ABCC7 p.Gly1237Ala
| CF databases: |
c.3709G>A
,
p.Gly1237Ser
(CFTR1)
?
, This mutation was found by SSCA and direct DNA sequencing in a woman 35 years old with bronchiectasis.
|
| Predicted by SNAP2: | A: N (61%), C: N (53%), D: D (59%), E: N (53%), F: D (80%), H: N (72%), I: D (59%), K: N (82%), L: D (53%), M: N (66%), N: N (82%), P: D (53%), Q: N (82%), R: N (82%), S: N (72%), T: N (66%), V: N (53%), W: D (85%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: N, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Alpha 1-antitrypsin deficiency alleles in cystic f... Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):390-6. Epub 2003 Apr 14. Frangolias DD, Ruan J, Wilcox PJ, Davidson AG, Wong LT, Berthiaume Y, Hennessey R, Freitag A, Pedder L, Corey M, Sweezey N, Zielenski J, Tullis E, Sandford AJ
Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease.
Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):390-6. Epub 2003 Apr 14., [PMID:12689922]
Abstract [show]
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. alpha1-antitrypsin (alpha1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha1-AT alleles (Z, S deficiency alleles and the 3' G1237-->A mutation) were associated with increased disease severity and the alpha1-AT acute phase response during pulmonary exacerbations. This was a multicenter Canadian study. Seven hundred sixteen patients with CF (age range, 5.0-63.6 yr) were genotyped for the Z, S, and G1237-->A polymorphisms of the alpha1-AT gene. Stable and acute levels of alpha1-AT were measured on 31 adult patients with CF and were correlated to clinical parameters. There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF heterozygous or homozygous for the A1237 allele, respectively. alpha1-AT genotype did not predict pulmonary disease severity, and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. Body mass index was a significant predictor of alpha1-AT levels during exacerbations. alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.
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82 Stepwise linear regression analysis was used to predict %change in ␣1-AT and parameters used included current age, sex, CF diagnosis age, CFTR genotype, TABLE 2 Clinical characteristics of study subjects stratified by ␣1-AT 3Ј G1237 →A genotype Total G1237G G1237A or A1237A P value Sex, M/F 379/337 331/283 48/54 0.20 Age, yr 22.8 (0.4) 22.7 (0.4) 23.5 (1.2) 0.49 CFTR genotype (⌬F508/⌬F508; ⌬F508/other; other/other) 391/296/72 343/244/60 48/52/12 0.14 Age of CF diagnosis, yr 4.7 (0.3) 4.6 (0.3) 5.4 (0.9) 0.38 %predFEV1 64.8 (0.9) 64.9 (1.0) 63.7 (2.3) 0.64 BMI, kg/m2 20.3 (0.2) 20.4 (0.2) 20.0 (0.4) 0.49 Pancreatic sufficiency status (sufficient/insufficient) 119/649 95/561 24/88 0.05 No. of P. aeruginosa-positive/not colonized 478/85 416/70 62/15 0.23 Age of first infection with P. aeruginosa 11.1 (0.5) 11.3 (0.5) 10.0 (1.1) 0.36 Age of chronic P. Aeruginosa infection 14.4 (0.8) 14.5 (0.9) 13.6 (1.6) 0.71 Frequency of intravenous treatment/yr 0.9 (0.1) 0.9 (0.1) 0.9 (0.2) 0.86 Days of intravenous treatment/yr 13.7 (1.2) 13.5 (1.6) 15.4 (4.5) 0.60 Dead or lung transplanted/alive 63/644 53/551 10/92 0.71 The study sample varied between 713 and 716 for univariate analyses. For analysis of age of first infection with P. aeruginosa and P. aeruginosa status, the study sample size was 461 and 555, respectively. For analysis of age of chronic infection with P. aeruginosa, the study sample was 159.
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ABCC7 p.Gly1237Ala 12689922:82:285
status: NEW[hide] Genetic modifiers of lung disease in cystic fibros... N Engl J Med. 2005 Oct 6;353(14):1443-53. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR
Genetic modifiers of lung disease in cystic fibrosis.
N Engl J Med. 2005 Oct 6;353(14):1443-53., 2005-10-06 [PMID:16207846]
Abstract [show]
BACKGROUND: Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS: We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1. RESULTS: In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02). CONCLUSIONS: Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.
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76 * Gene andReference†Variant‡ReferenceSNP Impairmentof LungFunctionGenotype Patientswith theGenotypeGenotype Patientswith theGenotypeGenotype Patientswith theGenotype Number ofPatients P Value§ %%% a1AP4-8Sallele17580SevereAA91.5AT8.5TT02601.00 (T2313A)MildAA91.4AT8.5TT0.2544 ZalleleNoneSevereGG96.0GA4.0AA02520.39 (G4627A)MildGG97.2GA2.8AA0529 3'enhancer11568814SevereGG85.8GA13.5AA0.82600.75 (G1237A)MildGG84.7GA14.7AA0.6544 ACE9DorIdeletionNASevereDD39.3DI39.3II21.42620.32 MildDD38.2DI44.7II17.1544 ADRb210(A46G)1042713SevereGG39.1GA48.5AA12.32350.62 MildGG41.7GA48.0AA10.3506 (C79G)1042714SevereCC26.8CG56.6GG16.62350.45 MildCC29.9CG51.6GG18.5508 GSTM111,13NulldeletionNASevereDD52.1--DN/NN47.92610.50 MildDD54.9--DN/NN45.1539 GSTP113(A1375G)947894SevereAA46.2AG44.2GG9.62600.81 MildAA44.0AG45.1GG10.9543 IL109(G-1082A)1800896SevereGG23.1GA55.4AA21.52600.96 MildGG24.1GA55.0AA21.0544 MBL214-18O¶NASevereAA59.5AO35.5OO5.02620.58 MildAA58.2AO37.5OO4.3536 XA/O¿NASevereOther85.8XA/O9.2O/O5.02621.00 MildOther85.6XA/O10.0O/O4.3536 NOS319T5220G1799983SevereGG43.5GT45.8TT10.82600.54 MildGG46.0GT41.7TT12.3544 TGFb19,20**Promoter1800469SevereCC43.8CT43.8TT12.32600.006 (C-509T)MildCC50.4CT43.8TT5.9544 Codon101982073SevereTT34.0TC46.3CC19.72590.0008 (C29T)††MildTT41.4TC48.4CC10.1543 Codon251800471SevereGG82.2GC17.4CC0.42590.06 (G74C)MildGG87.7GC11.6CC0.7544 TNFa9,12Promoter1800629SevereGG68.1GA29.0AA2.92380.91 (G-308A)MildGG68.7GA27.7AA3.6505 seen only for TGFb1 variants; the codon 10 variant hadamultiple-comparisoncorrectedPvalueof0.01 (the most significant association among the 16 in Table 2).
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ABCC7 p.Gly1237Ala 16207846:76:414
status: NEW[hide] Disease modifying genes in cystic fibrosis: therap... Naunyn Schmiedebergs Arch Pharmacol. 2006 Nov;374(2):65-77. Epub 2006 Oct 11. Buscher R, Grasemann H
Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?
Naunyn Schmiedebergs Arch Pharmacol. 2006 Nov;374(2):65-77. Epub 2006 Oct 11., [PMID:17033796]
Abstract [show]
Cystic fibrosis (CF) is the most common genetic disease among Caucasians and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organs but lung disease is the major determinant for morbidity and mortality. Many studies have focussed on the correlation between CFTR genotype and severity of disease. Since patients with identical CFTR mutations often show considerable variability in disease progression, genes other than CFTR are thought to have the potential to modify the course of lung disease in CF patients. Therefore, identification of CF-modifying genes has become the goal of several studies over the last 15 years. Pharmaceutical approaches for CF lung disease have been developed regardless of the underlying genetic defect and in general target symptoms such as airway obstruction and treatment of bacterial infection. Analysing the pathophysiological processes of modifiers may lead to the discovery of pathways involved in CF pathophysiology and possibly to the design of new therapeutics. The purpose of this review is not only to list potential CFTR modifier genes, but also to discuss new therapeutic strategies that could be derived from knowledge of these CF modifiers.
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39 Disease severity Stanke et al. 2006 MIF (MIF chromosome 22q11) American, ethnicity unspecified 167 CF patients, 166 healthy controls CATT-repeat -794, promoter: MIF5+=39%, MIF5- =61% [CF] vs MIF5+=43%, MIF5- =57% [controls] 5-CATT repeat with lowest promoter activity 5-CATT allele: colonisation with P. aeruginosa ↓; risk for pancreatic insufficiency ↓ Plant et al. 2005 IL10 (IL10 chromosome 1q31-q32) French, German 378 CF patients SNP -1082 G/A, promoter:CF patients: -1082GG: 24.9%, -1,082AG: 49.7%, -1082AA:25.4% [IL10] ↑ -1082G: colonisation with Aspergillus fumigatus ↑; risk for ABPA↑ Brouard et al. 2005 GSTM1 + GSTM3 (GSTM1 + GSTM3 chromosome 1p13.3) British, ethnicity unspecified 53 CF patients GSTM1 gene deletion: 49% of study population GSTM1 deficient (GSTM1-0/0) No protein Chrispin-Norman X-ray score ↓; +Shwachman-score ↓ in GSTM1-0/0 Hull and Thomson 1998 French 146 CF patients, 147 healthy controls GSTM3 3 base pair deletion in intron 6: GSTM3, A/A=0.68, A/B=0.29, B/B=0.03 [CF] vs A/A=0.65, A/B=0.31, B/B=0.04 [controls] [GSTM3] ↑ B-allele carriers: FEV1 and FVC ↑ (influenced by GSTM1 genotype) Flamant et al. 2004 American and Canadian, ethnicity unspecified 440 CF patients Glutamate-cysteine ligase subunit (GCLC) TNR GAG repeats: 7/7 allele pair 40%; 7/8 allele pair 17%; 7/9 allele pair 28%; other 15% [GSH] ↑ CF patients with milder CFTR genotype show strong association with lung disease severity McKone et al. 2006 GSTP1 (GSTP1 chromosome 11q13) French 106 CF patients 105Ile/Val: Ile =0.7, Val=0.3, [CF]; Ile=0.83, Val=0.17 [CF with liver disease] vs Ile=0.66, Val=0.34 [CF without liver disease] [GSTP1] ↑ 105Ile/Ile: Risk for liver cirrhosis increased ↑ Henrion-Caude et al. 2002 Table 1 (continued) Gene Population Number Gene variant + frequency Biological effect Phenotype ReferenceGene variant + frequency ReferencePhenotypeBiological effect Population Number α1AT (α1AT chromosome 14q32.1) British 79 CF patients SNP, 3`G1237A, enhancer polymorphism: 2.5% heterozygous for S-allele, 5.1% heterozygous for Z-allele [α1AT] ↓ No association with lung function Mahadeva et al. 1998a,b Irish 124 CF patients SNP G1237A, 5' enhancer polymorphism: A=0.13, G =0.87 [α1AT] ↓ Brasfield X-ray score ↑ 1237A allele carriers with better pulmonary prognosis 1237A: chronic colonisation with P. aeruginosa ↓ Henry et al. 2001 Canadian 716 CF patients SNP, 3`G1237A, enhancer polymorphism: A=0.14, G =0.86 [α1AT] ↓ No association with more severe clinical outcome (death or lung transplantation) or age at onset of P. aeruginosa infection Frangolias et al. 2003 Danish 215 CF patients SNP, codon 264SNP G/A, codon 342 [α1-AT] ↓ Earlier colonisation with P. aeruginosa serum Pseudomonas-antibodies ↑ Döring et al. 1994 α1ACT (α1ACT chromosome 14q31-q31.2) British 157 CF patients, 45 healthy controls SNP -15 G/APromoter (-15 Thr→Ala): G=0.66, A=0.34 [CF] vs.
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ABCC7 p.Gly1237Ala 17033796:39:2259
status: NEW108 The question of whether common α1AT alleles and polymorphisms such as Z and S deficiency alleles and the G1237A polymorphism are associated with CF disease severity has been investigated in a number of different studies that revealed inconsistent results (Mahadeva et al. 1998a,b; Henry et al. 2001; Frangolias et al. 2003; Döring et al. 1994; Table 1).
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ABCC7 p.Gly1237Ala 17033796:108:111
status: NEW[hide] Disease modifying genes in cystic fibrosis. J Cyst Fibros. 2005 Aug;4 Suppl 2:7-13. Slieker MG, Sanders EA, Rijkers GT, Ruven HJ, van der Ent CK
Disease modifying genes in cystic fibrosis.
J Cyst Fibros. 2005 Aug;4 Suppl 2:7-13., [PMID:15996905]
Abstract [show]
The variation in cystic fibrosis (CF) lung disease and development of CF related complications correlates poorly with the genotype of the CF transmembrane regulator (CFTR) and with environmental factors. Increasing evidence suggests that phenotypic variation in CF can be attributed to genetic variation in genes other than the CFTR gene, so-called modifier genes. In recent years, multiple candidate modifier genes have been investigated in CF, especially genes that are involved in the control of infection, immunity and inflammation. Some of these genes have been rather conclusively identified as modifiers of the CF phenotype, whereas associations found in other genes have not been confirmed or are conflicting. Identification of genetic variation in modifier genes, obtained by genotype-phenotype studies in well-defined patient populations, may be used as an aid to prognosis and may provide the possibility of new therapeutic interventions.
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102 Another polymorphism in the 3` non-coding region enhancer-binding element of the a1-AT gene (G1237A) may reduce the rise in the level of a1-antitrypsin during the acute phase response, whilst leaving baseline levels unaffected [33].
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ABCC7 p.Gly1237Ala 15996905:102:93
status: NEW105 In the latter study, no association between the G1237A polymorphism and lung function was found.
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ABCC7 p.Gly1237Ala 15996905:105:48
status: NEW107 Finally, in a large recent Canadian study (n = 716), one of the few that adjusted for confounders, none of the associations between deficiency Z and S genotypes or G1237A polymorphisms, and lung function or age of P. aeruginosa colonization could be confirmed [37].
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ABCC7 p.Gly1237Ala 15996905:107:164
status: NEW