5 research outputs found
Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT)
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived ânullâ variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5Ă10â8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS
Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years
Improving healthspan via changes in gut microbiota and fermentation
Dietary resistant starch impact on intestinal microbiome and improving healthspan is the topic of this review. In the elderly population, dietary fiber intake is lower than recommended. Dietary resistant starch as a source of fiber produces a profound change in gut microbiota and fermentation in animal models of aging. Dietary resistant starch has the potential for improving healthspan in the elderly through multiple mechanisms as follows: (1) enhancing gut microbiota profile and production of short-chain fatty acids, (2) improving gut barrier function, (3) increasing gut peptides that are important in glucose homeostasis and lipid metabolism, and (4) mimicking many of the effects of caloric restriction including upregulation of genes involved in xenobiotic metabolism
Discovery of (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)â2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371¡HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity
As
part of our ongoing efforts to identify novel ligands for the
metabotropic glutamate 2 and 3 (mGlu<sub>2/3</sub>) receptors, we
have incorporated substitution at the C3 and C4 positions of the (1<i>S</i>,2<i>R</i>,5<i>R</i>,6<i>R</i>)-2-amino-bicycloÂ[3.1.0]Âhexane-2,6-dicarboxylic acid scaffold to
generate mGlu<sub>2/3</sub> antagonists. Exploration of this structureâactivity
relationship (SAR) led to the identification of (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)-2-amino-3-[(3,4-difluorophenyl)Âsulfanylmethyl]-4-hydroxy-bicycloÂ[3.1.0]Âhexane-2,6-dicarboxylic
acid hydrochloride (LY3020371¡HCl, <b>19f</b>), a potent,
selective, and maximally efficacious mGlu<sub>2/3</sub> antagonist.
Further characterization of compound <b>19f</b> binding to the
human metabotropic 2 glutamate (hmGlu<sub>2</sub>) site was established
by cocrystallization of this molecule with the amino terminal domain
(ATD) of the hmGlu<sub>2</sub> receptor protein. The resulting cocrystal
structure revealed the specific ligandâprotein interactions,
which likely explain the high affinity of <b>19f</b> for this
site and support its functional mGlu<sub>2</sub> antagonist pharmacology.
Further characterization of <b>19f</b> in vivo demonstrated
an antidepressant-like signature in the mouse forced-swim test (mFST)
assay when brain levels of this compound exceeded the cellular mGlu<sub>2</sub> IC<sub>50</sub> value