scholarly journals Peptide YY (PYY) Gene Polymorphisms in the 3′-Untranslated Region and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

2009 ◽  
Vol 30 (6) ◽  
pp. 748-748
Author(s):  
Pei-an Betty Shih ◽  
Lei Wang ◽  
Stephane Chiron ◽  
Gen Wen ◽  
Caroline Nievergelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Gene Polymorphisms ◽  
Untranslated Region ◽  
Peptide Yy ◽  
Proximal Promoter ◽  
Cellular Gene ◽  
Promoter Regions ◽  
Cellular Gene Expression

scholarly journals Peptide YY (PYY) Gene Polymorphisms in the 3′-Untranslated Region and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

2009 ◽  
Vol 23 (10) ◽  
pp. 1715-1715
Author(s):  
Pei-an Betty Shih ◽  
Lei Wang ◽  
Stephane Chiron ◽  
Gen Wen ◽  
Caroline Nievergelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Genetic Variation ◽  
Untranslated Region ◽  
Peptide Yy ◽  
Disease Risk ◽  
Association Studies ◽  
Neuroendocrine Cells ◽  
Proximal Promoter ◽  
Common Genetic Variants

ABSTRACT Rationale Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk. Design To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3′-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells. Results Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3′-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3′-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016). Conclusions Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

scholarly journals Peptide YY (PYY) Gene Polymorphisms in the 3′-Untranslated Region and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

2009 ◽  
Vol 23 (12) ◽  
pp. 2120-2120
Author(s):  
Pei-an Betty Shih ◽  
Lei Wang ◽  
Stephane Chiron ◽  
Gen Wen ◽  
Caroline Nievergelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Genetic Variation ◽  
Untranslated Region ◽  
Peptide Yy ◽  
Disease Risk ◽  
Association Studies ◽  
Neuroendocrine Cells ◽  
Proximal Promoter ◽  
Common Genetic Variants

ABSTRACT Rationale Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk. Design To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3′-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells. Results Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3′-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3′-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016). Conclusions Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

scholarly journals Peptide YY (PYY) Gene Polymorphisms in the 3′-Untranslated Region and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

2009 ◽  
Vol 30 (7) ◽  
pp. 934-934
Author(s):  
Pei-an Betty Shih ◽  
Lei Wang ◽  
Stephane Chiron ◽  
Gen Wen ◽  
Caroline Nievergelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Genetic Variation ◽  
Untranslated Region ◽  
Peptide Yy ◽  
Disease Risk ◽  
Association Studies ◽  
Neuroendocrine Cells ◽  
Proximal Promoter ◽  
Common Genetic Variants

Abstract Rationale Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk. Design To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3′-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells. Results Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3′-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3′-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016). Conclusions Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

The Clonal Inventory of Gene Corrected Hematopoiesis in Three Successful Clinical Gene Therapy Trials

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3733-3733
Author(s):  
Kerstin Schwarzwaelder ◽  
Manfred Schmidt ◽  
Annette Deichmann ◽  
Steven J. Howe ◽  
Marion G. Ott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Sanger Sequencing ◽  
Integration Site ◽  
Cellular Gene ◽  
Post Transplantation ◽  
Cellular Gene Expression ◽  
Site Distribution ◽  
Clinical Gene Therapy

Abstract To enhance the safety and efficacy of future gene therapy trials using integrating vector systems it is necessary to analyse the clonality of the genetically modified cell pool. The comparative analyses of integration site distribution and cellular gene expression will further reveal causal mechanisms of in vivo clone selection. We followed the repopulation clonality of 21 patients which participated in 3 successful clinical gene therapy trials via linear amplification mediated PCR (LAM PCR). We identified the integration sites (IS) of pre and post transplantation samples by Sanger sequencing and accomplished RNA analyses. The comparative results from all trials showed that vector integration is favoured in gene coding regions, in particular transcriptional start sites. In both X-SCID trials significantly more post transplantation IS were located in or in the vicinity of genes encoding proteins with kinase or transferase activity. In pre transplantation samples no uniform gene class was overrepresented. In both trials we detected common insertion sites mainly post transplantation and the effect was more pronounced in the trial where 4 patients developed vector induced leukemia. Notably, we detected no significant differences regarding the IS distribution in leukemic versus non leukemic patients. The gene corrected repopulation of patient 1 and 2 of the X-CGD trial was polyclonal until 542 and 777 days after transplantation, respectively. 5 months after therapy dominant clones appeared. In patient 1, between 616 and 820 days post transplantation (post mortem time point) the number of participating clones and the contribution of a dominant clone decreased while the contribution of another dominant clone increased. In both patients the integrated vector induced the upregulation of the genes MDS1/EVI1, PRDM16 or SETBP1 and thus led to the in vivo expansion of affected cell clones. From these trials we sequenced >2000 unique IS by Sanger sequencing and several thousand via pyrosequencing (datamining is ongoing). Our data show that the integration site distribution was non random, that the integrated vector influenced the cellular gene expression which caused subtle to massive changes in the repopulation clonality and that it will soon be possible to define the clonal inventory of patients using next generation sequencing technologies.

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