(cache) GMS HLA

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	ref.
B*07	Ebola. Protective (with B*14). Non-Fatal response to Ebola	B07 + B14 are highly enriched in those who survive	1).
B*11	Chlamydia trachomatis. Protective against blindness from Chlamydia trachomatis	Predictive of those who do not develop blindness	2).
B*14	Ebola. Protective, (along with B*07). Non-Fatal response to Ebola	B07 + B14 are highly enriched in those who survive	1).
B*15	Ebola. **Sensitizes (with B67) a Fatal*** response to Ebola	B67 + B15 highly enriched in those who perish	1).
B*1502	Adverse Drug Response. Carbamazepine induced Stevens-Johnson in Chinese	FDA: All Chinese should be screened before Rx	3).
B*1502	Adverse Drug Response. Carbamazepineinduced Stevens-Johnson in Chinese	Only solid psychiatric marker for pharmacogenomics	4).
B*17	Lukemia in children. ALL high leukocyte counts at presentation	B17 and A33 may combine to predict male relapse	5).
B*27	Ankylosing Spondylitis. (reactive arthritis). B*27 explains 50% of risk	Severity of reactive arthritis strongly correlated with B*27	6).
B*27	Ankylosing Spondylitis (reactive arthritis). B*27 plus IL-1 explain 75% of risk	Severity of reactive arthritis strongly correlated with B*27	7).
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	8).
B*27	Reactive Arthritis. B*27 associated with Enhanced Risk of severe Reactive arthritis	Clinical B*27 Review in Nature	9).
B*27	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.	10).
*B27**	HIV-1. All B*27 alleles Protective, HIV-1 Elite Controller	Also seems to correlate with early work on vaccines	11).
*B27**	HIV-1. All B*27 alleles Protective, HIV-1 Elite Controller	HIV-1 can mutate out of suppression faster in B27,Relative to B57	12).
*B3503**	HIV-1. B3501 is protective for HIV progression, Other B35 alleles show rapid HIV progression	As for B57, a subtle change in B35 allele has significant effects	13).
B*39	Diabetes. Type I diabetes genetic risk explained by B*39 Plus HLA-DQB1 and HLA-DRB1	High profile whole genome scanning study in Nature	14).
B*4402	Cervical Cancer. Enhanced squamous cell cervical cancer RISK with one or more; A0201-Cw0501 DRB10401-DQB10301	HLA explains enhanced genetic risk for Cervical cancer. B*4402 is central theme	15).
B*51	Behçet's disease. Autoimmune disease of the vasculature	B*51 is strongly correlated with severity	16).
B*5401	Gastric Cancer. Reduced risk of gastric cancer	Mediated via H.Pilori infection	17).
B*57	HCV.Protective effect	All B*57’s correlated with spontaneous recovery	18).
*B5701**	Adverse Drug Response. Abacavir sensitivity	Large scale US. Screening trail confirms predictive power for ADR	19).
B*5701	Adverse Drug Response. Abacavir sensitivity	Described as “Gold standard” in 2009 for personalized medicine	20).
B*5701	Adverse Drug Response. Abacavir sensitivity	NEJM landmark paper. Large scale Australian Screening trail confirms high predictive power for ADR	21).
*B57**	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	22).
*B5701**	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	23).
*B5702**	HIV-1. Not Protective HIV-1 Elite Controller	B5701 & B5702 must be cleanly resolved at high resolution. For HIV progression & Abacvir ADR	24).
*B5703**	HIV-1. Protective Effect HIV-1 Elite Controller	Protective Mechanism is different than for B*5701	25).
B*5801	Adverse Drug Response. Allopurinol sensitivity in Chinese	Highly predictive of adverse response to allopurinol	26a). 26b).
B*5801	HIV-1.Protective Effect HIV-1 Elite Controller	More escape variants than for B*5701	27).
B*67	*Ebola. Sensitizes (with B15) Fatal** response to Ebola in Uganda	B67 + B15 highly enriched in those who perish	1).
B*67	Lukemia children. Male ALL relapse in Chinese		28).

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2). Abbas M, Bobo LD, Hsieh YH, Berka N, Dunston G, Bonney G, Apprey V, Quinn TC,
West SK (2008) Human Leukocyte Antigen (HLA)-B, -DRB1 and -DQB1 Allotypes Associated with Disease and Protection in Trachoma Endemic Villages. Invest Ophthalmol Vis Sci. Epub, Sept

3). Ferrell PB Jr, McLeod HL. Carbamazepine (2008) HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics, 10:1543-6.

4). de Leon J (2008). The Promise of Personalized Medicine for CNS Disorders.
Neuropsychopharmacology. Pharmacogenomics: Sep 17. [Epub ahead of print]

5). Ng MH, Lau KM, Hawkins BR, Chik KW, Chan NP, Wong WS, Tsang KS, Shing MM, Li CK (2006). HLA-B67 may be a male-specific HLA marker of susceptibility to relapsed childhood ALL in Hong Kong Chinese and HLA-A33 or HLA-B17 signifies a higher presentation leukocytosis: A retrospective analysis on 53 transplant candidates (1989-2003). Ann Hematol. 85(8):535-41.

6). Fussell H, Nesbeth D, Lenart I, Campbell EC, Lynch S, Santos S, Gould K, Powis SJ, Antoniou AN.
(2008) Novel detection of in vivo HLA-B27 conformations correlates with ankylosing spondylitis association. Arthritis Rheum. 58(11):3419-24.

7). Reveille JD (2006) Major histocompatibility genes and ankylosing spondylitis. Best Pract Res Clin Rheumatol. 20(3):601-9.

8). Schiellerup P, Krogfelt KA, Locht H (2008). A comparison of self-reported joint symptoms following infection with different enteric pathogens: effect of HLA-B27. J Rheumatol. 35(3):480-7

9). Inman RD (2006). Mechanisms of disease: infection and spondyloarthritis. Nat Clin Pract Rheumatol. 2(3):163-9.

10). Orchard TR, Holt H, Bradbury L, Hammersma J, McNally E, Jewell DP, Wordsworth BP (2008)
The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn's disease. Aliment Pharmacol Ther. Oct 9, [Epub ahead of print]

11). Kaslow RA, Rivers C, Tang J, Bender TJ, Goepfert PA, El Habib R, Weinhold K, Mulligan MJ (2001) NIAID AIDS vaccine evaluation group. Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines. J Virol. 75(18):8681-9.

12). Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, Rinaldo CR, Craggs
SL, Allgaier RL, Power KA, Kuntzen T, Tung CS, LaBute MX, Mueller SM, Harrer T,McMichael AJ, Goulder PJ, Aiken C, Brander C, Kelleher AD, Allen TM (2007). Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol. 81(22):12382-93. Epub 2007 Sep

13). Gao X, Nelson GW, Karacki P, Martin MP, Phair J, Kaslow R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, O'Brien SJ, Carrington M (2001) Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med. 344(22):1668-75. Comment in:
N Engl J Med. 2001 Sep 20;345(12):924-5.

14). Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, Hulme J, Maier LM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Clayton DG, Todd JA; Wellcome Trust Case Control Consortium (2007). Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 450(7171):887-92. Epub 2007 Nov 14. Comment in: Nature. 2007 Dec 6;450(7171):799-800.

15). Madeleine MM, Johnson LG, Smith AG, Hansen JA, Nisperos BB, Li S, Zhao LP, Daling JR, Schwartz SM, Galloway DA (2008). Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk. Cancer Res. 68(9):3532-9.

16). Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, Kjer-Nielsen L, Mifsud NA, Tait BD, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kellerher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J, McCluskey J (2008). Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity. 28(6):822-32. Erratum in: Immunity. 2008 29(1):165.

17). Hirata I, Murano M, Ishiguro T, Toshina K, Wang FY, Katsu K (2007). HLA genotype and development of gastric cancer in patients with Helicobacter pylori infection. Hepatogastroenterology. 54(76):990-4.

18). Chuang WC, Sarkodie F, Brown CJ, Owusu-Ofori S, Brown J, Li C, Navarrete C, Klenerman P, Allain JP (2007). Protective effect of HLA-B57 on HCV genotype 2 infection in a West African population. J Med Virol. 79(6):724-33.

19). Young B, Squires K, Patel P, Dejesus E, Bellos N, Berger D, Sutherland-Phillips DH, Liao Q, Shaefer M, Wannamaker P (2008) First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS. 22(13):1673-5.

20a). Phillips EJ, Mallal SA (2008). Pharmacogenetics and the potential for the individualization of antiretroviral therapy. Curr Opin Infect Dis. 21(1):16-24.

20b). Hammond E, Almeida CA, Mamotte C, Nolan D, Phillips E, Schollaardt TA, Gill MJ, Angel JB, Neurath D, Li J, Giulivi T, McIntyre C, Koultchitski G, Wong B, Reis M, Rachlis A, Cole DE, Chew CB, Neifer S, Lalonde R, Roger M, Jeanneau A, Mallal S (2007). External quality assessment of HLA-B*5701 reporting: an international multicentre survey. Antivir Ther. 12(7):1027-32.

21). Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N,Thorborn D, Benbow A; PREDICT-1 Study Team (2008). HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 358(6):568-79. Comment in: N Engl J Med. 358(6):637-9. N Engl J Med. 358(23):2514-5; author reply 2515-6. N Engl J Med. 358(23):2515; author reply 2515-6.

22) Carrington M, Martin MP, van Bergen J (2008) KIR-HLA intercourse in HIV disease. Trends Microbiol. 16(12):620-7. Epub 2008 Oct 29.

23). Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB (2007). A whole-genome association study of major determinants for host control of HIV-1. Science. 317(5840):944-7. Comment in: Science. 318(5849):390-1; author reply 390-1.

24). Cadogan M, Dalgleish AG (2008) Chapter 9 HIV Induced AIDS and Related Cancers Chronic Immune Activation and Future Therapeutic Strategies. Adv Cancer Res. 101:349-95.

25). Yu XG, Lichterfeld M, Chetty S, Williams KL, Mui SK, Miura T, Frahm N, Feeney ME, Tang Y, Pereyra F, Labute MX, Pfafferott K, Leslie A, Crawford H, Allgaier R,Hildebrand W, Kaslow R, Brander C, Allen TM, Rosenberg ES, Kiepiela P, Vajpayee M, Goepfert PA, Altfeld M, Goulder PJ, Walker BD (2007). Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes. J Virol. 81(4):1619-31.

26a). Chung WH, Hung SI, Chen YT (2007). Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol. 7(4):317-23.

26b). Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC,Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, ChenYT (2005).
HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 102(11):4134-9. Erratum in: Proc Natl Acad Sci U S A. 102(17):6237.

27). Chopera DR, Woodman Z, Mlisana K, Mlotshwa M, Martin DP, Seoighe C, Treurnicht F, de Rosa DA, Hide W, Karim SA, Gray CM, Williamson C; CAPRISA 002 Study Team (2008). Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage. PLoS Pathog. 4(3):e1000033.