Pharmacogenetic Testing in the United Kingdom Genetics and Immunogenetics Laboratories

Abstract

Aim: For certain drugs, pharmacogenetic tests can reduce adverse drug reactions and improve treatment efficacy. However, the adoption of pharmacogenetics into clinical practice has been relatively slow. One potential barrier is the capacity of laboratories to meet the demands of a clinical pharmacogenetic service. We aimed to establish the range, capacity to deliver, and demand for germline pharmacogenetic testing in the United Kingdom and Ireland, through an e-survey of 34 molecular genetics and 28 histocompatibility and immunogenetics (H&I) laboratories. Results: Thirty-five percent of molecular genetics laboratories and 54% of H&I laboratories responded to the survey. The majority of H&I laboratories (93%) offered pharmacogenetic testing, whereas only one molecular genetics laboratory provided a pharmacogenetic service. HLA-B*5701 was most commonly tested to identify those at risk of abacavir hypersensitivity among patients with HIV. A number of barriers to testing were identified, including lack of clinician knowledge and a lack of scientific evidence. All molecular genetics laboratories believed that national coordination of clinical pharmacogenetic services was required, whereas only 50% of H&I laboratories supported this view. Conclusions: In the United Kingdom, pharmacogenetic testing is currently being predominantly provided through H&I laboratories for a limited number of indications. The number of laboratories offering pharmacogenetic tests is increasing and is likely to continue to increase over the coming years.

Introduction

Pharmacogenetics is defined as the study of genetic variants that may influence the absorption, distribution, metabolism, and elimination of a drug and, as a consequence, its efficacy and toxicity (Roses, 2000). Essentially, this corresponds to the study of germline, or inherited, genetic variants with somatic, or acquired, genetic changes, particularly relevant in tumor tissue, being referred to as pharmacogenomics. Pharmacogenetic tests may be undertaken on genomic DNA, defining the presence of a specific genetic variant, for example, variant alleles in the CYP2D6 gene, or through phenotypic tests, for example, measurement of an enzyme level as in pseudocholinesterase deficiency, which predicts delayed recovery from anesthesia (Table 1). For some indications either a genetic test or an enzyme assay may be applied, for example, the association between thiopurine methyltransferase (TPMT) deficiency and azathioprine-induced neutropenia. The fact that many different tests may be applied in this area has led to the development of pharmacogenetic testing services in a number of specialist laboratories in the United Kingdom, including biochemistry, genetics, and histocompatibility and immunogenetics (tissue typing), rather than being the exclusive remit of a specific type of laboratory.

Table 1.

Examples of Pharmacogenetic Tests

Gene tested	Use of test
HLA-B5701*	To detect patients likely to have a hypersensitivity reaction to abacavir (HIV treatment)
HLA-B1502*	Tested in Asian patients treated with carbamazepine for epilepsy to detect those at risk of Stevens Johnson syndrome
Pseudocholinesterase (BChE)	Deficiency results in delayed recovery from the muscle relaxant, succinylcholine, used in general anesthesia
Thiopurine methyltransferase (TPMT)	TPMT-deficient individuals are more likely to become neutropenic if given a thiopurine drug, such as azathioprine
Cytochrome P450 2D6 (CYP2D6)	Involved in the metabolism of many drugs, including tamoxifen and selective serotonin reuptake inhibitors
Cytochrome P450 3A4 (CYP3A4)	Involved in the metabolism of many drugs, including the histamine H1-receptor antagonist tertenadine
Cytochrome P450 2C9 (CYP2C9)	Warfarin metabolism; tested to aid dosing of patients starting warfarin
Cytochrome P450 2C19 (CYPC19)	Involved in the metabolism of many drugs, including selective serotonin reuptake inhibitors and proton pump inhibitors, and in the antiplatelet effect of clopidogrel
UGT1A1	Tested to diagnose Gilbert syndrome (benign hyperbilirubinemia) or predict toxicity associated with irinotecan

Following initial research findings supporting a clinically relevant association, the adoption of pharmacogenetic testing into clinical practice has been slow or minimal for some with indications, for example, TPMT and CYP2D6, but much more rapid for other indications, for example, HLA-B*1502 and HLA-B*5701. The reasons for these differences are manifold but may reflect better evidence levels, improved clinician awareness, and increased availability of testing services (Newman and Payne, 2008). A large randomized controlled trial demonstrated the benefit of HLA-B*5701 genotyping in HIV patients treated with abacavir to avoid hypersensitivity reactions (Hughes et al., 2008; Mallal et al., 2008). Different forms of evidence have been used to support the adoption of other pharmacogenetic tests into clinical practice. In cases where the genetic change is rare, results in a severe adverse drug reaction, and has a high negative predictive value for the adverse drug reaction, for example, the risk of Stevens Johnson syndrome for Asian patients with HLA-B*1502 and treated with carbamazepine for epilepsy (Chung et al., 2004), small retrospective series have provided the evidence to support clinical adoption (Medicines and Healthcare Products Regulatory Agency, 2008).

An United Kingdom survey has been recently carried out to determine the frequency of testing for somatic mutations in noninherited aspects of cancer diagnosis, prognosis, and response to treatment (Wordsworth et al., 2008). They concluded that currently only a small number of testing is carried out, ∼1-5% of the workload of most laboratories, and that this is expected to increase (Wordsworth et al., 2008).

We aimed to determine the range, capacity to deliver, and demand for germline pharmacogenetic testing in the United Kingdom and Ireland's genetics and immunogenetics laboratories.

Materials and Methods

An E-mail letter introducing an e-survey was sent to 34 molecular genetics laboratories via the Clinical Molecular Genetics Society head of laboratories group and to 28 histocompatability and immunogenetics (H&I) laboratories via their National Network in the United Kingdom and Ireland during June 2008 to October 2008, respectively (see Table 2 for a list of organizations and their roles). A single E-mail reminder was sent after 2 weeks. The complete survey is available in Supplemental information, available online at www.liebertonline.com.

Table 2.

Professional Groups

The Royal College of Pathologists (RCPath; www.rcpath.org)

The College's mission statement is to promote excellence in the practice of pathology and to be responsible for maintaining standards through training, assessments, examinations, and professional development, for the benefit of the public.

Clinical Pathology Accreditation (CPA; www.cpa-uk.co.uk)

An United Kingdom-based scheme for the accreditation of pathology services.

National Academy of Clinical Biochemistry (NACB; www.aacc.org)

An United States organization (the Academy of the American Association for Clinical Chemistry). Dedicated to advancing the science and practice of clinical laboratory medicine through research and professional development.

Clinical Molecular Genetics Society (CMGS; www.cmgs.org)

CMGS aim to advance the science of clinical molecular genetics and to further public education. They have a strong interest in promoting the quality of molecular genetic testing in the United Kingdom through training, education, research, data collection, and quality schemes and is part of the federated British Society of Human Genetics (BSHG).

UK Genetic Testing Network (UKGTN; www.ukgtn.nhs.uk)

UKGTN advise the NHS on genetic testing across the whole of the United Kingdom. They aim to promote the provision of high-quality equitable genetic testing services. The Network comprise a collaborative group of genetic testing laboratories, clinicians, and commissioners of NHS genetic services and involve patient support groups.

A URL link and summary regarding the survey was subsequently distributed via the Royal College of Pathologists United Kingdom e-newsletter. This approach was adopted to canvass information from other clinical laboratories in the United Kingdom, including biochemistry and hematology services. However, as there were only three responders via this approach, these data were not formally analyzed.

Results

Of the surveyed genetics and H&I laboratories, 12 of the 34 (35%) and 15 of the 28 (54%), respectively, responded. Nonresponding laboratories were contacted by E-mail and only four gave reasons for not responding, the reasons being not offering any pharmacogenetic tests (n = 2) and lack of time to complete surveys (n = 2).

Genetics laboratories

All of the United Kingdom molecular genetics laboratories who responded had Clinical Pathology Accreditation. Four laboratories responded that they offered pharmacogenetic testing. However, two of these were in the process of setting up tests (TPMT and CYP2D6 testing) and one offered somatic mutation testing (C-KIT gene testing in gastrointestinal stromal tumors), rather than a germline pharmacogenetic test. Therefore, only one laboratory currently offered a pharmacogenetic test according to our definition. The laboratory provided UGT1A1 genotyping, which can be used to diagnose Gilbert syndrome (benign hyperbilirubinemia) or predict toxicity associated with irinotecan. The laboratory performed ∼190 UGT1A1 genotyping tests in 2007.

All 12 laboratories stated that a central coordinating body would be beneficial. However, two commented that this could be integrated with the United Kingdom genetic testing network. All laboratories believed that the use of pharmacogenetic tests would increase over the next 5 years. The key barriers identified were lack of supportive scientific evidence, lack of funding, and lack of clinician knowledge (see Table 3).

Table 3.

Perceived Barriers to Offering Pharmacogenetic Testing

Barrier	Genetics laboratories, n = 12	Immunology laboratories, n = 14
Lack of supportive scientific evidence	10 (83%)	10 (71%)
Lack of funding	9 (75%)	10 (71%)
Lack of knowledge by clinicians	8 (67%)	14 (100%)
Lack of standardized procedures or guidance	7 (58%)	10 (71%)
Cost of specific tests	7 (58%)	9 (64%)
Not considered a NHS priority area	7 (58%)	7 (50%)
Lack of laboratory equipment	2 (17%)	5 (36%)
Private sector competition	2 (17%)	0
New drugs released with better profiles	0	1 (7%)
Testing dispersed among different pathology disciplines	0	1 (7%)
Staffing—noncore activity	0	1 (7%)

Histocompatibility and immunogenetics laboratories

Clinical Pathology Accreditation was in place in all the UK NHS Laboratories. Germline pharmacogenetic tests were offered by 14 of the 15 (93%) laboratories. The single laboratory that did not offer any pharmacogenetic tests stated that this was due to a lack of demand.

The range of tests offered, the number performed per year, and the charges per test are shown in Table 4. There is a wide variation in the number and charge of the tests which are summarized in Tables 4 and 5. The charge levied for the test did not relate to the frequency with which the test was performed (Table 4).

Table 4.

Pharmacogenetic Tests Offered by Each Immunology Laboratory

Laboratory	Test	Number/year	Cost/test
1	HLA-B*1502	0-19	No response
	HLA-B*5701	600-699	No response
2	HLA-B*5701	700-799	£160-179
3	HLA-B*5701	200-219	No response
4	HLA-B*5701	20-39	£40-59
5	HLA-B*5701	500-599	£40-59
6	HLA-B*1502	0-19	No response
	HLA-B*5701	60-79	No response
7	No tests offered	-	-
8	HLA-B*5701	300-319	£40-59
9	HLA-B*1502	40-59	£100-119
	HLA-B*5701	over 1000	£40-59
	TPMT	40-59	£200-219
10	HLA-B*1502	0-19	No charge
	HLA-B*5701	180-199	No charge
	TPMT	60-79	No charge
11	HLA-B*5701	140-159	£40-59
12	HLA-B*1502	0-19	£40-59
	HLA-B*5701	600-699	£40-59
13	HLA-B*5701	40-59	£20-39
14	HLA-B*1502	No response	£80-99
	HLA-B*5701	40-59	£80-99
15	Cytochrome P450 3A4 (CYP3A4)	0-19	£10-19
	Fc gamma receptor	0-19	£10-19
	HLA-B*1502	0-19	£20-39
	HLA-B*5701	40-59	£20-39
	TPMT	20-39	£10-19

Table 5.

Summary of Pharmacogenetic Tests Offered

Pharmacogenetic test	Number of laboratories offering the test	Tests requested by	Number of tests carried out/year	Price of the test
Cytochrome P450 3A4 (CYP3A4)	1	Researchers	0-19	£10-19
Fc gamma receptor	1	Researchers	0-19	£10-19
HLA-B*1502	6	Clinicians	0-59	no charge/£119
HLA-B*5701	14	Clinicians	20 to >1000	no charge/£179
TPMT	3	Clinicians and researchers	20-79	no charge/£219

The need for an implementing body whose main function would be to coordinate pharmacogenetic laboratory services in the United Kingdom received a mixed response, with 50% supporting this function. Thirteen of 14 laboratories (93%) stated that there would be an increase in services offered over the next 5 years. The barriers to pharmacogenetic testing are shown in Table 3. Lack of knowledge relating to pharmacogenetics among clinicians was identified by all responders to this question as a barrier to pharmacogenetic testing.

Most of the laboratories (73%) providing pharmacogenetic services in our survey carried out only one or two types of test, suggesting that many potential tests are not currently used or provided in a routine clinical context. Two laboratories provided three tests and one laboratory five tests (Tables 4 and 5).

Discussion

Gardiner and Begg (2005) reported a similar survey of laboratory services providing pharmacogenetic testing across Australasia. Their survey of over 600 laboratories with 510 respondents highlighted that, apart from phenotyping tests for pseudocholinesterase and TPMT activity, there was very little provision or uptake of pharmacogenetic testing services. These findings were consistent with a German study that reported that 20% of clinical laboratories were providing pharmacogenetic tests (Kollek et al., 2006). Of the 35 responders (36%), 10 offered a pharmacogenetic test. The tests were offered by university hospitals and private laboratories, not general hospitals, and most offered only one test (Kollek et al., 2006).

Our study indicates a comparable limited range of pharmacogenetic testing that is clinically available at the present time in the United Kingdom and Ireland. Only one germline pharmacogenetic test that relies on DNA analysis is currently offered with any frequency (HLA-B*5701). However, most laboratories stated that the use of pharmacogenetic tests would increase in the next 5 years, with one commenting that pharmacogenetic testing will be routine and very cheap in a few years time.

It is important to note that the range of clinical laboratories in the United Kingdom is diverse and that pharmacogenetic testing is certainly carried out by biochemistry laboratories. However, our survey failed to get a representative picture of the availability and uptake of services in this sector. However, it is known that ∼50,000 TPMT tests are carried out by two biochemistry laboratories in the United Kingdom and that pseudocholinesterase testing is also widely available (Newman and Payne, 2008; Gurwitz et al., 2009a). Both TPMT and pseudocholinesterase tests are provided as phenotype assays, with use of genetic testing to confirm a TPMT-deficient phenotype or if the patient has undergone a recent blood transfusion (Sandwell and West Birmingham Hospitals, 2009). In addition, our survey did not formally assess the role and contribution of the commercial sector. At least two major laboratories, Medical Solutions (www.medical-solutions.co.uk) and Lab21 (www.lab21.com), have mature portfolios offering a number of pharmacogenetic tests to both the NHS and private healthcare providers.

Although only few pharmacogenetic tests are carried out routinely, the use of pharmacogenetic tests is increasing. This may be a good time to regulate and coordinate pharmacogenetic testing, possibly as part of an existing regulatory body. The H&I laboratories were less supportive of a national coordinating organization. This may reflect the fact that the tests that are being provided by these laboratories are extensions of techniques already employed in the laboratory and no new procedures need to be adopted to provide the tests and so the need for additional regulation or coordination was not seen as relevant. It is also unlikely that H&I laboratories would have ambitions to develop a larger portfolio of pharmacogenetic tests not involving HLA genotyping. The provision of HLA-based pharmacogenetic tests by H&I may explain their rapid adoption, as the laboratories have been able to respond quickly to the clinical demand. The molecular genetics laboratories have experience of providing genetic testing services for Mendelian conditions in a coordinated manner through the United Kingdom genetic testing network. The positive experience of this system most certainly influenced the results of this survey. The National Academy of Clinical Biochemistry in the United States has set out recommendations for pharmacogenetic testing that recognize that guidance is needed in a rapidly developing field with limited evidence for clinical application (NACB, 2007). In the United Kingdom, the House of Lords Science and Technology Committee have identified the need for a coordination of genetic services and evaluation of genetic tests, including pharmacogenetics, before adoption into clinical practice. It has made a recommendation to expand the remit of the National Institute for Health and Clinical Excellence to include a program for evaluating the validity, utility, and cost benefits of all new genomic tests for common diseases, including pharmacogenetic tests (House of Lords Science and Technology Committee, 2009).

Lack of supportive scientific evidence is also an important barrier to provision and uptake of pharmacogenetics. There are an increasing number of genetic variations that have been associated with response to medication in terms of efficacy or side effects. However, evidence demonstrating clinical validity and cost-effectiveness to support the clinical application of pharmacogenetic tests is limited (Gurwitz et al., 2009b).

Lack of knowledge by clinicians was perceived as a barrier to pharmacogenetic testing by both genetics and H&I laboratories. This contrasts with the survey of laboratories providing somatic pharmacogenomic testing, perhaps reflecting an increased awareness and acceptance of genetic tests by hematologists and oncologists (Wordsworth et al., 2008), and highlights the need for a good medical education in pharmacogenetics, which is not generally seen as a priority at present (Gurwitz et al., 2005; Higgs et al., 2009). In the United Kingdom, resources are being developed to provide information to both healthcare professionals, through the NHS National Genetics Education (www.geneticseducation.nhs.uk) and Development Centre, and patients, via Labtests online (www.labtestsonline.org.uk/understanding/features/pharmacogenomics-3.html), about pharmacogenetics.

Our survey demonstrates awareness among laboratories of the potential value of pharmacogenetic tests and a limited provision of such testing services where the demand is greatest and clinical evidence is strongest. It will be important to provide laboratories with the resources to develop services for pharmacogenetic testing as the clinical evidence emerges supporting increased use of these tests.

Footnotes

Acknowledgments

This study was supported through funding by the NIHR Manchester Biomedical Research Centre and MAHSC.

Disclosure Statement

No competing financial interests exist.

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