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BRIEF COMMUNICATIONS: O. H. Kantarci, D. D. Hebrink, S. J. Achenbach, S. J. Pittock, A. Altintas, J. L. Schaefer-Klein, E. J. Atkinson, M. de Andrade, C. T. McMurray, M. Rodriguez, and B. G. Weinshenker Association of APOE polymorphisms with disease severity in MS is limited to women Neurology 2004; 62: 811-814 [Abstract] [Full text] [PDF]

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Reply to Zwemmer et al

Brian G. Weinshenker, Orhun H. Kantarci   (6 April 2004)

Association of APOE polymorphisms with disease severity in MS is limited to women

Jack Zwemmer, Bernard Uitdehaag, Gerard van Kamp, Frederik Barkhof, Chris Polman   (6 April 2004)

Reply to Zwemmer et al 6 April 2004
Brian G. Weinshenker, Mayo Clinic College of Medicine 200 First St SW, Rochester MN 55905, Orhun H. Kantarci Send Correspondence to journal: Re: Reply to Zwemmer et al weinb{at}mayo.edu Brian G. Weinshenker, et al.	We thank Zwemmer et al for for comparing their results with our own. There are many reasons why our studies may have shown different results, many of which were detailed in our discussion. Unfortunately, we do not have access to the details of their study, which is not yet published. [1] Nevertheless, differences between the two study populations may contribute to the discrepancy. We studied a population-based sample of patients with nearly complete ascertainment. [2] As we discussed, our population includes a relatively high proportion of benign cases compared to clinic-based populations, which we assume that the population of Zwemmer et al represents. The proportion of primary progressive cases in Zwemmer's study is significantly higher than in our study (22% versus 6.4%), likley reflecting the tertiary-referral nature of their practice. We agree that the effects of APOE genotype on the course of MS remain controversial. However, our results are consistent with those of Schmidt et al who have demonstrated a favorable effect of the e2 allele in an independent study of familial MS patients. [3] Patients in that study were ascertained due to their relationship to index cases and no bias expected in favor of benign or severe cases of MS. We speculate that this may have contributed to the agreement in our results. Another potential reason for discrepancy may be due to differential distribution of genotypes between populations. The effect of APOE isoforms is known to be bipolar where e2 and e4 alleles have opposing effects. Thus, e2e4 genotypes may have a more neutral effect than e2e3 and e2e2 homozygotes. The latter genotype is rare. Hence, a different ratio of e2e4 versus e2e3 genotypes could prevent a favorable effect of the e2 allele from being detected. As is the nature of complex genetic diseases, replication of candidate association analysis has been difficult in MS. [4] However, well- characterized population-based samples of patients may help overcome some of the problems inherent in ascertainment bias in studies of the effects of genotype on the course of MS. We agree with the caveat raised by Zwemmer et al in generalizing results from one population to another. Formal metanalysis or larger studies may help resolve inconsistencies in some situations; however, different population backgrounds can dilute an effect that would otherwise be significant for a given population. References 1. Zwemmer JNP, van Veen T, van Winsen L, et al. No major association of APOE genotype with disease characteristics and MRI findings in multiple sclerosis. Mult Scler 2004, in press. 2. Kantarci OH, Hebrink DD, Achenbach SJ, et al. Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 2004;62:811-814. 3. Schmidt S, Barcellos LF, DeSombre K, et al. Multiple Sclerosis Genetics Group. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002;70:708–717. 4. Kantarci OH, de Andrade M, Weinshenker BG. Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002; 123: 144-159.
Association of APOE polymorphisms with disease severity in MS is limited to women 6 April 2004
Jack Zwemmer, Dept. of Neurology, VU Medical Center Postbox 7057, 1007 MB Amsterdam, The Netherlands, Bernard Uitdehaag, Gerard van Kamp, Frederik Barkhof, Chris Polman Send Correspondence to journal: Re: Association of APOE polymorphisms with disease severity in MS is limited to women jnp.zwemmer{at}vumc.nl Jack Zwemmer, et al.	We read the article by Kantarci et al with great interest. It examined the gender specific association of APOE polymorphisms with disease severity in MS.[1] Gender specificity is important and has not been previously addressed. We recently analyzed and described APOE polymorphisms in relation to MS susceptibility, disease characteristics (including age at onset and onset type), disease severity (progression index, time to reach EDSS 6) and MRI findings (lesion volumes and atrophy measures) in a cohort of 408 MS patients, but did not focus on gender specificity.[2] In an attempt to validate the findings by Kantarci et al, we re-analyzed our data applying similar methods. Our cohort included 250 women and 158 men, mean age at onset (± SD) 32.3 ± 9.5 years, mean disease duration 13.4 ± 8.0 years, median time to EDSS 6 9.2 (IQR 5.4 - 14.0) years, and 39% RR, 39% SP and 22% PP. Genotype and carrier frequencies were not significantly different between genders but they did contain a smaller percentage of epsilon 2 carriers (16.4%) compared to the cohort of Kantarci et al and the absolute number was larger. After stratification for gender, no favorable role for epsilon 2 carriership was found in women. In fact, a trend in the opposite direction was found: time to EDSS 6 in women was shorter in epsilon 2 carriers than in non-carriers (median (IQR): 6.8 (3.7 - 9.3) vs. 10.0 (5.8 - 12.9) years, p=0.10). This unfavorable association of epsilon 2 carriership was supported by MRI measures in partially overlapping subgroups for which repeated T2 (n=174) and T1 lesion loads (n=109) were available. Compared to non-carriers, female epsilon 2 carriers had a significantly higher relative increase in T2 (p=0.02) and T1 (p=0.03) lesion loads (linear regression with correction for age, onset type, disease duration and IFN- therapy). In men, no significant differences were found between epsilon 2 carriers and non-carriers. In conclusion, we were unable to confirm the findings by Kantarci et al that in women epsilon 2 carriership is associated with a more favorable disease course. In contrast, by applying likewise analysis we found a trend in the opposite direction. The findings from these two studies can be added to an increasing pool of controversial results regarding the association of APOE polymorphisms and MS. Larger studies or meta-analyses of existing data are necessary and caution should be taken when interpreting results regarding the association of the APOE polymorphism and MS, also with respect to gender specificity. References 1. Kantarci OH, Hebrink DD, Achenbach SJ, et al. Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 2004;62:811-814. 2. Zwemmer JNP, van Veen T, van Winsen L, et al. No major association of ApoE genotype with disease characteristics and MRI findings in multiple sclerosis. Mult Scler 2004; in press.