Note: p-Values are for allele frequency differences between cases and controls in this study.
Association Analysis of BRD2 (RING3) and Epilepsy in a Dutch Population
Article first published online: 12 NOV 2007
Volume 48, Issue 11, pages 2191–2192, November 2007
How to Cite
De Kovel, C. G.F., Pinto, D., De Haan, G. J., Trenité, D. G. K.-N., Lindhout, D. and Koeleman, B. P.C. (2007), Association Analysis of BRD2 (RING3) and Epilepsy in a Dutch Population. Epilepsia, 48: 2191–2192. doi: 10.1111/j.1528-1167.2007.01306.x
- Issue published online: 12 NOV 2007
- Article first published online: 12 NOV 2007
To the Editors:
The region between HLA-DQ and HLA-DP on 6p21 shows linkage to various syndromes within the idiopathic generalized epilepsy (IGE) spectrum, in particular to juvenile myoclonic epilepsy (JME) and visually sensitive syndromes (Greenberg et al., 1988; Durner et al., 1991; Weissbecker et al., 1991; Sander et al., 1997; Greenberg et al., 2000). Within this region, the gene BRD2 (bromodomain containing 2) is a good positional candidate and three association studies using markers in BRD2 have been published to date. The first is a study from the United States, which reported association with familial JME in patients of uncertain ethnic origin (Greenberg et al., 2000). The second study reported association between markers in the BRD2 region and photoparoxysmal response (PPR) in German individuals, 59% of whom also had IGE. However, for SNPs that were typed in both studies, the associated alleles were alternative ones. A multicenter study subsequently typed an SNP (rs3918149) in the promoter that had been reported in the American study, in JME patients from five European populations and found significant association in Irish and British patients, but not in Germans (Cavalleri et al., 2007).
We have further investigated the SNP markers (rs188254, rs206781, and rs516535) in the 3′-end of the BRD2 gene that showed the strongest association in the study with German individuals presenting with PPR. The SNPs were typed in a Dutch sample comprising 159 individuals with IGE, of whom 102 had JME and in 360 unrelated blood bank controls. For 33 patients, PPR or photo-sensitive epilepsy (PSE) was established, 71 were tested but were negative, while there was no information about visual sensitivity for 55 patients. Taqman assays (Applied Biosystems, Foster City, CA, U.S.A.) were available for all three SNPs (assay ID C_1024346_20, C_1024338_10, C_1024346_20), and the analysis was carried out according to the manufacturer's specifications.
We found no significant difference between the allele frequencies in cases and controls for either of the markers (p-values >0.05; Table 1). For comparison, we have included the results from the previous two studies with those SNPs. In Table 2, the analysis is split into individuals with and without JME. Again, no significant differences were found.
|SNP||Pala (2003)||Lorenzb (2006)||This study||p-Value, this study|
|Cases (20)||Controls (n.a.)||Cases (187)||Controls (666)||Cases (159)||Controls (360)|
|SNP||IGE/ not JME||JME||Total no. of cases (%)||Controls (%)||p (case– control)|
|CC||21||33||54 (37)||130 (41)||0.63|
|CT||28||39||67 (46)||133 (42)|
|TT||10||16||26 (18)||51 (16)|
|GG||13||15||28 (19)||66 (20)||0.88|
|GA||21||44||65 (43)||135 (42)|
|AA||26||32||58 (38)||121 (38)|
|AA||19||26||45 (31)||85 (26)||0.57|
|GA||24||37||61 (42)||145 (44)|
|GG||15||25||40 (27)||96 (29)|
Power to detect association at the level of α= 0.01 in this study was around 55% if genotype relative risks were 2.0 in a dominant model. Had the risk been as high as 6, as reported by Pal et al. (2003) for their multilocus haplotype, the power would have been well above 90%. If a mutation in BRD2 or its surrounding genes specifically causes PPR or epilepsy with PPR, this may have underpowered our study relative to samples consisting solely of JME patients—who have PPR more often—or of individuals selected for PPR. Our study, therefore, does not contradict the earlier findings, but neither can it support the hypothesis that BRD2 or another gene in its neighborhood is involved in IGE or JME.
In summary, association between JME or PPR and the 3′ end of BRD2 has been found with alternative alleles in different studies, and some populations have shown association with the promoter region, which is in low linkage disequilibrium with the 3′ end. Replication for both regions failed in some samples. Together, these results suggest the BRD2 region is involved in JME, or possibly in visual sensitivity, but they are still inconclusive about which gene and what phenotype.
We are grateful to all the people who participated in this study.
C.d.K. and B.K. are supported by The Netherlands Organisation for Health Research and Development (ZonMW), Vidi grant number: 917.66.315; D.T. is supported by FP6 with a Marie Curie Chair. The work was also supported by grant no. 04-08 from the Dutch Nationaal Epilepsie Fonds to B.K. D.P. has a Ter Meulen Fund fellowship 2007/TMF/DA/, and a Netherlands Organization for Scientific Research (NWO) Rubicon fellowship 2007/02470/ALW.
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