Genetic variation in
            <i>CFH</i>
            predicts phenytoin-induced maculopapular exanthema in European-descent patients

McCormack, Mark; Gui, Hongsheng; Ingason, Andrés; Speed, Doug; Wright, Galen E.B.; Zhang, Eunice J.; Secolin, Rodrigo; Yasuda, Clarissa Lin; Kwok, Maxwell; Wolking, Stefan; Becker, Felicitas; Rau, Sarah; Avberšek, Andreja; Heggeli, Kristin; Leu, Costin; Depondt, Chantal; Sills, Graeme J.; Marson, Anthony G; Auce, Pauls; Brodie, Martin J.; Francis, Ben; Johnson, Michael R.; Koeleman, Bobby P. C.; Striano, Pasquale; Coppola, Giangennaro; Zara, Federico; Kunz, Wolfram S.; Sander, Josemir W.; Lerche, Holger; Klein, Karl Martin; Weckhuysen, Sarah; Krenn, Martin; Gudmundsson, Larus J.; Stefánsson, Kári; Krause, Roland; Shear, Neil H.; Ross, Colin J.D.; Delanty, Norman; Pirmohamed, Munir; Carleton, Bruce; Cendes, Fernando; Lopes‐Cendes, Íscia; Liao, Wei‐Ping; O’Brien, Terence J.; Sisodiya, Sanjay M.; Cherny, Stacey S.; Kwan, Patrick; Baum, Larry; Cavalleri, Gianpiero L.

doi:10.1212/wnl.0000000000004853

Cited by 36 publications

(34 citation statements)

References 25 publications

(28 reference statements)

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“…For example, Olivar et al (2016) reported that Factor H pretreatment diminished T H 1 cell production of interferon (IFN)-c that is central to LPS-mediated stimulation of dendritic cells during this pathology. Further, genetic variations in Factor H was found among Europeans with phenytoin-induced MPE (McCormack et al 2018). Those authors concluded that this unique change made Factor H a potential useful prognostic marker for MPE.…”

Section: Discussionmentioning

confidence: 91%

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

Wang

Huang

et al. 2019

Journal of Immunotoxicology

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2020) Altered levels of complement components associated with nonimmediate drug hypersensitivity reactionsABSTRACT Nonimmediate drug hypersensitivity reactions (niDHRs) range from mild-type maculopapular exanthema (MPE) to severe type Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with unentirely clarified pathogenesis. This study sought to explore whether complement components participated in niDHRs. The participants comprised of three groups as follows: MPE (n ¼ 65), SJS/TEN (n ¼ 13, contains 7 SJS, 2 SJS-TEN overlap and 4 TEN), and equal healthy controls (n ¼ 78). Skin pathological changes were confirmed by hematoxylin and eosin staining. The mRNA and protein levels of complement components were assessed. In the MPE group, there were no alterations in complement components at the protein and mRNA levels found except for a decrease in factor H mRNA. In the SJS/TEN group, up-regulated levels of C3aR and C5aR mRNA and down-regulated factor H mRNA levels in blood were noted. A lower plasma protein level of C3, Factor H and a higher level of C3a, C5, C5a, C5b-9, Factor B (p < 0.05) were found in the SJS/TEN group compared with in the control (p < 0.05). In SJS/TEN skin lesions, indirect immunofluorescence assays showed positive specific staining for C5b-9, but not C3. Both C3aR and C5aR were positive staining in the SJS/TEN samples, while staining for C1q, mannose-binding lectin (MBL), Factor B, and Factor H were only weak or negative. The findings reported here are the first to define the expression profiles/extent of the presence of various complement components at the mRNA and protein levels in niDHRs, especially in SJS/TEN. These altered complement components might, at least in part, be integral to the mechanisms underlying the pathogeneses of SJS and TEN. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 91%

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

Wang

Huang

et al. 2019

Journal of Immunotoxicology

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“…For both lamotrigine-and phenytoin-induced MPE the HLA-B*15:02 frequency was not reported in either population. 19 Several alternate cohort studies also failed to demonstrate a HLA-B*15:02 association with carbamazepine-induced MPE (Singaporean, 45 Han Chinese 23,26,28,31,32 and Thai 34 ). This finding also extended to other AEDs including oxcarbazepine (Han Chinese, 54 Note.…”

Section: Aed-induced Mpe and Hla-b*15:02mentioning

confidence: 99%

HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

Mullan

Anderson

Illing

et al. 2019

HLA

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Adverse drug reactions (ADRs) are a common cause of hospital admissions (up to 19%), with the majority of cases due to off‐target predictable drug effects (type A reactions). However, idiosyncratic drug‐induced immune activated (type B) reactions contribute to a range of hypersensitivity reactions, with T‐cell‐mediated type IV hypersensitivity reactions mainly manifesting as cutaneous ADRs (cADRs). Aromatic antiepileptic drugs (AEDs), used in the treatment of epilepsy as well as bipolar disorder or neuropathic pain, have been implicated as culprit drugs in a spectrum of pathologies ranging from mild maculopapular exanthema (MPE) to severe and life‐threatening conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These AED‐induced cADRs are unpredictable based on pharmacological and clinical factors alone, thereby prompting investigations into genomic contributors mediating risk of pathology. The most strongly associated risk genes identified are from the human leukocyte antigen (HLA) class I alleles, which play a critical role in adaptive immunity by flagging either infected or aberrant cells for recognition by surveying T‐cells. In the setting of drug hypersensitivity, the immunogenicity of HLA molecules and their peptide cargo can be modulated by interactions with small drug molecules that drive inappropriate T‐cell responses. This review discusses the current understanding of HLA class I molecules in modifying risk of AED‐induced cADRs.

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“…Genotyping quality control was performed as described previously. 10 Principal components analysis (PCA) was performed with European-ancestral samples from the HapMap Project to assess cohort substructure and identify population outliers ( Figure S1). Eigenvectors were computed in the genome-wide complex trait analysis tool (GCTA) for each subject for inclusion as covariates in genetic-association testing.…”

Section: Sampling and Genotype Analysismentioning

confidence: 99%

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

et al. 2019

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Summary Objective To ascertain the clinical and genetic factors contributing to carbamazepine‐ and oxcarbazepine‐induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy. Methods We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ‐diol to unchanged drug precursor substrate as measured in serum. Results Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome‐wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome‐wide significant associations with CBZ metabolic ratio were found. Significance Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

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Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Cited by 36 publications

References 25 publications

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

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