Study to assess the prevalence of human leukocyte antigen-A*3101 allele among Indian epileptic patients and its influence on safety and efficacy of antiepileptic therapy
Keywords:Human leukocyte antigen-A*3101, Carbamazepine, Rashes, Genotyping
Background: The objective was to study the prevalence of human leukocyte antigen (HLA)-A*3101 allele among epileptic patients and to assess the safety and efficacy of antiepileptic therapy.
Methods: 295 subjects were selected and divided into two groups, Group I had 192 epileptic patients and Group II had 103 normal healthy controls. After written informed consent, 30 ml of mouthwash sample was collected from each subject and DNA was extracted by standard salting-out technique and used for HLA-A*3101 genotyping by two-step nested allele-specific polymerase chain reaction amplification and agarose gel electrophoresis.
Results: In Group I, 12 (6.25%) of the 192 patients were tested positive for HLA-A*3101 allele and all were taking carbamazepine (CBZ). Among them, 56 (30%) subjects had developed less severe adverse effects such as headache and giddiness, skin rashes and memory disturbances, and HLA-A*3101 was present in 8 of them while 136 had no adverse effects in which 4 of them were tested positive for the allele. In Group II, 3 (2.9%) of the 103 healthy controls were tested positive for the allele. No difference was found in response to antiepileptic therapy between allele positive and negative patients.
Conclusion: The present study had shown that HLA-A*3101 is prevalent in 6.25% of the Indian epileptic population under study. The presence of this allele has a significant association with the development of mild cutaneous reactions like skin rashes. However, no difference was observed in allele positive patients in response to antiepileptic therapy in comparison with allele negative patients.
Preventable Adverse Drug Reactions: a Focus on Drug Interactions. Available at http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm110632.htm#ADRs:%20Prevalence%20and%20Incidence. Accessed 13 October 2014.
Notes on Clinical Pharmacology: classification of Adverse Drug Reactions. http://www.edusanjalpharmacology.blogspot.in/2012/12/classification-of-adverse-drug-reactions.html. Accessed 13 October 2014.
Wei CY, Ko TM, Shen CY, Chen YT. A recent update of pharmacogenomics in drug-induced severe skin reactions. Drug Metab Pharmacokinet. 2012;27(1):132-41.
Verma R, Vasudevan B, Pragasam V. Severe cutaneous adverse drug reactions. Med J Armed Forces India. 2013;69(4):375-83.
Nayak S, Acharjya B. Adverse cutaneous drug reaction. Indian J Dermatol. 2008;53(1):2-8.
Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64(7):1134-8.
Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine – the commonest cause of toxic epidermal necrolysis and Stevens-Johnson syndrome: a study of 7 years. Indian J Dermatol Venereol Leprol. 2005;71(5):325-8.
Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: clinical pattern and causative agents – a 6 year series from Chandigarh, India. J Postgrad Med. 2001;47(2):95-9.
Kamaliah MD, Zainal D, Mokhtar N, Nazmi N. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in northeastern Malaysia. Int J Dermatol. 1998;37(7):520-3.
Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.
Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16(4):297-306.
Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia. 2007;48:1015-8.
Wu XT, Hu FY, An DM, Yan B, Jiang X, Kwan P, et al. Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China. Epilepsy Behav. 2010;19(3):405-8.
Liao WP, Shi YW, Cheng SH, Kwan P. Association between HLA-B*1502 allele and cutaneous reactions induced by carbamazepine or lamotrigine in Han Chinese. Epilepsia. 2009;50:252-3.
Zhang Y, Wang J, Zhao LM, Peng W, Shen GQ, Xue L, et al. Strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in mainland Han Chinese patients. Eur J Clin Pharmacol. 2011;67(9):885-7.
Wang Q, Zhou JQ, Zhou LM, Chen ZY, Fang ZY, Chen SD, et al. Association between HLA-B*1502 allele and carbamazepine-induced severe cutaneous adverse reactions in Han people of southern China mainland. Seizure. 2011;20:446-8.
Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008;49(12):2087-91.
Tassaneeyakul W, Tiamkao S, Jantararoungtong T, Chen P, Lin SY, Chen WH, et al. Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia. 2010;51(5):926-30.
Kulkantrakorn K, Tassaneeyakul W, Tiamkao S, Jantararoungtong T, Prabmechai N, Vannaprasaht S, et al. HLA-B*1502 strongly predicts carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Thai patients with neuropathic pain. Pain Pract. 2012;12(3):202-8.
Chang CC, Too CL, Murad S, Hussein SH. Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population. Int J Dermatol. 2011;50(2):221-4.
Then SM, Rani ZZ, Raymond AA, Ratnaningrum S, Jamal R. Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients. Asian Pac J Allergy Immunol. 2011;29(3):290-3.
Mehta TY, Prajapati LM, Mittal B, Joshi CG, Sheth JJ, Patel DB, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol. 2009;75(6):579-82.
Rajappa S, Venkatesan S. Prevalence of HLA-B*1502 allele in South Indian epileptic and non epileptic population. J Am Acad Neurol. 2012;78(meeting abstracts 1):s26-005. [Cited 2012 April 25].
Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia. 2010;51(12):2461-5.
Lonjou C, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. RegiSCAR Group. A marker for Stevens-Johnson syndrome: ethnicity matters. Pharmacogenomics J. 2006;6:265-8.
Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics. 2006;7(6):813-8.
Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet. 2011;20(5):1034-41.
Kashiwagi M, Aihara M, Takahashi Y, Yamazaki E, Yamane Y, Song Y, et al. Human leukocyte antigen genotypes in carbamazepine-induced severe cutaneous adverse drug response in Japanese patients. J Dermatol. 2008;35(10):683-5.
Niihara H, Kakamu T, Fujita Y, Kaneko S, Morita E. HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population. J Dermatol. 2012;39(7):594-601.
McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134-43.
Kim SH, Lee KW, Song WJ, Kim SH, Jee YK, Lee SM, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res. 2011;97(1-2):190-7.
Amstutz U, Ross CJ, Castro-Pastrana LI, Rieder MJ, Shear NH, Hayden MR, et al. HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin Pharmacol Ther. 2013;94(1):142-9.
McCormack M, Urban TJ, Shianna KV, Walley N, Pandolfo M, Depondt C, et al. Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012;13(4):399-405.
Shankarkumar U, Sridharan B, Pitchappan RM. HLA diversity among Nadars, a primitive Dravidian caste of South India. Tissue Antigens. 2003;62(6):542-7.
Rajasekar R, Kakkanaiah VN, Pitchappan RM. HLA antigens in South India: II. Selected caste groups of Tamil Nadu. Tissue Antigens. 1987;30:113-8.
Balakrishnan K, Pitchappan RM, Suzuki K, Kumar US, Santhakumari R, Tokunaga K. HLA affinities of Iyers, a Brahmin population of Tamil Nadu, South India. Hum Biol. 1996;68:523-37.
Shankarkumar U. HLA A19 subtypes and B loci related haplotype in selected caste groups from the Indian population. Indian J Human Genet. 2003;9(1):13-6.