PPARG P12A - GET-Evidence

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PPARG P12A

(PPARG Pro12Ala)


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Short summary

 

Variant evidence
Computational 3

PolyPhen2: Possibly damaging 0.782
SIFT: Tolerated 0.09
GVGD: GV 0.00; GD 26.87; Class C 25
Variant Effect Predictor (Ensembl):
SIFT=deleterious(0);
PolyPhen=possibly_damaging(0.782);
Condel=deleterious(0.900)
Mutation Tasting Prediction: Polymorphism, P value: 0.974499; protein features (might be) affected.

Functional 1
Case/Control 2
Familial 1
 
Clinical importance
Severity 3

Evidence has shown that this has a strong correlation with type 2 diabetes.

Treatability 2

Unclear as to the direct implications, however literature has stated that PPARG P12A has little or no effect on the beneficial response to troglitazone.

Penetrance 3
 

Impact

Moderate clinical importance, Uncertain not reviewed

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

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Summary of published research, and additional commentary

 

show discussion

Discussion

The P12A polymorphism of PPARG has commonly been associated with type 2 diabetes. In order to compare its direct or indirect impact, the progression from impaired glucose tolerance to diabetes was studied. Cox regression analysis was performed, permitting the analysis of multiple risk factors on survival. This, in combination with intervention, was carried out to detect any notable correlation with diabetes. As well genotyping the P12A variant, 5 other variants of this gene were also genotyped to infer the response to troglitazone (as PPARG is a target for troglitazone medications). This then enabled effective analysis of the variants’ effects on insulin sensitivity at 1 year. P/P heterozygotes at the PPARG P12A seemed to be more susceptible in getting diabetes as opposed to alanine carriers. This could be indicative of the type of purine that specifically relates more with diabetes susceptibility. However results showed that there was no significant interaction between genotype and intervention. Neither of the variants genotyped significantly affected the impact of troglitazone on insulin sensitivity at 1 year. Although the proline allele at PPARG P12A showed increase risk for diabetes in those impaired glucose tolerance, which was seen to be an effect modified by body mass index.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
Diabetes Mellitus with Acanthosis Nigricans and Hypertension
0 - - - - -

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Diabetes Mellitus with Acanthosis Nigricans and Hypertension
0 0 0 0 - -

 

Allele frequency

  • G @ chr3:12393125: 8.9% (954/10758) in EVS
  • G @ chr3:12368124: 6.2% (8/128) in GET-Evidence
  • Frequency shown in summary reports: 8.9% (954/10758)

Publications
 

Butt C, Gladman D, Rahman P. PPAR-gamma gene polymorphisms and psoriatic arthritis. J Rheumatol. 2006 Aug;33(8):1631-3. PubMed PMID: 16783862.

 

Added in this revision:

301 Moved Permanently

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PubMed PMID: 17213274

 

301 Moved Permanently

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PubMed PMID: 17463248

 

Genomes
 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het G @ chr3:12393125

 

 

 

GS06985 - var-GS06985-1100-36-ASM
het G @ chr3:12368125

 

GS07357 - var-GS07357-1100-36-ASM
het G @ chr3:12368125

 

GS18558 - var-GS18558-1100-36-ASM
het G @ chr3:12368125

 

Other external references
 

    dbSNP
  • rs1801282
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the PPARG gene
    Cardiovascular Disease Risk Factor (Carotid Intimal Medial Thick
    Diabetes Mellitus with Acanthosis Nigricans and Hypertension
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PPARG
    GWAS
  • Type 2 diabetes (rs1801282-C)
    Saxena 26-Apr-07 in Science
    OR or beta: 1.14 [1.08-1.20]
    Risk allele frequency: 0.86
    p-value: 0.000002 (DGI+FUSION+WTCCC)
    Initial sample: 1,464 cases, 1,467 controls
    Replication sample: 5,065 cases, 5,785 controls (also includes meta-analysis from DGI+FUSION+WTCCC)
    www.ncbi.nlm.nih.gov/pubmed/17463246
  • Type 2 diabetes (rs1801282-C)
    Scott 26-Apr-07 in Science
    OR or beta: 1.14 [1.08-1.20]
    Risk allele frequency: 0.82
    p-value: 0.000002 (DGI+FUSION+WTCCC)
    Initial sample: 1,161 cases, 1,174 controls
    Replication sample: 1,215 cases, 1,258 controls (also includes meta-analysis from DGI+FUSION+WTCCC)
    www.ncbi.nlm.nih.gov/pubmed/17463248
  • Type 2 diabetes (rs1801282-C)
    Zeggini 26-Apr-07 in Science
    OR or beta: 1.14 [1.08-1.20]
    p-value: 0.000002 (DGI+FUSION+WTCCC)
    Initial sample: 1,924 cases, 2,938 controls
    Replication sample: 3,757 cases, 5,346 controls (also includes meta-analysis from DGI+FUSION+WTCCC)
    www.ncbi.nlm.nih.gov/pubmed/17463249
    PharmGKB
  • [Arthritis, Psoriatic]
    Risk or phenotype-associated allele: G. Phenotype: For the Pro12Ala (rs1801282) SNP in the PPARG gene, an association was noted for the minor allele between psoriatic arthritis cases and controls (9.0% vs 13.8%, respectively; p = 0.017, OR 0.62, 95% CI 0.45-0.93). Study size: X. Study population/ethnicity: Caucasian
    www.ncbi.nlm.nih.gov/pubmed/16783862
  • [Diabetes Mellitus, Type 2]
    In a large Finnish case-control GWAS, rs1801282 was found to be associated with susceptibility to Type 2 Diabetes.
    www.ncbi.nlm.nih.gov/pubmed/17463248
    PolyPhen-2
  • Score: 0.979 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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