PPARG P12A - GET-Evidence

Curation:
Currentness:

PPARG P12A

(PPARG Pro12Ala)


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

undefined

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Unpublished cases/controls case+ case– control+ control– p-value odds ratio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.

 

Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuler D; Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab. 2007 Apr;92(4):1502-9. Epub 2007 Jan 9. PubMed PMID: 17213274; PubMed Central PMCID: PMC2267936.

The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes.We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo).This study included 3548 Diabetes Prevention Program participants.We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr.Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99-1.57; P=0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P=0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr.The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.

Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007 Jun 1;316(5829):1341-5. Epub 2007 Apr 26. 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":

Log in