Karla Köpke

Charité Universitätsmedizin Berlin, Berlin, Land Berlin, Germany

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Publications (13)88.11 Total impact

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    ABSTRACT: OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds. The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies. Eighteen exonic SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped by PCR and RFLP analysis in 300 German, 94 Turkish, and 115 African subjects. Calculation of pairwise linkage disequilibrium and estimation of population haplotype frequencies were carried out, and haplotype block structure was determined. Only eight genotyped SNPs (c.388A>G, c.411G>A, c.463C>A, c.521T>C, c.571C>T, c.597C>T, c.1463G>C, c.1929A>C) were found in at least one of our German, Turkish, or African samples. A total of 12 haplotypes with a frequency >or=1% in at least one of the three populations could be inferred. Between the Caucasian and African samples, significant differences in sequence variability were observed leading to a different haplotype profile in these populations. Our results demonstrate a high sequence variability of OATP1B1 within different popuations. In the future, distinct haplotypes should be taken into account when studying the effect of OATP1B1 on drugs in different populations.
    European Journal of Clinical Pharmacology 03/2008; 64(3):257-66. · 2.74 Impact Factor
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    ABSTRACT: Little was known about the sequence variability of the human Arrestin domain-containing 4 gene (ARRDC4). We sequenced its DNA from exon 2 to exon 8 in a sample of 92 Russians. Seven variants were identified; one of them has not been described yet. It causes an amino acid change from Thr to Met. Identified variants were genotyped in the complete sample of 253 unrelated men and women to analyze haplotype distribution. Fifteen haplotypes were inferred. Nine haplotypes had estimated frequencies > 1%. Ninety-five percent of all haplotypes were determined by five haplotype-tagging single nucleotide polymorphisms. Haplotypes form two clades. The two most common haplotypes cover 76% of all haplotypes. The certainty of the haplotype reconstruction does not depend on the haplotype-inferring algorithms, but is a result of the anomalous haplotype distribution of ARRDC4, which makes this gene a suitable candidate gene for haplotype association studies. Interestingly, there is a great evolutionary distance between the two most common haplotypes, which could suggest a more complicated coalescent process with either past gene flow, selections, or bottlenecks.
    Genetic Testing 03/2008; 12(1):147-52. · 1.17 Impact Factor
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    ABSTRACT: The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. Three hundred eighty-eight German IBD patients [244 with Crohn's disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype-phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (chi(2) = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (chi(2) = 16.054, df = 8, p = 0.034 for age at diagnosis >or=25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 - 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (chi(2) = 16.101, df = 6, p = 0.017 for age at diagnosis >or=25). No association of MDR1 genotypes with disease subgroups in CD was observed. While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.
    European Journal of Clinical Pharmacology 10/2007; 63(10):917-25. · 2.74 Impact Factor
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    ABSTRACT: The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined. Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms -129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study. Genotype-phenotype analysis was performed with simultaneous consideration of lifestyle risk factors. Our analysis confirmed the preponderate impact of smoking on colorectal cancer development. The risk of heavy smokers (>/=60 pack years) to develop colorectal cancer by far exceeded that of lifelong non-smokers (OR = 3.9, 95% CI: 1.4 to 10.6). Smoking is a more potent risk factor than is the genetic influence of MDR1 in our study. However, a smoking and age-stratified analysis, revealed a statistically significant association between MDR1 genotypes and colorectal cancer in life-long non-smokers with an age > or =63 years (the median age in our sample). The association was stronger for rectal cancer than for colon cancer. Patients who carried the genotypes (-129TT; 2677GG; 3435CC) or (-129TT; 2677TT; 3435TT) developed more frequently colorectal cancer than others (OR = 3.9; 95% CI: 2.0 to 7.7). Our results show that the interaction of genetic and lifestyle risk factors should be taken into account to elucidate the genetic influence of MDR1 variability on cancer susceptibility.
    European Journal of Clinical Pharmacology 01/2007; 63(1):9-16. · 2.74 Impact Factor
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    ABSTRACT: We analyzed allele frequencies and pairwise linkage disequilibria of 13 variants in the EDN1 gene of 298 young males, the majority of German ancestry. Our analysis comprises all common variants in the five exons and flanking intronic regions, as well as known polymorphisms in the promoter sequence. In addition to previously analyzed polymorphisms, our haplotype reconstruction included five recently described variants and was done by using three different algorithms to allow inference of result stability. More than 30 haplotypes were predicted. All haplotypes with frequencies > or = 1% were inferred by all three methods and can be described by seven haplotype tagging single-nucleotide polymorphisms (htSNPs), reducing the genotyping load to 65%. Three of these haplotypes with frequencies of about 11%, 9%, and 4% had been mistaken for one haplotype in the previous analysis, which included only six polymorphisms, some of them not being htSNPs. Systematic analysis of sequence variability and comprehensive haplotype analysis of the EDN1 gene determined a substantial part of its genetic variability for further association studies and helped to reduce the genotyping load for common phenotypes.
    Genetic Testing 01/2006; 10(3):163-8. · 1.17 Impact Factor
  • Karla Köpke
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2005; 132B(1):64. · 3.23 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2005; 43(05).
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    ABSTRACT: The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for blood pressure (BP) regulation and essential hypertension. To investigate whether AGT haplotype analysis adds significant information compared to single polymorphism analysis with respect to different BP phenotypes in an untreated hypertensive sample. Two hundred and twelve untreated hypertensive subjects of Caucasian origin were genotyped for the AGT polymorphisms C-532T, A-20C, C-18T, and G-6A. In single variant analyses, untreated hypertensives, carrying the AGT -532T or -6A alleles had significantly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as ambulatory BP values compared to respective non-carriers. In haplotype-based analyses, combining all four AGT promoter variants, we demonstrate that AGT haplotypes containing different allele combinations at positions -532 and -6 were significantly associated with different BP values: (1) -532T and -6A with higher, (2) -532C and -6G with lower, (3) -532C and -6A with intermediate BP values. Since the result for the -532C/-20A/-18C/-6G haplotype was due to differences between non-carriers and carriers of this haplotype on both chromosomes, a recessive inheritance model for BP effects could be assumed. Our results designate the C-532T and G-6A as the best candidates for functional studies on the AGT gene. Haplotype-based analyses should greatly aid in the dissection of the genetic basis of complex traits, such as BP regulation and hypertension.
    Journal of Hypertension 08/2004; 22(7):1289-97. · 4.22 Impact Factor
  • Karla Köpke
    Biometrical Journal 01/2004; 46:131-131. · 1.15 Impact Factor
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    ABSTRACT: The frequency of functionally important mutations and alleles of genes coding for xenobiotic metabolizing enzymes shows a wide ethnic variation. However, little is known of the frequency distribution of the major allelic variants in the Russian population. Using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) genotyping assays and the real-time PCR with fluorescent probes, the frequencies of functionally important variants of the cytochromes P450 (CYP) 2C9, 2C19, 2D6, 1A1 as well as arylamine N-acetyltransferase 2 (NAT2) and P-glycoprotein (MDR1) were determined in a sample of 290 Russian volunteers derived from Voronezh area. CYP2C9*2 and * 3 alleles were found with allelic frequencies of 10.5% and 6.7%, respectively. The novel intron-2 T>C mutation at exon 2 +73 bp occurred in 24.8% of alleles. CYP2C19*2 and *3 alleles occurred in 11.4% and 0.3%, respectively. Six persons (2.1%) carried two of these CYP2C19 alleles responsible for poor metabolizing activity. Of all subjects, 5.9% were CYP2D6 poor metabolizers, whereas 3.4% were addressed to ultra-rapid metabolizers (CYP2D6*1x2/*1). The CYP1A1*2A allele was found in 4.7%, *2B in 5.0%, *4 in 2.6%, and the 5'-mutations -3219C>T, -3229G>A, and the novel -4335G>A in 6.0%, 2.9% and 26.0% of alleles, respectively. Genotyping of eight different single nucleotide polymorphisms in the NAT2 gene provided in 58.0% a genotype associated with slow acetylation. The MDR1 triple variants G2677T and G2677A in exon 21 had an allelic frequency of 41.9% and 3.3%, respectively, and the variant C3435T in exon 26 one of 54.3%. Frequencies of functionally important haplotypes were calculated. The overview of allele distribution of important xenobiotic-metabolizing enzymes among a Russian population shows similarity to other Caucasians. The data will be useful for clinical pharmacokinetic investigations and for drug dosage recommendations in the Russian population.
    European Journal of Clinical Pharmacology 08/2003; 59(4):303-12. · 2.74 Impact Factor
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    ABSTRACT: The endothelin-converting enzyme (ECE)-1 gene is a candidate for human blood pressure (BP) regulation and we report the identification of the new gene variants T-839G, C-338A, L75F, A677V and C+295T. Transient transfection of the reporter constructs containing the -338A allele showed an increase in promoter activity compared with the wild-type promoter. EMSA revealed the specific binding of E2F-2 to both ECE-1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F-2 compared with -338C. The clinical relevance of this finding was analyzed in 704 hypertensive patients. In untreated hypertensive women, both the -338A and -839G alleles were significantly associated with ambulatory BP values. This study provides the first evidence of a link between the cell-cycle-associated E2F family and BP regulation via a component of the endothelin system.
    Human Molecular Genetics 03/2003; 12(4):423-33. · 7.69 Impact Factor
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    Christian Meisel, Karla Köpke, Ivar Roots
    New England Journal of Medicine 02/2003; 348(5):468-70; author reply 468-70. · 51.66 Impact Factor
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    ABSTRACT: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.
    Clinical Pharmacology &#38 Therapeutics 11/2002; 72(5):584-94. · 6.85 Impact Factor