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| HGVS representation | NC_000006.12:g.[=] |
|---|---|
| Translation Table | This haplotype is part of the set "Haplotype Set PA165980516 for HLA-B". There is a full translation table for Haplotype Set PA165980516 for HLA-B |
Any chromosomal positions listed below are assumed to be on the GRCh38 assembly. Be aware, the assembly may differ for variants elsewhere on the PharmGKB site.
| Variant Location | Allele | Reference Allele |
|---|
PharmGKB haplotype annotations provide information about haplotype-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
List of all variant annotations for HLA-B*15:02:01
There are direct annotations for this haplotype. Register or sign in to see them.
HLA-B*15:02 is strongly associated with Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients taking carbamazepine, an anticonvulsant and mood-stabilizing drug. Along with epilepsy and bipolar disorder, carbamazepine (CBZ) is also used to treat a variety of other conditions, such as schizophrenia, trigeminal neuralgia and carpal tunnel syndrome [Article:20001755]. SJS and TEN (or SJS/TEN when referencing both) are two forms of the same condition. Both involve severe mucotaneous blistering and epidermal detachment, and usually present one to three weeks after treatment begins. SJS and TEN are distinguished by the amount of skin detachment: SJS is classified as 1-10% detachment of body surface area (BSA), SJS and TEN overlap as 10-30% of BSA, and TEN as greater than 30% of BSA. Though the occurrence of these symptoms is rare (only two patients per million per year), SJS and TEN can be permanently disabling or even fatal. The mortality rate correlates with the level of skin detachment, ranging from a 1-5% mortality rate for SJS, to a 25-35% mortality rate for TEN [Articles:20536296, 19933789].
The allele frequency of *15:02 varies worldwide. Han Chinese have an average allele frequency of almost 6%, but this value can range anywhere from 1.9% to 12.4% depending on the population (http://www.allelefrequencies.net). Additionally, other Chinese populations, such as the Bulang, can have an allele frequency of close to 36% [Article:20637045]. Thai and Malaysian populations also have high allele frequencies, with average allele frequencies of close to 8%. In contrast, Koreans show a frequency of 0.3%, Japanese a frequency of 0.1%, and Caucasians a frequency of only 0.06% (http://www.allelefrequencies.net). These percentages correlate with the number and strength of studies finding significant results linking *15:02 with the development of SJS/TEN: studies in Caucasian [Articles:16981842, 23588310] and Japanese [Article:19018717] patients have been limited and have shown exclusively non-significant results. One study in Koreans found a significant association when comparing allele frequencies for SJS/TEN patients against population controls, but no significant association when comparing against carbamazapine-tolerant controls [Article:21917426]. In contrast, studies in Han Chinese are numerous and show very high odds ratios for CBZ-induced SJS/TEN [Articles:15057820, 21397523, 21424386, 22348435, 24268988, 24399721, 24322785, 24336023]. Studies in Indian [Article:19915237], Thai [Articles:18637831, 20345939, 21676164], Malaysian [Articles:21244392, 22053601] and Singaporean [Articles:24225276, 24394201] populations have also seen significant associations. These pharmacogenetic studies are summarized in Table 1 below; this table is updated as new findings come to our attention. Additionally, three meta-analyses (not included in the table below) that combined studies with Chinese, Korean, Malaysian and Thai patients, and both found odds ratios of approximately 80 for the development of CBZ-induced SJS/TEN in patients carrying the *15:02 allele [Articles:24336023, 23884208, 24897291].
There is no difference in phenotype depending on whether an individual has one or two HLA-B alleles, so most pharmacogenetic studies only consider whether an individual has the allele or not. Therefore, in this table, "prevalence" of an HLA-B allele refers to how many patients carry that allele, and not the frequency of the allele in the population.
| Table 1: Summary of carbamazepine and *15:02 pharmacogenetic studies. p-values and odds ratios (ORs) listed pertain to the risk for carbamazepine-induced Stevens-Johnson Syndrome or toxic epidermal necrolysis (SJS/TEN) in patients carrying the *15:02 allele as compared to non-carriers. p-values and ORs were calculated by comparing the frequency of *15:02 in patients who developed SJS/TEN to the frequency in carbamazepine-tolerant controls or in healthy population controls. Prevalence of *15:02 is listed for patients who developed SJS/TEN (case) and in those who were carbamazepine-tolerant (tolerant control) or from a healthy population (population control). |
| Reference | Population | *15:02 prevalence | p-value | Odds ratio (95% CI) |
|---|---|---|---|---|
| [Article:16981842] | British 1 | Case: 0/2 (0%) | ||
| Tolerant control: 0/43 (0%) | ||||
| [Article:23588310] | Canadian 2 | Case: 3/9 (33%) 3 | ||
| Tolerant control: 1/87 (1.0%) 4 | 0.002 | 38.7 (2.7 - 2240) | ||
| [Article:16415921] | European | Case: 4/12 (33%) 5 | ||
| [Article:24322785] | European | Case: 0/20 (0%) | ||
| Tolerant control: 0/43 (0%) | NS | |||
| Population control: 4/8862 (0.1%) | NS | |||
| [Article:21397523] | Han Chinese | Case: 9/9 (100%) | ||
| Tolerant control: 11/80 (13.8%) | <0.001 | 115 (6.3 - 2111) | ||
| Population control: 11/62 (17.7%) | <0.001 | 85.1 (4.6 - 1570) | ||
| [Article:21424386] | Han Chinese | Case: 16/17 (94%) | ||
| Tolerant control: 2/21 (9.5%) | <0.0001 | 152 (12 - 1835) | ||
| Population control: 17/185 (9.2%) | <0.0001 | 158 (19 - 1266) | ||
| [Article:15057820] | Han Chinese | Case: 44/44 (100%) | ||
| Tolerant control: 3/101 (3.0%) | 3.1x10 -27 | 2504 (126 - 49522) | ||
| Population control: 8/93 (8.6%) | 1.4 x 10 -21 | 895 (50 - 15869) | ||
| [Article:16538176] | Han Chinese | Case: 59/60 (98.3%) | ||
| Tolerant control: 6/144 (4.2%) | 1.6x10 -41 | 1357 (193 - 8838) | ||
| [Article:22348435] | Han Chinese | Case: 13/18 (72.2%) | ||
| Tolerant control: 12/93 (12.9%) | <0.001 | 17.6 (5.3 - 58.1) | ||
| Population control: 10/93 (10.8%) | <0.001 | 21.6 (6.4 - 73.3) | ||
| [Article:23692434] | Han Chinese | Case: 24/26 (92.3%) | ||
| Tolerant control: 16/135 (11.9%) | 3.5 x 10 -18 | 89.3 (19 - 414) | ||
| [Article:20833111] | Han Chinese | Case: 8/8 (100%) | ||
| Tolerant control: 4/50 (8.0%) | 184 (33.2 - 1021) | |||
| Population control: 6/71 (8.5%) | 173 (36 - 834.5) | |||
| [Article:24268988] | Han Chinese | Case: 99/112 (88%) | ||
| Tolerant control: 11/152 (7.0%) | 5.8 x 10 -43 | 97.6 (42 - 226) | ||
| [Article:24399721] | Han Chinese | Case: 8/35 (22.9%) | ||
| Tolerant control: 2/125 (1.6%) | 0.000 | 18.2 (3.7 - 90.7) | ||
| [Article:24322785] | Han Chinese | Case: 41/53 (77.4%) | ||
| Tolerant control: 4/72 (5.6%) | < 0.001 | 58.1 (17.6 - 192) | ||
| Population control: 60/710 (8.5%) | < 0.001 | 37.0 (18.5 - 74.2) | ||
| [Article:25305458] | Indian (North) | Case: 2/9 (22.2%) | ||
| Tolerant control: 0/37 (0%) | 0.035 | |||
| [Article:19915237] | Indian (Northwest) | Case (SJS only): 6/8 (75%) | ||
| Tolerant control: 0/10 (0%) | 0.0014 | 71.4 (3.0 - 1698) | ||
| [Article:25266342] | Indian (South) | Case: 2/5 (40%) | ||
| Tolerant control: 2/52 (3.8%) | 0.0349 | 16.7 (1.7 - 162.96) | ||
| [Article:19018717] | Japanese | Case: 0/7 (0%) | ||
| [Article:21917426] | Korean | Case: 1/7 (14.3%) | ||
| Tolerant control: 2/50 (4.0%) | NS | 23.3 (0.9 - 634) | ||
| Population control: 2/485 (0.4%) | 0.042 | 40.3 (3.2 - 506) | ||
| [Article:21244392] | Malaysian | Case: 12/16 (75%) | ||
| Population control: 47/300 (15.7%) | 7.9 x 10 -6 | 16.2 (4.6 - 62.4) | ||
| [Article:22053601] | Malaysian | Case (SJS only): 6/6 (100%) 6 | ||
| Tolerant control: 0/8 (0.0%) 7 | 0.0003 | |||
| [Article:24225276] | Singaporean 8 | Case: 5/5 (100%) 9 | ||
| Tolerant control: 1/10 (10%) 10 | 27.2 (2.67 - infinity) | |||
| [Article:24394201] | Singaporean | Case: 13/13 (100%) 11 | ||
| Tolerant control: 3/23 (13%) 12 | 6.9 x 10 -8 | 181 (8.7 - 3785) | ||
| [Article:18637831] | Thai | Case (SJS only): 6/6 (100%) | ||
| Tolerant control: 8/42 (19%) | 0.0005 | 25.5 (2.7 - 243) | ||
| [Article:20345939] | Thai | Case: 37/42 (88%) | ||
| Tolerant control: 5/42 (19%) | 2.9 x 10 -12 | 54.8 (14.6 - 205) | ||
| [Article:21676164] | Thai | Case: 32/34 (94.1%) | ||
| Tolerant control: 7/40 (17.5%) | <0.001 | 75.4 (13 - 719) | ||
Table last updated 05/21/2014
NS, non-significant; SJS, Stevens-Johnson Syndrome
1 - Caucasian only
2 - Pediatrics. Multiple ethnicities included, please refer to the paper directly for more information
3 - All three case patients with the allele were of Asian ancestry, countries unspecified
4 - The one tolerant control with the allele was of Asian ancestry, country unspecified
5 - Four patients with *15:02 were of Asian ancestry (Vietnam, China, Cambodia and Reunion Island). Remaining 8 patients without *15:02 were Caucasian (Germany, France)
6 - Four Malaysian, two Chinese
7 - Six Malaysian, two Chinese
8 - Pediatrics
9 - Three Malaysian, two Chinese
10 - Seven Chinese, two Malaysian, one Indian
11 - 10 Chinese, three Malaysian
12 - 20 Chinese, six Malaysian
Due to the low frequency in Korean, Japanese and Caucasian populations, screening for exclusively *15:02 may not be sufficient from a global perspective. Other alleles have shown significant relationships with SJS/TEN within these ethnicities, such as HLA-B*07:02 [Article:16981842] and HLA-A*31:01 [Articles:21428769, 24322785, 21149285, 24597466]. Several studies in Japanese, Korean and Han Chinese patients suggest that carriers of the HLA-B*15:11 alleles have an increased risk of developing SJS/TEN [Articles:21204807, 21917426, 22348435] . The average allele frequencies for *15:11 in Japanese and Korean populations are higher than for *15:02, with values of 0.4 - 0.8% for the Japanese, and 1.6% for Koreans (http://www.allelefrequencies.net). Both *15:02 and *15:11 are part of the same HLA-B75 serotype [Articles:21204807, 21917426], and the two alleles share a 98.6% amino acid sequence homology [Article:22348435]. Therefore, they may share similar structures that lead to the triggering of an immune reaction when carbamazepine is administered [Article:22348435]. Studies on *07:02, *31:01 and *15:11 are limited compared to those on *15:02, and research into alleles beyond *15:02 may help improve predictive genetic testing for SJS/TEN.
Unlike HLA-B*58:01, the associations between HLA-B*15:02 and carbamazepine are phenotype specific. Many of the studies mentioned above ([Articles:21397523, 23588310, 16538176, 18637831, 16981842, 22053601, 20833111, 24225276, 24268988, 24322785, 24336023]) also looked for associations with hypersensitivity syndrome (HSS), as well as maculopapular eruption (MPE). In contrast to SJS/TEN, HSS (also known as drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS)) typically has organ involvement, such as hepatitis or nephritis, in addition to fever and a severe rash [Articles:7794310, 15743917]; MPE consists of a rash containing macules and papules [Article:22909208]. None of the studies above found any association between *15:02 and carbamazepine-induced HSS or MPE, indicating that the allele may be particular to the development of SJS or TEN. One study has assessed the link between *15:11 and carbamazepine-induced HSS, and found no significant association [Article:21917426]. In contrast, HLA-A*31:01 has shown strong associations with carbamazepine-induced HSS or MPE in Caucasian [Articles:23588310, 21428769, 24322785], Han Chinese [Articles:16538176, 24322785], Japanese [Article:21149285] and Korean [Article:21917426] populations, as well as in a meta-analysis which included patients of all four aforementioned ethnicities [Article:24336023].
A 2011 study assessed the value of genotyping prior to carbamazepine treatment, with close to 4500 Taiwanese subjects of Han Chinese descent participating. The 367 patients who were found to be positive for *15:02 were told not to take the medication, while the remaining 4120 took the drug as normal. Due to ethical considerations, historical incidences of SJS/TEN were used as a control. While no cases of SJS/TEN occurred in the study, historical data estimations found that 10 cases of SJS/TEN would have likely appeared in the study cohort, a significant difference [Article:21428768]. While those of Caucasian ethnicity do tend to have lower frequencies of the *15:02 allele, genotyping prior to treatment is still valuable for these individuals, as they may be unaware of Asian ancestry, or fail to alert their doctor to their heritage. At this time, the US Food and Drug Administration (FDA) recommends genotyping for *15:02 prior to treatment with carbamazepine in all Asian populations, though does not make recommendations for patients of other ethnicities [Article:18855540]. The negative predictive value of this allele for patients in Taiwan is suggested to be 100%, and the positive predictive value 7.7% [Article:18855540]. This low positive predictive value implies that additional genetic or non-genetic factors likely play a role in the development of SJS/TEN in patients taking carbamazepine. Despite the low positive predictive value, it may be advisable to avoid the drug in *15:02-positive patients, given that there are effective alternatives to carbamazepine [Articles:18855540, 24597466]. Indeed, both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) recommend that a different agent be used if a patient is found to be a carrier of the *15:02 allele, due to a strong increased risk for SJS/TEN [Articles:23695185, 24597466].
The mechanism of CBZ-induced SJS/TEN is still unclear. In a recent study, Wei et al. found that peptide-loaded HLA-B*15:02 presented carbamazepine to cytotoxic T lymphocytes without any prior processing or drug metabolism. Only HLA-B*15:02 could bind CBZ, as opposed to HLA-B*15:01, *15:03, *40:01 or *51:01. Endogenous peptides already loaded onto the molecule were found to be required before CBZ could be presented [Article:22322005]. The authors suggested that the binding of CBZ to HLA-B*15:02 activates and induces clonal expansion of cytotoxic (CD8+) T lymphocytes, eliciting a severe immune reaction that leads to SJS or TEN [Article:22322005]. The skin reaction seen in cases of SJS or TEN are thought to be due to CD8+ T lymphocytes, which are found in abundance in skin blister cells of people with SJS/TEN, and are believed to release cytotoxic proteins that induce keratinocyte apoptosis [Articles:22322005, 19029983, 10629466]. In contrast, one of the studies that looked at the mechanism of abacavir-induced hypersensitivity reactions (see the HLA-B*57:01 VIP summary for more information) also found that CBZ binds to HLA-B*15:02, but no mention was made regarding whether loaded endogenous peptides are necessary. The authors noted that there is a repertoire shift in the peptides bound to HLA-B*15:02 in the presence of CBZ, albeit at a smaller magnitude than that of the peptides bound to *57:01 in the presence of abacavir. This change could lead to an immune reaction by the same mechanism suggested for an abacavir-induced hypersensitivity reaction [Article:22722860]. Further studies in this area should help elucidate the precise manner by which the *15:02 allele affects the development of SJS/TEN in patients taking carbamazepine.
*15:02 is also associated with SJS/TEN in people taking phenytoin, another antiepileptic. Pharmacogenetic results are presented in Table 2 below; this table is updated as new studies come to our attention. Studies linking *15:02 with SJS/TEN include four in Han Chinese patients [Articles:23692434, 20235791, 21216202, 25096692] and one in Thai patients limited to SJS cases only [Article:18637831]. Additionally, a meta-analysis of four studies found a significant association between *15:02 and phenytoin-induced SJS/TEN [Article:24897291]. Though these studies have shown statistically strong results, they have been limited in number and population size. One study in Thai children found no link between *15:02 and phenytoin-induced SCARs [Article:23551241]. Variations within the CYP2C9 gene have also shown associations with phenytoin-related adverse reactions. Phenytoin is primarily metabolized to its inactive form by CYP2C9, and alleles that result in decreased enzymatic activity, specifically CYP2C9*2 and *3, have been linked with increased phenytoin concentrations [Articles:9333104, 21068649, 14659971, 23159358] and an increased risk for neurological toxicities [Articles:20390258, 19617466] and cutaneous adverse drug reactions [Articles:25096692, 15024534]. Consideration of both HLA-B*15:02 and CYP2C9*2 and *3 may be important in any future clinical pre-treatment screening programs.
| Table 2. Summary of phenytoin and *15:02 pharmacogenetic studies. p-values and odds ratios (ORs) listed pertain to the risk for phenytoin-induced Stevens-Johnson Syndrome or toxic epidermal necrolysis (SJS/TEN) in patients carrying the *15:02 allele as compared to non-carriers. p-values and ORs were calculated by comparing the frequency of *15:02 in patients who developed SJS/TEN to the frequency in phenytoin-tolerant controls. Prevalence of *15:02 is listed for patients who developed SJS/TEN (case) and in those who were carbamazepine-tolerant (tolerant control). |
| Reference | Population | *15:02 prevalence | p-value | Odds ratio (95% CI) |
|---|---|---|---|---|
| [Article:23692434] | Han Chinese | Case (SJS/TEN): 7/15 (46.7%) | ||
| Tolerant control: 15/75 (20%) | 0.045 | 3.5 (1.1 - 11.2) | ||
| [Article:20235791] | Han Chinese | Case (SJS/TEN): 8/26 (30.8%) | ||
| Tolerant control: 9/113 (8.0%) | 0.0041 | 5.1 (1.8 - 15.1) | ||
| [Article:21216202] | Han Chinese | Case (SJS): 1/2 (50%) | ||
| Combined case (SJS/TEN) 1: 10/29 (35%) | ||||
| Tolerant control: 9/113 (8%) | 0.001 2 | 6.1 (2.2 - 17) | ||
| [Article:25305458] | Indian (North) | Case (SJS/TEN): 0/8 (0%) | ||
| Tolerant control: 0/13 (0%) | ||||
| [Article:25096692] | Taiwanese | Case (SJS/TEN): 13/48 (27.1%) | ||
| Tolerant control: 9/130 (6.9%) | 0.025 3 | 5.0 (2.0 - 13) | ||
| [Article:18637831] | Thai | Case (SJS): 4/4 (100%) | ||
| Tolerant control: 0/7 (0.0%) | 0.005 | 18.5 (1.8 - 188) | ||
| [Article:23551241] | Thai | Case (SCAR): 1/17 (5.88%) | ||
| Tolerant control: 3/17 (17.6%) | 0.35 | 0.35 (0.03 - 3.9) |
Table last updated 10/17/2014
SJS, Steven-Johnsons Syndrome; TEN, toxic epidermal necrolysis; SCAR, severe cutaneous adverse reaction
1 - Combined study results from [PMID: 17509004, 20235791, 18637831]
2 - p-value for comparison in *15:02 frequencies between tolerant controls and combined cases
3 - Bonferroni-corrected p-value
Though these studies have shown statistically strong results, they have been limited in number and population size. Additionally, one study in Thai children found no link between *15:02 and phenytoin-induced SCARs [Article:23551241]. However, the FDA does recommend that physicians consider the risks associated with SJS/TEN in patients taking phenytoin who have Asian ancestry and carry the *15:02 allele, particularly in light of the strong evidence linking *15:02 with CBZ-induced SJS/TEN [Article:19109108]. Phenytoin, carbamazepine, oxcarbazepine and lamotrigine are all known as aromatic antiepileptic drugs (AEDs) due to the presence of an aromatic ring in their structure - symptoms of hypersensitivity were found to occur twice as often in patients given aromatic AEDs as opposed to non-aromatic AEDs (e.g. levetiracetam or topiramate) [Article:17896897], suggesting that the presence of the ring may be involved in the higher risk for adverse reactions [Article:18636788]. A recent study looking at children taking carbamazepine, oxcarbazepine or phenobarbital found that those who developed SJS had a higher frequency of the *15:02 allele as compared to tolerant controls or healthy population controls [Article:24496695]. Wei et al., in their study on the mechanism by which *15:02 is associated with CBZ-induced SJS/TEN, noted that oxcarbazepine, which has a tricyclic ring structure similar to CBZ, was also capable of binding with HLA-B*15:02, though not as strongly as CBZ [Article:22322005]. However, studies linking HLA-B*15:02 with oxcarbazepine-induced SJS or MPE have shown mixed results [Articles:22818943, 23829937, 21169036, 20235791]. Though no individual studies have found significant associations between *15:02 and lamotrigine-induced adverse reactions [Articles:23692434, 20235791, 21071176, 21306565], a meta-analysis of four studies did find a significantly increased risk for SJS/TEN for patients carrying *15:02 who receive lamotrigine [Article:24897291].
| Drugs / Other Molecules | |
|---|---|
| Diseases | Epidermal Necrolysis, Toxic 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 Stevens-Johnson Syndrome 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 |