high density lipoprotein cholesterol (HDL-C) levels are common cardiometabolic risk factors in children. From a systems genetics standpoint, Visualization of Statistical Epistasis Networks (ViSEN) is a nonparametric entropy-based method that can characterize the global structure of interacting genetic factors. We identified a novel set of connected genetic and cardiometabolic risk factors with strong and significant interaction effects on two important dyslipidemia phenotypes (low HDL-C and high TG) in children and adolescents. Study participants were recruited from five schools in Istanbul, Turkey ( n=360; 170 boys, 190 girls). Participants with TG levels≥75th and HDL-C levels≤25th percentile were defined as 'high TG' and 'low HDL-C', respectively. We genotyped participants for six single nucleotide polymorphisms (SNPs) in five genes with known associations to lipid levels (rs328 in LPL, rs708272 in CETP, rs1800588 in LIPC, rs1800977 in ABCA1, rs1799941 and rs6257 in SHBG gene). ViSEN was used to identify associations with dyslipidemia phenotypes. There were 71 (50 males, 21 females) and 93 (60 males and 33 females) subjects with low HDL-C and high TG, respectively. Biological variables including age, gender, and BMI were significantly associated with both phenotypes ( p<0.001). Importantly, a single SNP, rs708272, was associated with low HDL-C (IG=2.24%, p=0.026). Pairwise and higher order interaction analyses in the full dataset for low HDL-C and high TG revealed the largest effects in the models containing rs1800977, rs708272, age (IG=6.20%, p=0.046) and rs1800588, age, BMI (IG, 3.06%, p=0.022), respectively. In conclusion, the present study brings us a step closer to a systems genetic approach in understanding lipid phenotypes in children. Further efforts can integrate population and laboratory-based studies, hence accelerate the preventive medicine efforts. [ABSTRACT FROM AUTHOR]
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- 2015
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16. A Single Nucleotide Polymorphism in SLC7A5 Is Associated with Gastrointestinal Toxicity after High-Dose Melphalan and Autologous Stem Cell Transplantation for Multiple Myeloma.
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Giglia, Jennifer L., White, Marquitta J., Hart, Andrew J., Toro, Juan J., Freytes, César O., Holt, Cherish C., Cai, Ying, Williams, Scott M., and Brandt, Stephen J.
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SINGLE nucleotide polymorphisms , *GASTROINTESTINAL agents , *MELPHALAN , *DRUG dosage , *STEM cell transplantation , *MYELOMA proteins - Abstract
Abstract: Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant nonhematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to interindividual differences in the development of gastrointestinal complications of HDM, we analyzed single nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma. [Copyright &y& Elsevier]
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- 2014
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17. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
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Jie Huang, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David, So-Youn Shin, Jingzhong Ding, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Johnson, Andrew D., Smith, Nicholas L., Williams, Scott M., Ikram, Mohammad A., Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Weihong Tang, Qiong Yang, and Sennblad, Bengt
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SINGLE nucleotide polymorphisms , *PLASMINOGEN activator inhibitors , *TYPE 2 diabetes , *CORONARY disease , *GENE expression - Abstract
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PA I-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery metaanalysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P<5 × 10-8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, as sessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10-10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10-8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P= 2.9 × 10-8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (p < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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