Bioinformatic and functional analysis of TGFBR1 polymorphisms

Schirmer, Markus; Hoffmann, Arne O.; Campean, Radu; Janke, Jörg H.; Zidek, Laura M; Hoffmann, Marion; Kruse, Moritz; Sehrt, Daniel; Tzvetkov, Mladen V.; Rave-Fränk, Margret; Brockmöller, Jürgen

doi:10.1097/fpc.0b013e32831cb5a7

Cited by 7 publications

(6 citation statements)

References 36 publications

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“…We also analyzed in vitro how OCT1 polymorphisms influence the uptake of O ‐desmethyltramadol. We induced overexpression of OCT1 variants carrying the five most common functional amino acid substitutions in Caucasians (Arg61Cys, Cys88Arg, Gly401Ser, Met420del, and Gly465Arg 16 , 18 , 21 , 22 , 23 ) and compared their activity with the activity of the wild‐type OCT1. Only combinations of amino acid substitutions that are natively found as polymorphisms in Caucasian populations were analyzed 16 , 20 .…”

Section: Resultsmentioning

confidence: 99%

“…Genomic DNA was isolated from venous blood samples using an automated solid‐phase extraction method in accordance with the manufacturer's instructions (EZ1 DNA Blood 350 µl Kit used with the BioRobot EZ1, both from Qiagen, Hilden, Germany). The genotyping of OCT1 (alternative gene name SLC22A1 ) was performed using a single‐base primer extension method as described previously 16 , 21 , 22 , 23 . The method was modified, and only the amino acid substitutions Arg61Cys, Cys88Arg, Gly401Ser, and Gly465Arg and the Met420 deletion were genotyped.…”

Section: Methodsmentioning

confidence: 99%

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Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

Tzvetkov¹,

Saadatmand²,

Lötsch³

et al. 2011

Clin Pharmacol Ther

134

141

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We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

Tzvetkov¹,

Saadatmand²,

Lötsch³

et al. 2011

Clin Pharmacol Ther

134

141

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“…One study has confirmed that negative feedback regulation in terms of SMAD3 expression was attenuated and radiation-induced cell death as a cellular endpoint was enhanced for cells harboring the TGFBR1* 6A mutation [47]. We have shown that TGFBR1* 6A enhances MCF-7 cell migration and invasion through RHOA and MAPK1 pathway activation and downregulation of ARHGAP5 and FN1 [41].…”

Section: Characterization Of Tgfbr1*6amentioning

confidence: 90%

“…To date, functional analysis of TGFBR1* 6A indicates that this mutation may confer a growth advantage to cancer cells by switching TGF-β growth inhibitory signals into growth stimulatory signals [47]. One study has confirmed that negative feedback regulation in terms of SMAD3 expression was attenuated and radiation-induced cell death as a cellular endpoint was enhanced for cells harboring the TGFBR1* 6A mutation [47].…”

Section: Characterization Of Tgfbr1*6amentioning

confidence: 99%

TGFBR1 Signaling and Breast Cancer

Moore-Smith

Pasche

2011

J Mammary Gland Biol Neoplasia

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Over the past decade mutations discovered in genes such as BRCA1, BRCA2, TP53 and PTEN, have emerged as high-penetrance susceptibility genes and are clinically relevant for determination of breast cancer risk. Genetic counseling and subsequent screening for mutations and gene rearrangement has improved patient outcome through early detection and prophylactic interventions in patients with familial breast cancer syndromes. However, these high-penetrance genes only account for a small fraction of the hereditary linked breast cancers. It is currently believed that low-penetrance susceptibility alleles and/or environmental factors may play an important role in the remaining cases. TGFBR1*6A (*6A) is a common hypomorphic variant of the type I TGF-β receptor gene (TGFBR1) that has been associated with risk for several forms of cancer, in particular breast cancer. Several epidemiological studies have suggested that patients who carry the *6A allele have an increased risk of breast cancer. Furthermore, functional analysis suggests that this mutation alters TGF-β signaling and promotes tumorigenesis. Although a decade of research has provided basic information in regards to the prevalence of this mutation in several cancer types and populations the molecular underpinning of its functional effects are poorly understood. A better understanding of the molecular mechanism of TGFBR1 signaling in breast cancer may have an impact on breast cancer risk assessment and breast cancer prevention.

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“…A nine base pair deletion in the repeat sequence of exon 1 of the TGFBR1 gene, giving rise to the TGFBR1*6A allele [17], was found to result in weaker cytokine induced response compared to the wild type, TGFBR1*9A allele [18]. The hypomorphic behavior of this allele was also reflected in its association with weaker radiation induced response of lymphocytes [19]. Moreover, the allele has been implicated in TGF β independent enhancement of migration and invasion of MCF-7 cells [20].…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor β Signaling Pathway Associated Gene Polymorphisms May Explain Lower Breast Cancer Risk in Western Indian Women

et al. 2011

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Transforming growth factor β1 (TGFB1) T29C and TGF β receptor type 1 (TGFBR1) 6A/9A polymorphisms have been implicated in the modulation of risk for breast cancer in Caucasian women. We analyzed these polymorphisms and combinations of their genotypes, in pre menopausal breast cancer patients (N = 182) and healthy women (N = 236) from western India as well as in breast cancer patients and healthy women from the Parsi community (N = 48 & 171, respectively). Western Indian women were characterized by a higher frequency of TGFB1*C allele of the TGF β T29C polymorphism (0.48 vs 0.44) and a significantly lower frequency of TGFBR1*6A allele of the TGFBR1 6A/9A polymorphism (0.02 vs 0.068, p<0.01) as compared to healthy Parsi women. A strong protective effect of TGFB1*29C allele was seen in younger western Indian women (<40 yrs; OR = 0.45, 95% CI 0.25–0.81). Compared to healthy women, the strikingly higher frequencies of low or intermediate TGF β signalers in patients suggested a strong influence of the combination of these genotypes on the risk for breast cancer in Parsi women (for intermediate signalers, OR = 4.47 95%CI 1.01–19.69). The frequency of low signalers in Parsi healthy women, while comparable to that reported in Europeans and Americans, was three times higher than that in healthy women from western India (10.6% vs 3.3%, p<0.01). These observations, in conjunction with the low incidence rate of breast cancer in Indian women compared to White women, raise a possibility that the higher frequency of TGFB1*29C allele and lower frequency of TGFBR1*6A allele may represent important genetic determinants that together contribute to a lower risk of breast cancer in western Indian women.

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Bioinformatic and functional analysis of TGFBR1 polymorphisms

Abstract: The *6A deletion and the linked rs11568785 polymorphisms seem to attenuate TGFB signaling. This should be considered not only for clinical-epidemiological studies on cancer susceptibility but may also be relevant for side effects from drugs or radiotherapy.

Cited by 7 publications

References 36 publications

Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

TGFBR1 Signaling and Breast Cancer

Transforming Growth Factor β Signaling Pathway Associated Gene Polymorphisms May Explain Lower Breast Cancer Risk in Western Indian Women

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