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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.

Table 1.  Comparison of allele frequencies in cases and controls in two published studies and this study
SNPPala (2003)Lorenzb (2006)This study p-Value, this study
  1. Note: p-Values are for allele frequency differences between cases and controls in this study.

  2. cn.t., not tested.

 Cases (20)Controls (n.a.)Cases (187)Controls (666)Cases (159)Controls (360) 
rs516535_C0.480.310.370.440.400.370.37
rs206781_T0.700.650.560.630.600.580.68
rs188245_Gn.t.cn.t.0.530.460.480.520.33
Table 2.  Comparison of genotype frequencies in different phenotypes (with percentages)
SNPIGE/ not JMEJMETotal no. of cases (%)Controls (%)p (case– control)
  1. Note: p-Values are given for genotype frequency comparisons between all cases and controls.

rs516535
CC213354 (37)130 (41)0.63
CT283967 (46)133 (42) 
TT101626 (18) 51 (16) 
rs206781
GG131528 (19) 66 (20)0.88
GA214465 (43)135 (42) 
AA263258 (38)121 (38) 
rs188245
AA192645 (31) 85 (26)0.57
GA243761 (42)145 (44) 
GG152540 (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.

References

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  2. References
  • Cavalleri GL, Walley NM, Soranzo N, Mulley J, Doherty CP, Kapoor A, Depondt C, Lynch JM, Scheffer IE, Heils A, Gehrmann A, Kinirons P, Gandhi S, Satishchandra P, Wood NW, Anand A, Sander T, Berkovic SF, Delanty N, Goldstein DB, Sisodiya SM. (2007) A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy. Epilepsia 48:706712.
  • Durner M, Sander T, Greenberg DA, Johnson K, Beckmannagetta G, Janz D. (1991) Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 41:16511655.
  • Greenberg DA, Delgadoescueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado HM, Park MS, Terasaki PI. (1988) Juvenile myoclonic epilepsy (JME) may be linked to the Bf and Hla loci on human chromosome-6. Am J Med Genet 31:185192.
  • Greenberg DA, Durner M, Keddache M, Shinnar S, Resor SR, Moshe SL, Rosenbaum D, Cohen J, Harden C, Kang H, Wallace S, Luciano D, Ballaban-Gil K, Tomasini L, Zhou GL, Klotz I, Dicker E. (2000) Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet 66:508516.
  • Lorenz S, Taylor KP, Gehrmann A, Becker T, Muhle H, Gresch M, Tauer U, Sander T, Stephani U. (2006) Association of BRDZ pdymorphisms with photoparoxysmal response. Neurosci Lett 400:135139.
  • Pal DK, Evgrafov OV, Tabares P, Zhang FL, Durner M, Greenberg DA. (2003) BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet 73:261270.
  • Sander T, Bockenkamp B, Hildmann T, Blasczyk R, Kretz R, Wienker TF, Volz A, Schmitz B, Beck-Mannagetta G, Riess O, Epplen JT, Janz D, Ziegler A. (1997) Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology 49:842847.
  • Weissbecker KA, Durner M, Janz D, Scaramelli A, Sparkes RS, Spence MA. (1991) Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. Am J Med Genet 38:3236.