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Abstract

The authors have investigated the allele frequencies and the distribution of genotypes of the MDR1 C3435T polymorphism in a healthy Greek population (n = 100) and in patients with ulcerative colitis (N = 85) and Crohn’s disease (n = 120). In all 3 groups, the frequency of the C-allele was reported to be greater than 30%. However, no single individual with the homozygous CC3435 genotype (wild-type) was detected in the work by Gazouli et al. According to the Hardy-Weinberg equilibrium equation (p2+2pq+q2=1), which is a commonly used algebraic formula to estimate genotype frequencies in a population, their genotyping results are contradictory and therefore questionable.1Vogel F. Motulsky A.G. Hardy-Weinberg law and its applications. 3rd ed. Springer, Berlin, Heidelberg, Germany1997: 147-153Google Scholar Based on the allelic frequencies of the Greek control group, the expected frequencies of the CC, CT, and TT genotypes are 13.7%, 46.6%, and 39.7%, respectively. The C3435T polymorphism has been characterized in a number of different ethnic populations.2Schwab M. Eichelbaum M. Fromm M.F. Genetic polymorphisms of the human MDR1 drug transporter.Annu Rev Pharmacol Toxicol. 2003; 43: 285-307Crossref PubMed Scopus (273) Google Scholar Although marked differences in the genotype frequencies of this SNP are evident between the Caucasian/Asian populations and Africans, individuals with the CC genotype have been identified in all these ethnic groups. In 9 Caucasian populations from Europe, the CC3435 genotype frequency varied between 19% and 28% (Figure 1) and the observed genotype frequency distributions did not show a significant deviation from the Hardy-Weinberg equilibrium. To conclude, the distribution of the genotypes for the MDR1 C3435T polymorphism among healthy Greeks is extremely unlikely and raises grave concerns about the validity of the genotyping procedure by Gazouli et al. We agree with the authors Glas et al. that case-control studies need careful interpretation. A key factor in association studies is the patient recruitment. This includes appropriate and uniform diagnostic criteria for the disease being studied, especially if subgroup analysis involving the stage or severity of the disease will be performed. There are also many pitfalls in control recruitment. It is often convenient to use hospital staff or patients suffering from another disease as controls.3Daly A.K. Day C.P. Candidate gene case-control association studies advantages and potential pitfalls.Br J Clin Pharmacol. 2001; 52: 489-499Crossref PubMed Scopus (137) Google Scholar However, this strategy cannot be assumed to be representative of community-based controls. Therefore, we have applied appropriate precautions in our case-control study4Schwab M. Schaeffeler E. Marx C. Fromm M.F. Kaskas B. Metzler J. Stange E. Herfarth H. Schoelmerich J. Gregor M. Walker S. Cascorbi I. Roots I. Brinkmann U. Zanger U.M. Eichelbaum M. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.Gastroenterology. 2003; 124: 26-33Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar and have strictly followed the guidelines to authors of genetic association studies by Bird et al.5Bird T.D. Jarvik G.P. Wood N.W. Genetic association studies genes in search of diseases.Neurology. 2001; 57: 1153-1154Crossref PubMed Scopus (95) Google Scholar However, in the letter by Glas et al., detailed information with regard to phenotype of IBD patients is missing. In general it is not clear why the authors have used 2 different control groups. Moreover, the matching between cases and controls was not done in a ratio of 1:1. Nevertheless, the data from Glas et al. support the notion that there is an association between the MDR1 polymorphism and ulcerative colitis which appears to be an interesting issue in understanding the pathogenesis of chronic inflammatory bowel disease.