Testing association of rare genetic variants with resistance to three common antiseizure medications

被引：27

作者：

Wolking, Stefan ^{[1
,2
]}

Moreau, Claudia ^{[3
]}

Nies, Anne T. ^{[4
,5
]}

Schaeffeler, Elke ^{[4
,5
]}

McCormack, Mark ^{[6
]}

Auce, Pauls ^{[7
]}

Avbersek, Andreja ^{[8
,9
]}

Becker, Felicitas ^{[1
]}

Krenn, Martin ^{[10
]}

Moller, Rikke S. ^{[11
,12
]}

Nikanorova, Marina ^{[12
]}

Weber, Yvonne G. ^{[1
,13
]}

Weckhuysen, Sarah ^{[14
,15
,16
]}

Cavalleri, Gianpiero L. ^{[6
,17
]}

Delanty, Norman ^{[6
,18
,19
]}

Depondt, Chantal ^{[20
]}

Johnson, Michael R. ^{[17
]}

Koeleman, Bobby P. C. ^{[21
]}

Kunz, Wolfram S. ^{[22
,23
]}

Marson, Anthony G. ^{[24
]}

Sander, Josemir W. ^{[8
,9
,25
]}

Sills, Graeme J. ^{[24
]}

Striano, Pasquale ^{[26
,27
]}

Zara, Federico ^{[27
]}

Zimprich, Fritz ^{[10
]}

Schwab, Matthias ^{[4
,5
,28
]}

Krause, Roland ^{[29
]}

Sisodiya, Sanjay M. ^{[8
,9
]}

Cossette, Patrick ^{[2
]}

Girard, Simon L. ^{[3
]}

Lerche, Holger ^{[1
]}

机构：

[1] Univ Tubingen, Hertie Inst Clin Brain Res, Neurol & Epileptol, Tubingen, Germany

[2] Univ Montreal, Univ Montreal Hosp Ctr CRCHUM, Res Ctr, Dept Neurosci, Montreal, PQ, Canada

[3] Univ Quebec Chicoutimi, Dept Appl Sci, Saguenay, PQ, Canada

[4] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[5] Univ Tubingen, Tubingen, Germany

[6] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland

[7] Walton Ctr NHS Fdn Trust, Liverpool, Merseyside, England

[8] UCL Queen Sq Inst Neurol, Dept Clin & Expt Epilepsy, London, England

[9] Chalfont Ctr Epilepsy, London, England

[10] Med Univ Vienna, Dept Neurol, Vienna, Austria

[11] Danish Epilepsy Ctr Filadelfia, Dianalund, Denmark

[12] Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark

[13] Univ Aachen, Dept Epileptol & Neurol, Aachen, Germany

[14] VIB UAntwerp, Ctr Mol Neurol, Neurogenet Grp, Antwerp, Belgium

[15] Univ Antwerp, Inst Born Bunge, Lab Neurogenet, Antwerp, Belgium

[16] Antwerp Univ Hosp, Dept Neurol, Antwerp, Belgium

[17] Imperial Coll Fac Med, Div Brain Sci, London, England

[18] Beaumont Hosp, Div Neurol, Dublin, Ireland

[19] Royal Coll Surgeons Ireland, FutureNeuro Res Ctr, Dublin, Ireland

[20] Univ Libre Bruxelles, Dept Neurol, Hop Erasme, Brussels, Belgium

[21] Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands

[22] Univ Bonn, Inst Expt Epileptol & Cognit Res, Bonn, Germany

[23] Univ Bonn, Dept Epileptol, Bonn, Germany

[24] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England

[25] SEIN, Heemstede, Netherlands

[26] IRCCS G Gaslini Inst, Genoa, Italy

[27] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy

[28] Univ Tubingen, Dept Clin Pharmacol Pharm & Biochem, Tubingen, Germany

[29] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg

来源：

EPILEPSIA | 2020年 / 61卷 / 04期

基金：

英国医学研究理事会; 欧盟地平线“2020”;

关键词：

burden analysis; lamotrigine; levetiracetam; pharmacogenomics; rare variants; valproic acid; VALPROIC ACID; ANTIEPILEPTIC DRUGS; ILAE COMMISSION; EPILEPSY; SV2A; HYPOTHESIS; PHARMACORESISTANCE; LAMOTRIGINE; EXPRESSION; MICROSOMES;

D O I：

10.1111/epi.16467

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

引用

页码：657 / 666

页数：10

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