NucleaRDB: Extraction of mutation data from the literature

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This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes different point mutations at a given position and provides links to other documents. The sentence(s) where the point mutations in PPAT_HUMAN at position 12 were found are listed after the table.

Point mutations at position P12 in PPAT_HUMAN

ProteinPPAT_HUMAN (P37231)    Gene: PPARG,NR1C    (other point mutations)Swiss-Prot
Cross-reference table
Family page
Protein isoforms2
PositionP12
General numbering (NucleaRDB) -
DomainN-term
Family alignments 1C3 PPAR gamma
1C Peroxisome proliferator activated (PPAR)
1 Thyroid hormone like (TR,RAR,ROR,PPAR,VDR
Other point mutations at the same position
Reference #1Evans D, de Heer J, Hagemann C, Wendt D, Wolf A, Beisiegel U, Mann WA
Exp Clin Endocrinol Diabetes 2001;109(3):151-4.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Reference #2Schaffler A, Barth N, Schmitz G, Zietz B, Palitzsch KD, Scholmerich J
Endocrine 2001 Apr;14(3):369-73.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #3Witchel SF, White C, Siegel ME, Aston CE
Fertil Steril 2001 Oct;76(4):741-7.		Medline
Text sourceHTML full text
Point mutationP12A (True positive)
Reference #4Ek J, Andersen G, Urhammer SA, Gaede PH, Drivsholm T, Borch-Johnsen K, Hansen T, Pedersen O
Diabetologia 2001 Dec;44(12):2220-6.		Medline
Text sourceHTML full text
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #5Zietz B, Barth N, Spiegel D, Schmitz G, Scholmerich J, Schaffler A
Exp Clin Endocrinol Diabetes 2002 Apr;110(2):60-6.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #6Tomita S, Kawamata H, Imura J, Omotehara F, Ueda Y, Fujimori T
Int J Mol Med 2002 May;9(5):485-8.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #7Ardlie KG, Lunetta KL, Seielstad M
Am J Hum Genet 2002 Aug;71(2):304-11.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #8Lindi VI, Uusitupa MI, Lindstrom J, Louheranta A, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Tuomilehto J
Diabetes 2002 Aug;51(8):2581-6.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Point mutationP12P (True positive)
Cited point mutationPro12Pro
Reference #9Simon I, Vendrell J, Gutierrez C, Fernandez-Real JM, Vendrell I, Gallart L, Fontova R, Richart C
Horm Res 2002;58(3):143-9.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #10Vaccaro O, Mancini FP, Ruffa G, Sabatino L, Iovine C, Masulli M, Colantuoni V, Riccardi G
Clin Endocrinol (Oxf) 2002 Oct;57(4):481-6.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #11Ahluwalia M, Evans M, Morris K, Currie C, Davies S, Rees A, Thomas A
Diabetes Obes Metab 2002 Nov;4(6):376-8.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #12Rosmond R, Chagnon M, Bouchard C
Diabetes Metab Res Rev 2003 Mar-Apr;19(2):159-63.		Medline
Text sourceHTML full text
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #13Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS
Diabetes 2003 May;52(5):1265-9.		Medline
Text sourceHTML full text
Point mutationP12A (Not yet checked)
Cited point mutationPro12Ala
Reference #14Bluher M, Paschke R
Exp Clin Endocrinol Diabetes 2003 Apr;111(2):85-90.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #15Gurnell M, Savage DB, Chatterjee VK, O'Rahilly S
J Clin Endocrinol Metab 2003 Jun;88(6):2412-21.		Medline
Text sourceHTML full text
Point mutationP12A (Not yet checked)
Cited point mutationPro12Ala
Reference #16Yang WS, Hsiung CA, Ho LT, Chen YT, He CT, Curb JD, Grove J, Quertermous T, Chen YD, Kuo SS, Chuang LM
Diabetologia 2003 Jul;46(7):977-83. Epub 2003 Jun 21.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala
Reference #17Iwata E, Yamamoto I, Motomura T, Tsubakimori S, Nohnen S, Ohmoto M, Igarashi T, Azuma J
Diabetes Res Clin Pract 2003 Oct;62(1):55-9.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Cited point mutationPro12Ala,Pro12
Reference #18Bosse Y, Weisnagel SJ, Bouchard C, Despres JP, Perusse L, Vohl MC
J Hum Genet 2003;48(12):614-21. Epub 2003 Nov 20.		Medline
Text sourceabstract
Point mutationP12A (True positive)
Reference #19Damcott CM, Moffett SP, Feingold E, Barmada MM, Marshall JA, Hamman RF, Ferrell RE
Metabolism 2004 Mar;53(3):303-9.		Medline
Text sourceHTML full text
Point mutationP12A (Not yet checked)
Cited point mutationPro12Ala

Relevant sentences

Reference #1 (Evans D et al.): P12A
  • Therefore we investigated the association between the P12A and c1431t polymorphisms in the PPAR gamma gene and type 2 diabetes

  • The incidence of the P12A polymorphism was determined by PCR-RFLP and the c1431t by single-strand conformation polymorphism analysis in 219 patients with , and 429 without type 2 diabetes

  • The frequency of the A allele of P12A polymorphism was 0.16 and the t allele of c1431t polymorphism , 0.13 in patients with type 2 diabetes , and 0.13 and 0.12 respectively in subjects without diabetes 3.2% of patients with and 1.4% without type 2 diabetes were A12A

Reference #3 (Witchel SF et al.): P12A
  • Intervention(s): Assay for P12A and P115Q variants and measure BMI

  • Result(s): Fourteen subjects were heterozygous for P12A ; two were homozygous

  • Thirty-nine subjects had BMI values at two time points ; mean BMI was significantly greater in the P12A carriers at time point 2

  • Those P12A carriers obese at time point 1 became more obese ; lean mutation carriers tended to remain lean

  • Annual rate of increase in BMI was significantly greater in the P12A carriers than the noncarriers

  • Conclusion(s): Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adolescence

  • Future studies are needed to determine whether the divergent effects of P12A persist into adulthood , to elucidate the mechanism of this effect , and to replicate our findings in other populations

  • Author Keywords: Body mass index ; premature pubarche ; hyperandrogenism ; obesity ; PPAR ; polycystic ovary syndrome Article Outline Materials and methods Subjects Hormone studies Genetic analysis Statistical analysis Results Subjects Genotype analysis Is P12A associated with increased BMI? Is P12A associated with increased rate of change in BMI? Discussion The peroxisome proliferator-activated receptor-small gamma , Greek (PPAR-small gamma , Greek) is a nuclear ligand-dependent transcription factor that promotes adipocyte differentiation and influences insulin sensitivity [1 and 2 ]

  • One change , C rightwards arrow G at nucleotide 34 , predicts the substitution of proline by alanine at codon 12 (P12A) , a nonconservative missense mutation

  • Allele frequency for the P12A variant is reported to range from 0.01 in Chinese to 0.12 in whites [8 ]

  • Functional analysis demonstrated that the P12A variant has lower transactivation activity than the P12 variant [9 and 10 ]

  • In some studies , P12A has been associated with obesity or diabetes [11 , 12 and 13 ]

  • In other populations , the P12A allele appears to be associated with a modest decrease in the risk for diabetes [14 and 15 ]

  • Among obese white women , the P12A variant appeared to be protective against diabetes , but was associated with early age of onset of obesity [16 ]

  • Divergent effects on body mass index (BMI) were observed among Danish adult men where , in a 25-year follow-up , the rate of increase in BMI (capital Delta , GreekBMI / yr) was greater among obese homozygous P12A carriers than the capital Delta , GreekBMI / yr among lean homozygous P12A carriers [17 ]

  • To ascertain whether either of these genetic variants , P12A or P115Q , plays a role in the development of obesity in childhood and adolescence , we determined the BMI in 98 children with premature pubarche and adolescent girls with hyperandrogenism

  • For P12A , the polymerase chain reaction (PCR) primers , sense (5'-GCCAATTCAAGCCCAGTC-3') and anti-sense (5'-GATATGTTTGCAGACAGTGTATCAGTGAAGGAATCGCTTTCCG-3') , generated a 270-bp product

  • A BstUI site is introduced in the presence of the C rightwards arrow G change at nucleotide 34 predicted to generate the P12A missense mutation

  • After BstUI digestion at 60°C for 2 hours and electrophoresis using a 2.5% agarose gel , expected sizes are 270 bp for the wild-type (P12) allele ; 270 , 227 , and 43 bp for heterozygotes ; and 227 and 43 bp for P12A homozygotes [8 ]

  • Genotype analysis Of the 45 girls in group 1 , 34 were homozygous for the wild-type allele , 10 were heterozygous for P12 A , and one was homozygous for P12A

  • Frequency of the P12A allele was 13.3%

  • For group 2 , 17 children were homozygous for the wild-type allele and one girl was heterozygous for P12A

  • Frequency of P12A was 3.1% for group 2

  • For group 3 , 31 girls were homozygous for the wild-type allele , three were heterozygous , and one was homozygous for P12A

  • Frequency of the P12A allele was 7.1% in group 3

  • Overall allele frequency for P12A in our 98 patients was 9% , which compares well with the reported frequency of 12% in whites [8 ]

  • Is P12A associated with increased BMI? Our hypothesis is that PPAR affects development of obesity by increasing the rate of increase in BMI over time in carriers of the P12A mutant allele

  • For group 1 , children <8 years , the mean BMI was 18.8 ± 3.2 kg / m2 for the 34 subjects homozygous for the P12 allele: P12A noncarriers

  • For the purpose of this correlation , the single subject homozygous for the P12A allele was included with the heterozygous subjects: P12A carriers

  • There were no significant differences in BMI , mean basal androstenedione concentrations , or SHBG concentrations between P12A carriers and noncarriers

  • All the boys in group 2 were P12A noncarriers

  • Only one girl in group 2 was a P12A carrier ; her BMI was 27.8 kg / m2 at age 8.4 years

  • The mean BMI was 24.1 ± 6.2 kg / m2 for the remaining 10 girls who were P12A noncarriers

  • For group 3 , mean BMI was 30.7 ± 7.5 kg / m2 for the 31 P12A noncarriers

  • Again , the single subject homozygous for the P12A allele was included with the three heterozygous subjects

  • Mean BMI for these four P12A carriers was 35.7 ± 5.5 kg / m2 (range , 29.1– ; 42.0 kg / m2)

  • All four subjects who carried the P12A variant were obese

  • Mean basal androstenedione concentrations did not differ significantly between the subjects homozygous for the P12 allele and the P12A carriers

  • The SHBG concentrations were available for only two of the P12A carriers , both had values of 0.4 small mu , Greekg / dL

  • Is P12A associated with increased rate of change in BMI? For 39 subjects , BMI values at two time points at least 2 years apart were available

  • Of these 39 subjects , there were 28 girls homozygous for P12 (P12A noncarriers) , 10 girls heterozygous for P12A , and one girl homozygous for P12A

  • As there was only a single homozygous subject , she was included with the heterozygous subjects as a P12A carrier for the analyses

  • Mean chronologic ages did not differ significantly between P12A noncarriers and the P12A carriers at either time point (Table 2 )

  • For the 39 subjects , mean BMI at time point 1 did not differ between the P12A noncarriers and P12A carriers

  • At time point 2 , mean BMI was significantly greater among the P12A carriers than the noncarriers , P = .029 (Table 2 )

  • Characteristics of the 39 subjects (mean ± SD) for whom two time points were available.legend , legend View Table (7K) Because mean BMI was greater among P12A carriers at time point 2 , the subjects were classified as to whether their initial BMI was greater or less than the 85th percentile expected for their chronologic age [29 ] to determine whether BMI status at time point 1 influenced BMI status at time point 2

  • Seventeen (61%) of 28 P12A noncarriers and 7 (63.6%) of 11 P12A carriers had BMI values greater than the 85th percentile expected for their chronologic age at time point 1

  • Mean BMI at time point 1 did not differ significantly between obese P12A carriers and noncarriers

  • Furthermore , when BMI values were expressed as the difference from predicted 85th percentile for BMI for chronologic age at time point 1 to standardize for age , there was no significant difference in mean BMI between obese P12A carriers and noncarriers (Table 3 ) , P = .20

  • Characteristics of the 39 subjects (mean ± SD) for whom two time points were available , classified by whether they were initially obese or nonobese.legend , legend View Table (8K) At time point 2 , 17 P12A noncarriers (15 of the original 17) and nine P12A carriers (including the original 7) had BMI values greater than the 85th percentile for their age

  • Of the four girls with BMI values greater than 40 kg / m2 , three were heterozygous for P12A

  • Mean BMI at time point 2 was significantly greater in the seven initially obese P12A carriers compared to obese noncarriers , P = .029 (Table 3 ) , as were BMI values expressed as the difference from predicted 85th percentile for BMI for chronologic age at time point 2 , P = .018

  • Of the four P12A carriers with BMI values less than the 85th percentile at time point 1 , three had BMI values less than 23 kg / m2 at the second time point

  • For one heterozygous carrier of P12A , her initial BMI was 16.5 kg / m2 and most recent BMI , 12.5 years later , was 42.8 kg / m2

  • Mean BMI at time point 2 was not significantly different in the four initially nonobese P12A carriers , P = .20 (Table 3 )

  • The rate of increase in BMI per year (capital Delta , GreekBMI / yr) for the 39 subjects was significantly greater in the P12A carriers than the noncarriers , 1.7 ± 0.7 vs

  • The original results reported for adults suggested that P12A carriers who were initially obese showed a higher rate of increase in BMI than noncarriers [17 ]

  • The parameter estimates from the generalized linear model showed that the effect of being a P12A carrier of increasing capital Delta , GreekBMI / yr , escalated with greater BMI at time point 1

  • Among our subjects , there were no significant differences in BMI values between P12A carriers and noncarriers in any of the three groups

  • Three of the four lean (<85% BMI for age) P12A carriers remained lean , whereas the obese P12A carriers showed both significantly greater mean BMI and greater mean gain in BMI per year

  • Thus , P12A may protect lean individuals from obesity while predisposing obese individuals to greater weight gain

  • Of interest , in a 25-year follow-up study of Danes , obese homozygous P12A carriers showed higher BMI and greater capital Delta , GreekBMI / yr (0.27 ± 0.24 kg / m2 / yr) than P12A noncarriers [17 ]

  • Nonobese homozygous P12A carriers showed a lower capital Delta , GreekBMI / yr (0.11 ± 0.11 kg / m2 / yr) compared to nonobese P12A noncarriers [17 ]

  • Similar to our findings , the P12A variant in the presence of preexisting obesity was associated with increased weight gain , whereas lean individuals appeared to be protected from obesity [17 ]

  • The difference between our findings in children and those reported among the Danish men is that our subjects were heterozygous for P12A , whereas the BMI increase was greater only in obese Danish men homozygous for P12A

  • An alternative explanation is that the effect of the P12A variant is influenced by the ratio of dietary polyunsaturated fat to saturated fat in that P12A carriers show greater BMI when the dietary polyunsaturated fat to saturated fat ratio is low [39 ]

  • Among women of Canadian Oji-Cree descent , P12A was associated with type 2 diabetes mellitus [42 ]

  • Similar to lean humans carrying P12A , mice heterozygous for null mutations show greater insulin sensitivity without any significant difference in body weight compared to wild-type animals [44 and 45 ]

  • Herein , we report that the P12A variant of PPAR-small gamma , Greek2 in obese children with premature pubarche is associated with an increased risk for obesity during adolescence independent of risk due to preexisting obesity

  • Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adulthood

  • Future studies are necessary to determine whether the divergent effects of P12A persist into adulthood , to elucidate the mechanisms of this effect , and to replicate our findings in other populations

Reference #11 (Ahluwalia M et al.): P12A
  • We therefore assessed the associations between the most common variant of the PPAR-gamma , the Pro12Ala (P12A) substitution in the PPAR-gamma 2 gene , with BMI , blood pressure , fasting plasma glucose , HbA1c , total cholesterol , LDL and HDL cholesterol and plasma triglyceride in 183 treatment-naive patients with type 2 diabetes (T2D)

  • The P12A allele associated with lower fasting plasma glucose but had no influence on HbA1c or BMI

  • In obese patients (BMI > 29 kg / m2) , the P12A substitution associated with elevated total and non-HDL cholesterol levels.

Reference #18 (Bosse Y et al.): P12A
  • Two polymorphisms , namely PPARgamma2 P12A and PPARalpha L162V , were investigated for their individual and interaction effects on glucose and insulin homeostasis

Reference #19 (Damcott CM et al.): P12A
  • Diabetes 2001 ; 50:886-890.MEDLINE > 46.   Hegele RA , Cao H , Harris SB , et al. Peroxisome proliferator-activated receptor- gamma2 P12A and type 2 diabetes in Canadian Oji-Cree

Reference #17 (Iwata E et al.): Pro12
  • In this study , the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population

  • Recently , some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes

  • We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations

  • The homozygotes of the Pro12 allele were 143 (93%) , the heterozygotes of the Pro12 and Ala12 allele were 11 (7%) and the homozygote of the Ala12 allele was not detected

  • The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.

Reference #2 (Schaffler A et al.): Pro12Ala
  • Recently , two missense single-point mutations have been described in the PPARgamma2 gene: Pro12Ala and Pro115Gln

  • Subsequent to genomic polymerase chain reaction amplification , the HpaII restriction fragment length polymorphism (RFLP) analysis and the HindII RFLP analysis were used for genotyping the Pro12Ala and Pro115Gln polymorphism , respectively

  • For the Pro12Ala polymorphism , 276 subjects (76.9%) were homozygous for the wild-type allele , 80 (22.3%) were heterozygous , and only 3 (0.8%) were homozygous for the mutated allele

Reference #4 (Ek J et al.): Pro12Ala
  • Furthermore , a potential interaction between the Pro12Ala polymorphism of PPAR-n2 and the PGC-1 Gly482Ser variant on risk of Type II diabetes was investigated

  • No interaction between this variant and the Pro12Ala polymorphism of PPAR-n2 was observed

Reference #5 (Zietz B et al.): Pro12Ala
  • Aim of our study was to determine the frequency of a missense point mutation within exon 2 of PPAR(gamma2) , Pro12Ala , and its possible association with metabolic parameters as well as diabetic retinopathy (in a population-based sample of 560 (318 male ad 242 female) type 2 diabetic patients

  • Pro12Ala polymorphism of PPAR(gamma2) gene is not associated with diabetic retinopathy but is associated with dyslipidemia in male type 2 diabetic patients.

Reference #6 (Tomita S et al.): Pro12Ala
  • Homozygous polymorphism (Ala12Ala) in PPARgamma gene was found only in one patient , but heterozygous polymorphism (Pro12Ala) was found in 9 of 29 patients

Reference #7 (Ardlie KG et al.): Pro12Ala
  • Both diabetes populations were typed for the PPARg Pro12Ala polymorphism , to replicate this well-supported association (Altshuler et al. 2000)

Reference #8 (Lindi VI et al.): Pro12Ala
  • The association of the Pro12Ala polymorphism of the PPAR-gamma2 gene with the incidence of type 2 diabetes was investigated in 522 subjects with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study

Reference #9 (Simon I et al.): Pro12Ala
  • OBJECTIVE: To analyze the relationship between the peroxisome proliferator-activated receptor-gamma (PPARgamma2) Pro12Ala variant and type-2 diabetes mellitus and its correlation with some cytokine determinants of insulin resistance such as tumor necrosis factor (TNF)-alpha and leptin

  • METHODS: The PPARgamma2 Pro12Ala genetic polymorphism was studied in 167 type-2 diabetic patients and 63 healthy controls

  • RESULTS: Women carriers of the Pro12Ala mutation exhibited higher leptin levels than women non-carriers (median 31.4 vs

  • Analysis by the multiple linear regression model of leptin-body mass index controlled by the PPARgamma2 genotype showed that leptin levels were determined by the Pro12Ala mutation in type-2 diabetic women but not in men

Reference #10 (Vaccaro O et al.): Pro12Ala
  • BACKGROUND: The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma gene has been associated in some , but not all , studies with lower body mass index (BMI) and improved insulin sensitivity ; how an altered transcriptional activity of PPARgamma2 could influence insulin sensitivity is currently unclear

  • The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity ; however , no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions

  • OBJECTIVE: To investigate in a population-based sample of Caucasians the relation of the Pro12Ala polymorphism with plasma concentrations of FFAs and other markers of lipid and glucose metabolism described as components of the insulin resistance syndrome

  • MEASUREMENTS: The Pro12Ala polymorphism of the PPARgamma was studied together with plasma FFAs , insulin , glucose , triglycerides , high density lipoprotein (HDL) cholesterol , blood pressure and anthropometry

  • RESULTS: Carriers and noncarriers of the Pro12Ala polymorphism showed very similar circulating levels of FFA (0.46 + / - 0.2 vs

  • Circulating plasma FFA concentrations , as well as triglycerides , blood pressure and HOMA , were significantly higher in overweight than normal-weight , as expected , but no significant differences were detected between carriers and noncarriers of the Pro12Ala polymorphism within each BMI group (0.49 + / - 0.2 vs

  • The Pro12Ala polymorphism was also analysed across increasing quartiles of FFA concentrations and no relationship was observed between the frequency of the polymorphism and FFA values (overall chi2 = 0.48 , NS)

  • CONCLUSION: This study does not show any relationship between the Pro12Ala polymorphism of the PPARgamma gene and fasting FFAs in the general population

Reference #11 (Ahluwalia M et al.): Pro12Ala
  • We therefore assessed the associations between the most common variant of the PPAR-gamma , the Pro12Ala (P12A) substitution in the PPAR-gamma 2 gene , with BMI , blood pressure , fasting plasma glucose , HbA1c , total cholesterol , LDL and HDL cholesterol and plasma triglyceride in 183 treatment-naive patients with type 2 diabetes (T2D)

Reference #12 (Rosmond R et al.): Pro12Ala
  • The Pro12Ala PPAR(image)2 polymorphism has been variably associated with obesity , insulin sensitivity , and dyslipidemia

  • Aims and methodsIn the present study , we addressed the hypothesis that the Pro12Ala variant is associated with obesity and estimates of insulin , glucose , and lipid metabolism as well as circulating hormones including salivary cortisol in 284 unrelated Swedish men born in 1944

Reference #13 (Li S et al.): Pro12Ala
  • The Peroxisome Proliferator-Activated Receptor- gamma 2 Gene Polymorphism (Pro12Ala) Beneficially Influences Insulin Resistance and Its Tracking From Childhood to Adulthood The Bogalusa Heart Study Shengxu Li1 , Wei Chen1 , Sathanur R

  • Berenson1 1 Tulane Center for Cardiovascular Health and Department of Epidemiology , Tulane University Health Sciences Center , New Orleans , Louisiana 2 Human Genetics Center and Institute of Molecular Medicine , University of Texas-Houston Health Science Center , Houston , Texas ABSTRACT (image)TOP (image)ABSTRACT (image)RESEARCH DESIGN AND METHODS (image)RESULTS (image)DISCUSSION (image)REFERENCES The peroxisome proliferator-activated receptor (PPAR)- gamma 2 gene polymorphism Pro12Ala has been associated with increased insulin sensitivity in some but not all studies

  • In conclusion , the Pro12Ala polymorphism of the PPAR- gamma 2 gene beneficially influences insulin resistance and its tracking from childhood to adulthood

  • Within this functional domain , a missense mutation that results in a substitution of proline by alanine in codon 12 (Pro12Ala) has been found (9 ) and associated with improved insulin sensitivity and decreased risk of type 2 diabetes in many (10 -17 ) but not all studies (18 -21 )

  • Whether Pro12Ala polymorphism in the PPAR- gamma 2 gene influences tracking of insulin resistance status from childhood to adulthood is not known

  • As part of the Bogalusa Heart Study , a long-term com munity-based study of CVD risk beginning in childhood (33 ) , the present study examines 1) the effect of Pro12Ala genotypes on measures of insulin resistance and their tracking from childhood to adulthood and 2) the body fatness-genotype interaction effect on insulin resistance measures

  • Of those , 1 , 093 unrelated individuals (771 whites , 322 blacks) who had PPAR- gamma 2 Pro12Ala genotype data were available to estimate the allele frequency

  • Genotyping of the PPAR- gamma 2 Pro12Ala polymorphism was performed using the TaqMan assay (Applied Biosystems)

  • Based on the analysis of 67 blind duplicate pairs , there was 98.5% concordance in Pro12Ala genotyping

  • The general linear model was used to examine the effects of the Pro12Ala polymorphism on levels of insulin resistance measures (fasting insulin and glucose and HOMA-IR)

  • View this table: [in this window] [in a new window]   TABLE 1 Levels of fasting insulin , glucose , and HOMA-IR in childhood and adulthood by the Pro12Ala genotype of PPAR- gamma 2 in whites: the Bogalusa Heart Study A significant genotype-BMI interaction effect on the positive association of BMI with insulin (P = 0.020) , glucose (P = 0.007) , and HOMA-IR (P = 0.001) was found in adulthood , with carriers of the Ala12 allele showing an attenuated relationship with BMI

  • Changes in HOMA-IR with BMI in white children and young adults by the Pro12Ala genotype of PPAR- gamma 2: the Bogalusa Heart Study

  • Tracking by the Pro12Ala genotype was examined in terms of persistence in ranking at the bottom or top age- and sex-specific quartiles of insulin , glucose , and HOMA-IR

  • The modulating effect of Pro12Ala polymorphism on insulin sensitivity is considered primarily through its influence on body fatness because adjusting for adiposity eliminated the association (13 )

  • However , as in previous studies (11 , 14 ) , the present study found that the association between Pro12Ala polymorphism and measures of insulin resistance persisted after adjusting for BMI

  • In the current study , the Pro12Ala polymorphism modulated the well-known adverse associations of body fatness with insulin resistance measures in that increases in fasting insulin , glucose , and HOMA-IR with increasing BMI were blunted significantly in young adults

Reference #14 (Bluher M et al.): Pro12Ala
  • The Pro115 Gln , Pro12Ala , Pro467Leu , Val290Met and a silent polymorphism C478 T were examined in 48 subjects with IGT and insulin resistance (IR) , characterized by euglycemic hyperinsulinemic clamps , and in 52 healthy insulin sensitive (IS) controls

  • The Pro12Ala variant was not associated with differences in BMI , in the degree of insulin resistance between the IR and IS group

  • In conclusion , the Pro115 Gln variant , but not the Pro12Ala mutation in the PPAR-gamma 2 gene , could be a rare cause of severe insulin resistance.

Reference #15 (Gurnell M et al.): Pro12Ala
  • a , Schematic representation of the domain structure of PPAR gamma , denoting the location of several of the natural mutations and one polymorphism (Pro12Ala) , which have been identified in the human receptor

  • © American Diabetes Association.] Since its isolation , many groups have described a polymorphism (Pro12Ala) or different mutations in the human PPAR gamma gene (Fig. 1A(image) ) in association with distinct clinical phenotypes , providing unique insights into the physiological roles of this receptor

  • In contrast , by far the most prevalent human PPAR gamma genetic variant reported to date is a polymorphism , replacing alanine for proline at codon 12 (Pro12Ala) in the unique PPAR gamma 2 amino-terminal domain , with an allelic frequency that approaches 15% in some Caucasian populations (40 , 41 )

  • In some functional assays , the Pro12Ala variant exhibits reduced binding to DNA and modest impairment in transcriptional activation , and these functional properties have been correlated with the association of this polymorphism with reduced BMI , although subsequent studies have failed to confirm this finding (41 , 43 )

  • In contrast , the Pro12Ala polymorphism in PPAR gamma 2 , with weaker effects on receptor function (43 ) , may be of greater relevance by virtue of its higher prevalence in the population

  • Evidence for an association between Pro12Ala and T2DM was first reported in a population of middle-aged and elderly Finns , in whom a lower BMI appeared to correlate with improved insulin sensitivity in those carrying the Ala allele (43 )

  • The authors argued that collectively existing published data were consistent with their observed effect but with most individual studies having been underpowered , thereby leading earlier authors to inappropriately dismiss a role for Pro12Ala in diabetes risk

  • Together this suggests that the effects of Pro12Ala on fat mass and BMI are subtle and subject to modification by other genetic and environmental influences

  • The finding that a less transcriptionally active human receptor variant (Pro12Ala) predisposes to increased insulin sensitivity may also accord with observations in transgenic mouse models of PPAR gamma action

  • It has , therefore , been proposed that a complex U-shaped curve best describes the relationship between PPAR gamma activity and insulin sensitivity (52 ) ; thus , a modest reduction in receptor function and adipogenesis (as observed with the human Pro12Ala variant or heterozygous null mice) improves insulin action

  • In contrast , a modest reduction in activity (++) , as is observed with the Pro12Ala PPAR gamma variant , has less dramatic effects on adipogenesis but improves insulin sensitivity

  • Altshuler D , Hirschhorn JN , Klannemark M , Lindgren CM , Vohl MC , Nemesh J , Lane CR , Schaffner SF , Bolk S , Brewer C , Tuomi T , Gaudet D , Hudson TJ , Daly M , Groop L , Lander ES 2000 The common PPAR gamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

  • Stumvoll M , Haring H 2002 The peroxisome proliferator-activated receptor- gamma2 Pro12Ala polymorphism

  • Deeb SS , Fajas L , Nemoto M , Pihlajamaki J , Mykkanen L , Kuusisto J , Laakso M , Fujimoto W , Auwerx J 1998 A Pro12Ala substitution in PPAR gamma 2 associated with decreased receptor activity , lower body mass index and improved insulin sensitivity

  • Mancini FP , Vaccaro O , Sabatino L , Tufano A , Rivellese AA , Riccardi G , Colantuoni V 1999 Pro12Ala substitution in the peroxisome proliferator-activated receptor- gamma2 is not associated with type 2 diabetes

  • Ringel J , Engeli S , Distler A , Sharma AM 1999 Pro12Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus

  • Meirhaeghe A , Fajas L , Helbecque N , et al. 2000 Impact of the peroxisome proliferator activated receptor gamma2 Pro12Ala polymorphism on adiposity , lipids and non-insulin-dependent diabetes mellitus

  • Hara K , Okada T , Tobe K , Yasuda K , Mori Y , Kadowaki H , Hagura R , Akanuma Y , Ki mura S , Ito C , Kadowaki T 2000 The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes

  • Clement K , Hercberg S , Passinge B , Galan P , Varroud-Vial M , Shuldiner AR , Beamer BA , Charpentier G , Guy-Grand B , Froguel P , Vaisse C 2000 The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes

  • Beamer BA , Yen C-J , Andersen RE , Muller D , Elahi D , Cheskin LJ , Andres R , Roth J , Shuldiner AR 1998 Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor- gamma 2 gene with obesity in two Caucasian populations

  • Cole SA , Mitchell BD , Hsueh WC , Pineda P , Beamer BA , Shuldiner AR , Co muzzie AG , Blangero J , Hixson JE 2000 The Pro12Ala variant of peroxisome proliferator-activated receptor- gamma2 (PPAR- gamma2) is associated with measures of obesity in Mexican Americans

Reference #16 (Yang WS et al.): Pro12Ala
  • METHODS: We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms

Reference #17 (Iwata E et al.): Pro12Ala
  • In this study , the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population

  • Recently , some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes

  • We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations

  • The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.

Reference #19 (Damcott CM et al.): Pro12Ala
  • In this study , we tested the hypothesis that the polymorphisms , FABP4-376 and PPAR(image) Pro12Ala , interactively influence insulin sensitivity and body composition in nondiabetic , Hispanic and non-Hispanic white males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS)

  • While the PPAR(image) Pro12Ala site was the only statistically significant predictor of fat mass in the 2-way model (P = .012) , the FABP4 and PPAR(image) main effect terms individually became stronger when considered in one model compared with the analysis of each polymorphism separately

  • 17 Association studies of the Pro12Ala site involving BMI have shown variable results

  • 18 -23 However , in a large study of Scandinavian individuals , the Pro12Ala variant was the only polymorphism out of 16 common single nucleotide polymorphisms (SNPs) in candidate genes that were previously reported to influence diabetes risk to show a reproducible association with reduced diabetes risk

  • The previously reported Pro12Ala polymorphism in the PPAR(image) gene (C to G transversion) was detected using an engineered BstUI restriction enzyme site

  • Two-way ANCOVA was used to explore the multilocus effects and interactions between the FABP4 -376 and PPAR(image) Pro12Ala sites on each outcome variable

  • The PPAR(image) Pro12Ala variant , originally reported by Yen et al , 15 was also genotyped

  • Table 1(image) shows the genotype counts and allele frequencies for the FABP4 -376 and PPAR(image) Pro12Ala polymorphic sites

  • Two-Way ANCOVA for HOMA-IR ------------------------------------------------------------------------ > Model(image)-CoefficientsP ValueR2 (P value)All malesConstant27.2<.001.065 (.004)FABP4 -376 (AA)-8.0.158PPAR(image) Pro12Ala (CC)-8.3.123FABP4 (AA) * PPAR(image) (CC)10.2.014Ethnicity (Hispanic)3.6.011Age (yr)-0.06.299Physical activity (kcal / kg / h)-0.02.065Smoking status (ever smoked)2.3.114Non-Hispanic white malesConstant20.3.005.053 (.114)FABP4 -376 (AA)-6.4.182PPAR(image) Pro12Ala (CC)-4.1.855FABP4 (AA) * PPAR(image) (CC)7.4.076Age (yr)0.06.432Physical activity (kcal / kg / h)-0.02.073Smoking status (ever smoked)2.5.112Hispanic malesConstant50.5<.001.088 (.094)FABP4 -376 (AA)-14.6.401PPAR(image) Pro12Ala (CC)-20.2.053FABP4 (AA) * PPAR(image) (CC)20.9.034Age (yr)-0.2.090Physical activity (kcal / kg / h)-0.02.311Smoking status (ever smoked)3.7.227 ------------------------------------------------------------------------ > In the model for the entire male cohort , the interaction between the FABP4 and PPAR sites was a statistically significant predictor of HOMA-IR (P = .014)

  • Bar chart of adjusted means for HOMA-IR in the FABP4 -376 / PPAR(image) Pro12Ala genotype groups

  • Two-Way ANCOVA for Lean Mass (g) ------------------------------------------------------------------------ > Model(image)-CoefficientsP ValueR2 (P value)All males (n = 297)Constant76 , 973<.001.330 (<.001)FABP4 -376 (AA)-4 , 927.140PPAR(image) Pro12Ala (CC)-3 , 778.210FABP4 (AA) * PPAR(image) (CC)4 , 930.019Ethnicity (Hispanic)-6 , 578<.001Age (yr)-204<.001Physical activity (kcal / kg / h)6.191Smoking status (ever smoked)890.234Non-Hispanic white males (n = 180)Constant67 , 257<.001.120 (.001)FABP4 -376 (AA)-5 , 281.084PPAR(image) Pro12Ala (CC)-3 , 985.464FABP4 (AA) * PPAR(image) (CC)6 , 060.020Age (yr)-146.002Physical activity (kcal / kg / h)3.615Smoking status (ever smoked)2 , 140.032Hispanic males (n = 117)Constant65 , 189<.001.295 (<.001)FABP4 -376 (AA)64.641PPAR(image) Pro12Ala (CC)-848.993FABP4 (AA) * PPAR(image) (CC)1 , 664.659Age (yr)-261<.001Physical activity (kcal / kg / h)5.492Smoking status (ever smoked)-689.568 ------------------------------------------------------------------------ > For all males , the interaction between the FABP4 and Pro12Ala sites was a statistically significant predictor of lean mass ( P = .019)

  • Bar chart of adjusted means for lean mass in the FABP4 -376 / PPAR(image) Pro12Ala genotype groups

  • Two-Way ANCOVA for Fat Mass (g) ------------------------------------------------------------------------ > Model(image)-CoefficientsP ValueR2 (P value)All males (n = 297)Constant35 , 071<.001.065 (.006)FABP4 -376 (AA)-4 , 485.070PPAR(image) Pro12Ala (CC)-5 , 390.012FABP4 (AA) * PPAR(image) (CC)4 , 205.106Ethnicity (Hispanic)-2 , 650.004Age (yr)-42.283Physical activity (kcal / kg / h)-3.625Smoking status (ever smoked)1 , 146.217Non-Hispanic white males (n = 180)Constant28 , 871<.001.070 (.047)FABP4 -376 (AA)-6 , 458.014PPAR(image) Pro12Ala (CC)-5 , 329.086FABP4 (AA) * PPAR(image) (CC)5 , 324.085Age (yr)31.561Physical activity (kcal / kg / h)-7.360Smoking status (ever smoked)2 , 349.047Hispanic males (n = 117)Constant31 , 334<.001.068 (.250)FABP4 -376 (AA)1 , 436.462PPAR(image) Pro12Ala (CC)-2 , 694.384FABP4 (AA) * PPAR(image) (CC)902.858Age (yr)-125.038Physical activity (kcal / kg / h)-4.695Smoking status (ever smoked)-131.935 ------------------------------------------------------------------------ > The model for the entire male cohort included the Pro12Ala site ( P = .012) as a statistically significant predictor of fat mass

  • Bar chart of adjusted means for fat mass in the FABP4 -376 / PPAR(image) Pro12Ala genotype groups

  • In the entire male cohort , we found that individually the FABP4 -376 and the PPAR(image) Pro12Ala variants were not statistically significantly associated with measures of insulin sensitivity and body composition ; however , statistically significant effects were observed when both sites were considered in one model

  • In particular , carriers of the less common alleles at FABP4 -376 and Pro12Ala showed greater HOMA-IR indices , lean mass , and fat mass

  • Although the model for fat mass did not show similar evidence of an interactive effect , the Pro12Ala variant was a statistically significant predictor of fat mass when considered in 2-way ANCOVA with FABP4

  • In previous studies examining the functional effects of the PPAR(image) Pro12Ala site in vitro , the alanine allele has been shown to reduce transcriptional activity , resulting in lower levels of lipolysis and adipogenesis

  • 40 , 41 In this study , individuals with the less common alleles at both the FABP4 -376 and PPAR(image) Pro12Ala show higher HOMA-IR indices (see Fig 1(image) ) , which would be consistent with impaired insulin sensitivity in peripheral tissues through this mechanism

  • These findings suggest that it is important to consider other genes in the lipid metabolism pathways when evaluating the effects of the PPAR(image) Pro12Ala polymorphism

  • While we cannot make a definitive conclusion about the interactive effects on fat mass , PPAR(image) Pro12Ala was found to be a significant predictor of fat mass only when considered in a model with the FABP4 variant

  • J Biol Chem 1997 ; 272:25252-25259.MEDLINE > 15.   Yen CJ , Beamer BA , Negri C , et al. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: Identification of a Pro12Ala PPAR gamma 2 missense mutation

  • Biochem Biophys Res Com mun 2000 ; 268:178-182.MEDLINE > 17.   Stumvoll M , Wahl HG , Loblein K , et al. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor- gamma2 gene is associated with increased antilipolytic insulin sensitivity

  • Diabetes 2001 ; 50:876-881.MEDLINE > 18.   Beamer BA , Yen CJ , Andersen RE , et al. Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor- gamma2 gene with obesity in two Caucasian populations

  • Diabetes 1998 ; 47:1806-1808.MEDLINE > 19.   Cole SA , Mitchell BD , Hsueh WC , et al. The Pro12Ala variant of peroxisome proliferator-activated receptor- gamma2 (PPAR- gamma2) is associated with measures of obesity in Mexican Americans

  • Int J Obes Relat Metab Disord 2000 ; 24:522-524.MEDLINE > 20.   Meirhaeghe A , Fajas L , Helbecque N , et al. Impact of the peroxisome proliferator activated receptor gamma2 Pro12Ala polymorphism on adiposity , lipids and non-insulin-dependent diabetes mellitus

  • Int J Obes Relat Metab Disord 2000 ; 24:195-199.MEDLINE > 21.   Deeb SS , Fajas L , Nemoto M , et al. A Pro12Ala substitution in PPAR gamma2 associated with decreased receptor activity , lower body mass index and improved insulin sensitivity

  • Nat Genet 1998 ; 20:284-287.MEDLINE > 22.   Ek J , Urhammer SA , Sorensen TI , et al. Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor- gamma2 (PPAR- gamma2): Divergent modulating effects on body mass index in obese and lean Caucasian men

  • Diabetologia 1999 ; 42:892-895.MEDLINE > 23.   Mori Y , Kim-Motoyama H , Katakura T , et al. Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity , fat distribution , and insulin sensitivity in Japanese men

  • Biochem Biophys Res Com mun 1998 ; 251:195-198.MEDLINE > 24.   Altshuler D , Hirschhorn JN , Klannemark M , et al. The common PPAR gamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

  • Diabetes 2000 ; 49:904-911.MEDLINE > 43.   Lei HH , Chen MH , Yang WS , et al. Peroxisome proliferator-activated receptor gamma 2 Pro12Ala gene variant is strongly associated with larger body mass in the Taiwanese

  • Metabolism 2000 ; 49:1267-1270.MEDLINE > 44.   Hara K , Okada T , Tobe K , et al. The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes

Reference #8 (Lindi VI et al.): Pro12Pro
  • By 3 years of intervention , the odds ratio of the development of type 2 diabetes for subjects with the Ala12 allele was 2.11-fold compared with that for subjects with the Pro12Pro genotype (95% CI 1.20-3.72)

  • In the intervention group , subjects with the Ala12Ala genotype lost more weight during the follow-up than subjects with other genotypes (Pro12Pro vs

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F.Horn (nucleardbcmbi.kun.nl), 21-Apr-2005