HLA At A Glance

The Human Leukocyte Antigen (HLA) genes are those which are responsible for detecting foreign substances and triggering the immune system. Such HLA screening includes the detection of drug molecules, bacteria and viruses as well as the process of self recognition, such as the screening of tumor cells and autoimmunity. HLA variation is, of course, also the basis for organ transplant rejection. As a result, complex HLA genetic testing is now the standard of care for all of transplantation medicine, performed on @100,000 individuals per year worldwide and, as such, is the recognized gold standard for the field of personalized medicine. It has also been widely suspected, for at least 30 years, that ordinary heritable variation in the HLA genes would also give rise to personal variation in the response to viral or bacterial infection; undesirable or lethal inflammatory responses to drugs; personalized sensitivity to inflammatory diseases like arthritis or Crohn’s disease; cancers like melanoma, and perhaps most importantly, personal variation in the response to vaccination.

HLA testing, as performed for organ transplantation today, or as may be used for vaccination screening and personalized drug therapy in the near future, is an example of how quickly the field of genetic testing has evolved. An HLA test requires that about 6 genes are screened in parallel, with each displaying about 100 important (known) local variants each. Consequently, HLA testing is about 100-times more complex than a genetic test to determine paternity, or forensic ID or neonatal screening for a genetic birth defect such as cystic fibrosis or sickle cell anemia. In concept, a complex “HLA-like” genetic test is ideally suited to microarray technology, since microarrays can easily detect one thousand to one million local DNA changes in parallel. In spite of that apparently-ideal fit, there are only  a  couple  of microarray tests used in HLA testing today; the reason being that the existing microarray technologies were developed as research tools, not as a platform for clinical or public health screening. Thus, in their current form, microarrays are too complex, too expensive, and require a sample size that is too big to be implemented, practically, as part of large scale genetic testing.

Beyond organ transplantation and vaccine response, there is now very strong evidence that personal variation in the HLA genes is also directly related to personal variation in the risk of viral infection; the risk of inflammatory joint disease; and very importantly, the dose limiting inflammatory response to drugs, known as “drug rash” or in extreme cases, the life-threatening Stevens-Johnson Syndrome (SJS).

Specifically, a wealth of HIV literature has shown that for AIDS, personal variation in HLA and a few HLA-coupled genes can predict those who will not develop AIDS upon infection. The so-called “Elite Controllers”, can also predict those who will respond poorly to abacavir, the anti-retroviral drug which is the first line of defense against HIV. Indeed, the field of Pharmacogenomics now considers the role of HLA in defining the Elite Controllers and defining dose-limiting abacavir hypersensivity to be the gold standard for the entire field of personalized medicine.  Variation within HLA is a strong predictor for personalized variation in acabavir & nevirapam hypersensitivity (Table I), the major dose-limiting toxicity for those two first-tier AIDS antiretroviral drugs (specific examples include Steven’s-Johnson Syndrome [SJS] and related types of severe drug rash). A number of extremely high profile studies have confirmed that HLA-B*5701 is strongly predictive of dose-limiting abacavir hypersensitivity, and has led the FDA to a call for B*5701 genotyping as part of routine pre-treatment evaluation of all infected patients. Thus, the relationship between HLA-B*5701 and adverse drug reaction to abacavir is now considered to be the “gold standard” for all of personalized pharmaceutics. More broadly, HLA-B*1502 is now also thought to be strongly predictive of Steven’s Johnson-like adverse drug reaction to carbamazepine (first tier epilepsy drug), and B*5801 is thought to be strongly predictive of a Steven’s Johnson-like adverse drug reaction to allopurinol (standard gout & kidney stone treatment), thus positioning those HLA-B relationships near the top of the current understanding of heritable risk of adverse drug reaction. New indications are being actively discovered.  

Immunology has long predicted that HLA might play a role in immuno-surveillance, especially the ability to detect and destroy cancerous cells or hyperplastic lesions. Additionally, given the active search for therapeutic vaccines against cancer, the role of personalized HLA variation in vaccine response becomes of direct importance to cancer therapeutics. The opportunities for HLA screening in melanoma are becoming particularly well known. There is now growing evidence that melanoma risk is strongly coupled to HLA variation, especially at the Type II DQB locus. In  terms of vaccine therapy, the development of melanoma vaccines is becoming driven by rational vaccine design, especially in the context of HLA-A mediated epitope presentation.

Table I. The Current Role (late 2008) for High Resolution HLA-B Testing: For AIDS Risk, Acacabir Pharmacogenomics, Reactive  Arthritis & other HLA-based diseases.

HLA-B Allele

Clinical Indication correlated with Allele

Comments Relative to Clinical Utility of HLA-B screening



Ebola. Protective (with B*14). Non-Fatal response to Ebola

B*07 + B*14 are highly enriched in those who survive



Chlamydia trachomatis. Protective against blindness from Chlamydia trachomatis

Predictive of those who do not develop blindness



Ebola. Protective, (along with B*07). Non-Fatal response to Ebola

B*07 + B*14 are highly enriched in those who survive



Ebola. Sensitizes (with B*67) a Fatal response to Ebola

B*67 + B*15 highly enriched in those who perish



Adverse Drug Response. Carbamazepine induced Stevens-Johnson in Chinese

FDA: All Chinese should be screened before Rx



Adverse Drug Response. Carbamazepineinduced Stevens-Johnson in Chinese

Only solid psychiatric marker for pharmacogenomics



Lukemia in children. ALL high leukocyte counts at presentation

B*17 and A*33 may combine to predict male relapse



Ankylosing Spondylitis. (reactive arthritis). B*27 explains 50% of risk

Severity of reactive arthritis strongly correlated with B*27



Ankylosing Spondylitis (reactive arthritis). B*27 plus IL-1 explain 75% of risk

Severity of reactive arthritis strongly correlated with B*27



Ankylosing Spondylitis. (reactive arthritis). B*27 Correlates with increased arthritic pain in Reactive arthritis after a triggering infection

Severity of reactive arthritis strongly correlated with B*27



Reactive Arthritis. B*27 associated with Enhanced Risk of severe Reactive arthritis

Clinical B*27 Review in Nature



Chrone’s Disease. HLA-B27 appears to convey a very high risk of developing axial inflammation in Crohn's disease.

B*27 not associated with absolute Chrone’s risk, but with subsequent inflammation.



HIV-1. All B*27 alleles Protective, HIV-1 Elite Controller

Also seems to correlate with early work on vaccines



HIV-1. All B*27 alleles Protective, HIV-1 Elite Controller

HIV-1 can mutate out of suppression faster in B*27,Relative to B*57



HIV-1. B*3501 is protective for HIV progression, Other B*35 alleles show rapid HIV progression

As for B*57, a subtle change in B*35 allele has significant effects



Diabetes. Type I diabetes genetic risk explained by B*39 Plus HLA-DQB1 and HLA-DRB1

High profile whole genome scanning study in Nature



Cervical Cancer. Enhanced squamous cell cervical cancer RISK with one or more; A*0201-Cw*0501 DRB1*0401-DQB1*0301

HLA explains enhanced genetic risk for Cervical cancer. B*4402 is central theme



Behçet's disease. Autoimmune disease of the vasculature

B*51 is strongly correlated with severity



Gastric Cancer. Reduced risk of gastric cancer

Mediated via H.Pilori infection



HCV.Protective effect

All B*57’s correlated with spontaneous recovery



Adverse Drug Response. Abacavir sensitivity

Large scale US. Screening trail confirms predictive power for ADR



Adverse Drug Response. Abacavir sensitivity

Described as “Gold standard” in 2009 for personalized medicine



Adverse Drug Response. Abacavir sensitivity

NEJM landmark paper. Large scale Australian Screening trail confirms high predictive power for ADR



HIV-1. Protective effect HIV-1, the Elite Controllers. HLA-B and KIR3DL1/KIR3DS1

Clinical Screening is now routine. The best characterized host protective effect in modern infectious disease research




HIV-1. Protective Effect HIV-1 Elite Controller. Highest genetic correlation. HLA-C may be a secondary player

The role of B*5701 in HIV risk upon infection is the gold standard in host effects in infectious disease



HIV-1. Not Protective HIV-1 Elite Controller

B*5701 & B*5702 must be cleanly resolved at high resolution. For HIV progression & Abacvir ADR



HIV-1. Protective Effect HIV-1 Elite Controller

Protective Mechanism is different than for B*5701



Adverse Drug Response. Allopurinol sensitivity in Chinese

Highly predictive of adverse response to allopurinol




HIV-1.Protective Effect HIV-1 Elite Controller

More escape variants than for B*5701



Ebola. Sensitizes (with B*15) Fatal response to Ebola in Uganda

B*67 + B*15 highly enriched in those who perish



Lukemia children. Male ALL relapse in Chinese




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