HLA-A & HLA-B

Human Leukocyte Antigen, Class I, A & B

מידע לרופאים ואנשי מקצוע

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HLA-A & HLA-B

Human Leukocyte Antigen, Class I, A & B

קבוצה:       גנים פרמקודינמיים

תפקיד פזיולוגי:    אנטיגנים אימונולוגיים

גנוטיפים:   HLA-A*31:01 – סיכון לתופעות לוואי עוריות חמורות בחשיפה ל- carbamazepine
HLA-B*15:02 סיכון לתופעות לוואי עוריות חמורות בחשיפה ל carbamazepine, oxcarbazepine, phenytoin, fosphenytoin and possibly lamotrigine, phenobarbital and eslicarbazepine

תרופות:     נוגדי פרכוסים

קליניקה:    בחולים עם אחד מהגנוטיפים המצוינים אין לרשום תרופות מהרשימה הנ"ל

דירוג רמת הראיות  LOE:    1A

HLA-A & HLA-B אנטיגנים לויקוציטים אנושיים (Human Leukocyte Antigen) הם קבוצה של גנים המקודדת חלבונים הנמצאים על פני רוב התאים הגרעיניים ואחראים על ויסות מערכת החיסון. סוג הגנים של HLA-1 כולל HLA-A, HLA-B ו- HLA-C ומקודד את השרשראות הכבדות של מולקולות המציגות אנטיגן מסוג I. גנים אלה הם פולימורפיים ביותר ומקודדים לחלבונים הקושרים ומציגים אנטיגנים לתאי החיסון.144

גנוטיפים שונים שינויים ספציפיים בגן זה נקשרו לתגובה שלילית לטגרטול (Carbamazepine, קרבמזפין), כמו גם לאוקסקרבזפין, פניטואין / פוספניטואין, ואולי גם ללמוטריג'ין ונוגדי פרכוסים ארומטיים אחרים (אסליקארבזפין, פנוברביטל).

טגרטול תסמונת סטיבנס-ג'ונסון (SJS) ונקרוליזה רעילה של האפידרמיס (TEN) SJS ו- TEN הם מצבים מסכני חיים המאופיינים בנגעים נרחבים על פני העור. בשל חומרת ה- SJS / TEN המושרה על ידי קרבמזפין, ה- FDA ביצע שינויים התוויתיים בתרופה זו, בנוסף הציע לערוך בדיקה גנטית לחולים ממוצא אסייתי לפני תחילת הטיפול בקרבמזפין [155].

HLA-A*31:01 HLA-A * 31: 01 קשורה לסיכון לפתח תסמונת סטיבנס-ג'ונסון (SJS) ולנקרוליזה רעילה של האפידרמיס (TEN), בעיקר בחולים ממוצא אסייתי בעת נטילת קרבמזפין. HLA-A * 31: 01 נקשר מאוד רק ל- SJS ו- TEN המושרה על ידי קרבמזפין. [145-149] בקונסורציום יישום הפרמקוגנטיקה הקלינית (CPIC) יש גם הנחיות לרישום ל- HLA-A * 31: 01, הכוללות קרבמזפין, אוקסקרבזפין ונוגדי פרכוסים ארומטיים אחרים. [147]

 

HLA-B*15:02 HLA-B * 15: 02 קשורה לסיכון לפתח תסמונת סטיבנס-ג'ונסון (SJS) ולנקרוליזה רעילה של האפידרמיס (TEN), בעיקר בחולים ממוצא אסייתי בעת נטילת קרבמזפין. HLA-B * 15: 02 מגביר את הסיכון להפרעות SJS ו-TEN עם קרבמזפין, אוקסקרבזפין, פניטואין ואולי גם נוגדי פרכוסים ארומטיים אחרים. [146, 147, 150-154]. בקונסורציום יישום הפרמקוגנטיקה הקלינית (CPIC) יש גם הנחיות לרישום ל- HLA-B * 15: 02, הכוללות קרבמזפין, אוקסקרבזפין ונוגדי פרכוסים ארומטיים אחרים. [147]

ג'נומיינד (Genomind) היא הבדיקה הפרמקוגנטית (PGx) המתקדמת ביותר בפסיכיאטריה. היא בודקת 24 גנים, הקשורים לפירוק תרופות. קבלת תשובת הבדיקה בתוך 10 ימים מנטילת דגימת הרוק, בצורת דו"ח מעמיק ונוח לקריאה. הדו"ח מכיל מידע פרמקוגנטי על יותר מ-130 תכשירים פסיכיאטריים, והתאמתם הגנטית לנבדק. מחקרים שנערכו על הבדיקה הוכיחו את יתרונותיה בקיצור הזמן להשגת אפקט טיפולי ושיפור הההיענות לטיפול.

References

144. Choo, S.Y., The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J, 2007. 48(1): p. 11-23.

145. Mushiroda, T., et al., Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine- Induced Cutaneous Adverse Reactions in a Japanese Population. JAMA Neurol, 2018.

146. Zhang, J., et al., Association between HLA gene polymorphism and cutaneous adverse reactions caused by antiepileptic drugs. Exp Ther Med, 2018. 15(4): p. 3399-3403.

147. Phillips, E.J., et al., Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther, 2018. 103(4): p. 574-581.

148. McCormack, M., et al., Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology, 2018. 90(4): p. e332-e341.

149. Ksouda, K., et al., HLA-A*31:01 and carbamazepine-induced DRESS syndrom in a sample of North African population. Seizure, 2017. 53: p. 42-46.

150. Chouchi, M., et al., The HLA-B*15:02 polymorphism and Tegretol((R))-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis. Rev Neurol (Paris), 2018.  174(5): p. 278-291.

151. Liu, Y., et al., Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a meta-analysis. Pharmacogenomics, 2018. 19(6): p. 547-552.

152. Sukasem, C., et al., Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients. J Immunol Res, 2018. 2018: p. 2780272.

153. Koomdee, N., et al., Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population. Front Pharmacol, 2017. 8: p. 879.

154. Yuliwulandari, R., et al., Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype. Pharmacogenomics, 2017. 18(18): p. 1643-1648.

155. Ferrell, P.B., Jr. and H.L. McLeod, Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics, 2008. 9(10): p. 1543-6.

 

Adverse Reactions in a Japanese Population.

https://www.ncbi.nlm.nih.gov/pubmed/29610831 [145]

“Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLAA* 31:01 and alternative drugs for those who tested positive for HLA-A*31:01…Of the 1130 included

patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0- 95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert

dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients,

maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis.

Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for

the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001).” [145]

Association between HLA gene polymorphism and cutaneous adverse reactions caused by antiepileptic drugs.

https://www.ncbi.nlm.nih.gov/pubmed/29545861 [146]

“Through the case-control study, 30 child patients with AED-induced cADRs (cADRs group), 60 AED tolerant child patients (AED-tolerant group) and 60 normal children not taking AEDs (normal group)

were collected. The HLA-B*15:02 and HLA-A*31:01 genotypes were detected using the polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) probe method, and the correlation of HLAB* 15:02 and HLA-A*31:01 genes with the incidence of cADRs was analyzed. The positive rate of HLAB* 15:02 gene was 83.33% in the cADRs group, which was significantly increased compared with that in the AED-tolerant and normal groups (P<0.01). The positive rate of HLA-A*31:01 gene was 63.33% in the cADRs group, which was obviously increased compared with that in the AED-tolerant and normal groups (P<0.01). There were no significant differences in HLA-B*15:02 and HLA-A*31:01 genotypes between the AED-tolerant and normal groups (P>0.05). The results showed that HLA-B*15:02 and HLAA* 31:01 are significantly associated with cADRs in a Chinese Han population in Shanghai, suggesting that HLA-B*15:02 and HLA-A*31:01 genotypes should be detected in the application of AEDs.” [146]

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

https://www.ncbi.nlm.nih.gov/pubmed/29288229 [148]

“HLA-A*31:01 was the most strongly associated marker with carbamazepine-induced MPE in Europeans in this study. Forty-three of the 95 cases studied here were also included in the discovery

publication,8 but the effect of the allele remains significant when we restrict to new cases only (p = 4 × 10−7), thus providing an additional independent replication of the initial finding.” [148]

HLA-A*31:01 and carbamazepine-induced DRESS syndrome in a sample of North African population.

https://www.ncbi.nlm.nih.gov/pubmed/29125944 [149]

“The HLA-A*31:01 allele, which has a prevalence of 1% in Tunisian population, was significantly associated with DRESS syndrome. It was detected in 57.14% of cases (4/7) and only 4% of controls

subjects (1/25). Thus, the carrier frequency of HLA-A*31:01 allele in the cases group was also significantly higher than in the controls group (57, 14% vs 4% P = 0,004). Odds ratio is estimated 32

(OR = 32 [2.6; 389.2])… Similarly to other ethnicities, the presence of the HLA-A*31:01 allele was associated with carbamazepine-DRESS syndrome in a sample of North African population. Future study

must be conducted on a larger sample in order to confirm these results.” [149]

Clinical Pharmacogenetics Implemtation Consortium Guideline for HLA Genotype and Use of

Carbamazepine and Oxcarbazepine: 2017 Update.

https://www.ncbi.nlm.nih.gov/pubmed/29392710 [147]

“The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.”

[147]

Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations.

https://www.ncbi.nlm.nih.gov/pubmed/?term=18855540 [155]

“Current recommendations for genotyping all Asian patients are based on a strong correlation between HLA-B*1502 and carbamazepine-SJS/TEN in Han Chinese. Importantly, there is a wide access to highresolution HLA typing within the USA and other developed countries. The relative lack of information regarding the correlation in both Asian population groups who have a high frequency of HLA-B*1502

should prompt further investigation. Given the availability of other effective medications for similar indications, it is likely prudent to avoid carbamazepine when patients have tested positive, despite the

low estimated positive predictive value of the test.”[155]

HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity in Hong Kong Han Chinese

https://www.ncbi.nlm.nih.gov/pubmed/?term=28398356 [156]

Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a

Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic

associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles

A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity.[156]

The HLA-B*15:02 polymorphism and Tegretol®-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis.

https://www.ncbi.nlm.nih.gov/pubmed/29685430 [150]

“Out of 807 articles, nine were included in the present meta-analysis to assess the association between human leukocyte antigen (HLA)-B*15:02 polymorphisms and CBZ-induced serious cutaneous reactions (SCRs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in epilepsy. It was found that HLA-B*15:02 polymorphisms were significantly associated with CBZ SCR risk (OR: 27.325, 95% CI: 9.933-51.166), while subgroup analyses by ethnicity showed that the association was significant in Han Chinese (OR: 42.059, 95% CI: 9.587-184.514). The HLA-B*15:02 polymorphism was

also strongly associated with the CBZ-SJS subgroup (OR: 152.089, 95% CI: 34.737-665.901) and significantly associated with the CBZ-SJS/TEN subgroup (OR: 13.993, 95% CI: 7.291-26.856). Also, the allele was overrepresented in the Han Chinese population (OR: 17.886, 95% CI: 8.411-38.034) within the CBZ-SJS/TEN subgroup. Although the number of studies available in other Asian ethnicities was

insufficient for determining publication bias, it nevertheless showed a relationship between the HLAB* 15:02 polymorphism and SCRs. In addition, despite the small number of included studies, the results

reveal strong evidence that the HLA-B*15:02 polymorphism can induce SCRs among Asian CBZ users. These findings should prompt physicians to individualize CBZ therapy for patients with epilepsy.” [150]

Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a metaanalysis.

https://www.ncbi.nlm.nih.gov/pubmed/29629814 [151]

In the tolerant control group, an association was found between HLA-B*15:02 genotype and OXC [oxcarbazepine]-induced sCAR [severe cutaneous adverse reaction] (odds ratio [OR]: 18.13; 95% CI:

6.77-48.56), but not in mcADR [mild cutaneous adverse reaction] (OR: 1.43; 95% CI: 0.56-3.64). In population control group, an association was found between HLA-B*15:02 genotype and OXC-induced

sCAR, (OR: 8.22; 95% CI: 3.03-22.34), but not in mcADR (OR: 2.06; 95% CI: 0.91-4.67). Our study demonstrates that the genetic risk factor HLA-B*15:02 may be a factor in OXC-induced sCAR. [151]

Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients.

https://www.ncbi.nlm.nih.gov/pubmed/29546073 [152]

“The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepinetolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04-25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10-13; OR (95% CI) = 70.91(19.67-255.65)) when compared with carbamazepinetolerant controls.” [152]

Association between HLA gene polymorphism and cutaneous adverse reactions caused by antiepileptic drugs.

https://www.ncbi.nlm.nih.gov/pubmed/29545861 [146]

“Through the case-control study, 30 child patients with AED-induced cADRs (cADRs group), 60 AED tolerant child patients (AED-tolerant group) and 60 normal children not taking AEDs (normal group)

were collected. The HLA-B*15:02 and HLA-A*31:01 genotypes were detected using the polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) probe method, and the correlation of HLAB* 15:02 and HLA-A*31:01 genes with the incidence of cADRs was analyzed. The positive rate of HLAB* 15:02 gene was 83.33% in the cADRs group, which was significantly increased compared with that in the AED-tolerant and normal groups (P<0.01). The positive rate of HLA-A*31:01 gene was 63.33% in the cADRs group, which was obviously increased compared with that in the AED-tolerant and normal groups (P<0.01). There were no significant differences in HLA-B*15:02 and HLA-A*31:01 genotypes between the AED-tolerant and normal groups (P>0.05). The results showed that HLA-B*15:02 and HLAA* 31:01 are significantly associated with cADRs in a Chinese Han population in Shanghai, suggesting that HLA-B*15:02 and HLA-A*31:01 genotypes should be detected in the application of AEDs.” [146]

Clinical Pharmacogenetics Implemtation Consortium Guideline for HLA Genotype and Use of

Carbamazepine and Oxcarbazepine: 2017 Update.

https://www.ncbi.nlm.nih.gov/pubmed/29392710 [147]

“The variant allele HLA-B*15:02 is strongly associated with greater risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine…

We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.” [147]

Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population.

https://www.ncbi.nlm.nih.gov/pubmed/29238301 [153]

The proportion of HLA-A02:07 and HLA-B15:02 allele carriers were significantly higher in the LTGinduced CADR [cutaneous adverse reactions] group than in the tolerant controls [odds ratio (OR): 7.83; 95% confidence interval (CI): 1.60-38.25; P = 0.013, and OR: 4.89; 95% CI: 1.28-18.67; P = 0.014]. In addition, subjects with HLA-A33:03, HLA-B15:02, and HLA-B44:03 were significantly higher in the LTG-induced MPE [maculopapular exanthema] group than in the tolerant controls (OR: 8.27; 95% CI: 1.83-37.41; P = 0.005, OR: 7.33; 95% CI: 1.63-33.02; P = 0.005; and OR: 10.29; 95% CI: 1.45-72.81; P = 0.029). In contrast to the LTG-induced MPE group, there were no significant differences between HLA alleles and LTG-induced SCAR [severe cutaneous adverse reactions] group. [153]

Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sudanese population of Indonesia: the important role of the HLA-B75 serotype.

https://www.ncbi.nlm.nih.gov/pubmed/29053440 [154]

“Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sudanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was

found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2-33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78;

95% CI: 1.96-23.38).” [154] 

HLA-B 15:13 associated with phenytoin related Stevens-Johnson syndrome and toxic epidermal necrolysis

https://www.ncbi.nlm.nih.gov/pubmed/26927288 [157]

“Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHTSJS/ TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.”

 

 

אין במידע ו/או בתכנים המופיעים במאמר משום מתן עצה רפואית, חוות דעת מקצועית, תחליף להתייעצות עם מומחה או מתן אבחנה בנוגע לטיפול במצב רפואי מסויים. לשם קבלת ייעוץ אישי יש לפנות להתייעצות עם רופא בתחום המומחיות המתאים. מבלי לגרוע מכלליות האמור, כל הסתמכות על התכנים המופיעים במאמר ופעולה על פיהם נעשים על אחריותך הבלעדית והמלאה ולא תהיה לך כל תביעה ו/או טענה ו/או דרישה כנגד כותבי ומפרסמי המאמר או מי מטעמם, בגין נזקים הנובעים משימוש במידע הכלול במאמר זה.