Genetic testing

Letters to the Editor

Genetic

testing

StR-In your well-intentioned editorial (Jan 20, p 133)1you ask for a bold solution to the use of genetic test results by insurance companies, to preserve equality of access to health care insurance. The consequences of accepting your proposals would be an embargo on all insurance underwriting-not only that based on genetic tests. Your proposal would further fail to differentiate between health care insurance and life insurance, thus extending the ban to both. There are two important counter-arguments, ethical and practical. Few would argue with equality of access for health care, but what of life insurance? Such insurance is generally linked to a loan for business or home, and provides protection for the lender in the event of untimely death of the borrower. It hardly has the status of a basic human right, unlike access to health care. Removal of the right to underwrite life insurance-which seeks to equate the risk to the life fund with the premium paid into it-will lead to unsupportable pressure on insurance companies. In reality, premiums would rise for all, to ensure adequate funds to pay the higher number of claims. Families would need to spend more on insurance premiums, which would be most damaging to the less well paid. Moreover, those who would previously have obtained standard rates may seek their life insurance elsewhere (overseas if necessary) weakening the life fund further. Insurance companies have collapsed in this way before, and may do so again, leaving their policyholders without the protection they expect. If society, through the government, does deem access to life insurance essential, it could create a national life insurance company, akin to the National Health Service. This truly bold solution is unlikely to happen; the escape route to which you allude-that of transferring the problem to the insurance companies-is likely to prevail, despite its immorality and impracticability. The "tinkering" you condemn-ie, painstaking between all interested much more parties-is negotiation to a solution that could be to all. likely provide acceptable G H Hall, *W T Hamilton 5a Victoria Park Road, Exeter; and *Barnfield Hill Exeter EX1 1SR. UK

1 Editorial. Have you had

a

Surgery,

gene test? Lancet

12 Barnfield Hill,

1996; 347: 133.

SIR-In your editorial’ you highlight the potential for the creation of myriad bands of insurance premiums on the basis of assessment of genotype rather than individual and familial phenotype. The call for a long-term solution based on the wishes and needs of society as a whole is attractive, but the pressure from the insurance industry and genetically low-risk individuals will not be easy for politicians to ignore, and in this climate of uncertainty there are implications for research.

Some form of genotyping is now commonplace in all types of clinical research; in large epidemiological studies and small mechanistic investigations, and it is no longer solely the province of the clinical geneticist. Healthy or other volunteers often want feedback from studies in which they participate and may think it only a curiosity to be told that they carry a certain polymorphism of the gene for angiotensin-converting enzyme gene or nitric oxide synthase or some other gene of current interest and unknown importance with respect to risk (how many volunteers were innocently told their apolipoprotein E status before a link with dementia was recognised?). If the results of genetic tests are to be made available to research volunteers (even if they are only told that they have had such a test and are not given the result), they need to be made fully aware of the potential consequences-social as well as medical. These concerns must not be allowed to impede research, but it will be some time before the position is clear, and in the interim local research ethics committees should take care to protect volunteers, researchers, and themselves. National guidelines would help to ensure a unified approach. Patrick Vallance Centre for Clinical Pharmacology, Cruciform Project for Strategic Medical Research, Department of Medicine, University College London, London W1P 9LN, UK

1

Editorial. Have you had

a

gene test? Lancet

1996; 347: 133.

SiR-Harper (Dec 23/30, p 1645)’ focuses on the challenges for long-term health service resource allocation as the scope of genetic testing extends beyond simple mendelian inheritances. We report a simplification in the logistics of specimen collection during population screening as a timely contribution to stretching existing genetic resources. Model genetic screening programmes have been developed for various autosomal recessive conditions.2,3 These involve enzymatic or DNA analysis of blood samples to identify symptom-free heterozygotes, who can then be offered genetic counselling. Alternative specimens to peripheral blood have been proposed for genetic diagnosis, including buccal cells, mouthwash, hair roots, urine, and Guthrie cards. We have evaluated a mouthwash specimen protocol.4 Specimens for genetic analysis were obtained by healthy volunteers vigorously rinsing the mouth with about 30 mL tap-water. We isolated DNA by centrifuging the specimen (500 g, 10 min), boiling the pellet in 400 µL of 50 mmol/L NaOH, cooling, adding 200 µL of 0-1mmol/L Tris-HCL pH 8, and centrifuging (10 000 g, 1 min) to pellet the debris. A single, well-collected mouthwash yielded an average of 150 Ilg of DNA (equivalent to a 4 mL peripheral blood collection). There was no degradation of genomic DNA by intrinsic nucleases in the specimen for up to 2 weeks between specimen collection and DNA isolation, even when specimens were stored at room temperature. Genetic analysis by PCR-amplified fragment-length polymorphism (AFLP) showed no inhibition of amplification in more than 120 mouthwash samples, including those obtained from individuals after cigarette smoking, eating, brushing teeth 685

with toothpaste, gargling with peroxide, or inhaling or salbutamol beclomethasone. Genetic analysis of mouthwash was in accord with leucocyte DNA AFLP results, and (for Tay-Sachs disease testing) with serum hexosaminidase A classification. We tested the stability of the crude DNA preparation by storing it at -20°C for up to 6 months, and found specimens thus stored could be successfully reamplified and analysed. We tested client acceptance of mouthwash samples at several metropolitan senior high schools as part of a Tay-Sachs disease community genetic screening programme. There was a 25% increase in the rate of client consent for testing when mouthwash was offered as an alternative to venepuncture. This simplified mouthwash collection and analysis technique seems ideal for genetic screening. Mouthwashes can be easily and rapidly collected, have high client acceptance, require no collection equipment, are amenable to delay between collection and analysis, yield large amounts of DNA that is readily amplified with ease and without encountering inhibitors, and can be stored in ordinary freezers.

response

Viive M Howell, *Leslie Burnett

Is mutated MTHFR tube defects?

a

SiR-Three studies have 677T-C mutation in

suggested

Department of Clinical Chemistry and Molecular Genetics, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2145,

the report of the House of Commons Select Committee on Science and Technology on Human Genetics states, "There is no intention to devolve funding for all the functions and elements, or the collaborative and coordinating roles, of the genetic services to GP fund holders". Assuming the continuing support of genetic centres as partners, the Royal College of General Practitioners has asked its northwest faculty to define (with advice from geneticists) what aspects of genetics are appropriate for primary care and what training GPs, trainees, and other primary care staff will need. Clifford

(January, 1996)

to

Kay, Hilary Harris, *Rodney Harris

Primary Care Genetics Group, Royal College of General Practitioners; Brooklands Medical Practice, Manchester; and *Medical Genetics, St Mary’s Hospital, Manchester M13 0JH, UK

1

Harper PS. Genetic testing, common diseases, provision. Lancet 1995; 346: 1645-46.

and health service

risk factor for neural

Australia

1

2

3

4

Harper PS. Genetic testing, common diseases, and health service provision. Lancet 1995; 346: 1645-46. Kaback M, Lim-Steele J, Dabholkar D, et al. Tay-Sachs disease-carrier screening, prenatal diagnosis and the molecular era: an international perspective, 1970 to 1993. JAMA 1993; 270: 2307-15. US Congress, Office of Technology Assessment. Cystic fibrosis and DNA tests: implications of carrier screening, OTA-BA-532 (Washington DC: US Government Printing Office, August 1992). Gilfillan A, Axton R, Brock DJH. Mass screening for cystic fibrosis heterozygotes: two assay systems compared. Clin Chem 1994; 40: 197-99.

SiR-Harper’ argues that a long period of appraisal is necessary before investment in new services to exploit the genetic prediction of common disease susceptibility. But the UK National Health Service (NHS) has an immediate difficulty. Molecular genetics and public expectations are outstripping the capacity of existing genetic centres to offer counselling, screening, and diagnosis for traditional singlegene and chromosomal

disorders, and general practitioners

(GPs) are having difficulty coping with their patients’ anxieties about family histories, especially of breast and bowel cancer. Cancer family referrals to genetic centres, harbingers of other potentially hereditary common diseases, are increasing rapidly and we cannot afford to be complacent. Although an expansion of genetics services is badly needed, the situation would be less alarming if primary care teams were trained to refer appropriately to specialists, and to deal with the rest themselves. At the moment this ability is limited by workloads in general practice, and by a deficit of clinically relevant genetics education in medical schools and in GP training courses. But things are changing rapidly. Genetics and primary care are top of the list of priorities for NHS research and development and health technology assessment. The government (in common with many other governments in Europe) is encouraging the transfer of some hospital services into the community. Managed care is topical, which at its best means continuity of care involving hospitals, primary care, and other agencies, including social services and patient support groups. The primary care team is becoming increasingly sophisticated and computerised. Specialist nurses are increasing in numbers. To help to reassure those who feared a take-over by fundholding GPs, ill-equipped to provide genetics services, the government’s 686

that

homozygosity for the the gene coding for a 5,10methylenetetrahydrofolate reductase (MTHFR), which results in a thermolabile variant of the MTHFR enzyme, is a risk factor for neural tube defects (NTDs).’-3 We have reviewed pooled results from these studies and raise methodological issues in interpreting these data in relation to the known protective effects of folic acid against these defects. These studies are summarised in the table. Compared with the homozygous normal genotype, homozygotes for the 677T-C mutation with low enzyme activity have an increased risk of NTDs, whereas the risk is only slightly increased in heterozygotes with intermediate enzyme activity (table). Assuming a causal association with 677T-C mutation homozygosity, and with the Miettinen formula for attributable fraction, we calculate that 13% of NTD cases can be attributed to the homozygous 677T-C mutation. If 677T-C heterozygosity is a causal risk factor, an additional 11 % of NTD cases may be attributed to the mutation. These attributable fractions fall well below the 50-70% reduction in NTD rates that occur with adequate periconceptional consumption of folic acid. Therefore, the protective effect of folic acid against NTDs probably involves additional biological interactions with other mutations in this gene, other genes, or other NTD risk factors. Further to these calculations, four methodological issues need to be considered when interpreting the findings from these studies. First, none of these studies had an appropriate control group derived from the same population in which the cases occurred. The use of convenience controls raises concern the about potential for confounding by race/ethnicity or other NTD risk factors. This is especially important since the frequency of 677T-C homozygosity varies among populations (eg, French Canadians [12%] and Italians [163%]).’ Second, because 677T-C homozygosity can be associated with a higher risk of morbidity and mortality from vascular disease, the use of prevalent NTD cases rather than incident cases raises the concern that the finding may indicate an effect on intrauterine and postnatal survival, rather than a causal role on the genesis of NTDs. Third, it is not clear from these studies whether the MTHFR association is due to the maternal or fetal genotypes, or both. Disentangling maternal effects from fetal