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Three subgroups of the Human Genetics Commission, the main advisory body to the UK Government on issues to do with genetics, have recently published minutes of meetings held earlier in the year. The Business Committee affirmed the HGC's strong interest in the plans for the UK Population Biomedical Collection, and its wish to be closely involved in the discussions. While the Commission in general is likely to be concerned mainly with the ethical issues surrounding the proposed study, the Horizon Scanning subgroup noted that many scientific aspects also need scrutiny, and that it would contribute to the discussion in this area. The Horizon Scanning subgroup is also preparing a briefing paper for the HGC on the current scientific status of testing and screening technologies, as a contribution to an information-gathering session on "FISH and Chips" planned for the HGC's plenary meeting in June.

The Genetic Testing subgroup has been continuing work on finalising the HGC's contribution to the report arising from the joint consultation with the Human Fertilisation and Embryology Authority on preimplantation genetic diagnosis. The subgroup discussed the issue of aneuploidy screening (testing for chromosomal abnormalites). Members agreed that there should be equivalence in this respect between PGD and prenatal genetic diagnosis (PND), where aneuploidy screening to detect serious chromosomal abnormalities is a routine part of the service. However, the subgroup thought it was important that PGD should not be seen as a way of selecting for particular desired characteristics. In the area of prenatal genetic testing and screening, the HGC intends to work increasingly closely with the National Screening Committee, to ensure consistency of approach. Two issues of immediate concern, discussed by the subgroup, are the introduction of a national antenatal and neonatal screening programme for haemoglobinopathies (pledged in the NHS Plan), and the publication of advice on prenatal genetic diagnosis.

Most individuals suffering from the iron-overload disease hereditary haemochromatosis carry mutations in both copies of their HFE gene. The two disease-associated mutations that have been identified are known as C282Y and H63D. As the population prevalence of genetically defined hereditary haemochromatosis has been estimated to be between 1 in 200 and 1 in 500, and a relatively straightforward preventive treatment is available (regular phlebotomy), it has often been suggested that population screening for hereditary haemochromatosis should be offered. However, accurate information is lacking on the prevalence and penetrance of haemochromatosis-associated mutations, and on the financial and social consequences of treating people who have a disease susceptibility rather than the disease itself. Steinberg et al contribute an important piece of information to the analysis: population-based estimates of the prevalence of C282Y and H63D mutations in the US population [Steinberg, K et al (2001) JAMA 285, 2216-2222 (Abstract)]. Using DNA from cell lines established as part of the Third National Health and Nutrition Examination Study (NHANES III), they genotyped 5171 individuals who described their race as non-Hispanic white, non-Hispanic black, or Mexican American. They estimate that overall approximately 0.26% (1 in 385) Americans are homozygous for C282Y, 1.89% are homozygous for H63D and 1.97% are compound heterozygotes (i.e. C282Y/H63D). The prevalence of the C282Y allele is significantly higher in non-Hispanic whites than in the other two racial/ethnic groups.

Comment: The results of this study are broadly in line with previous estimates from smaller studies, confirming a relatively high prevalence of genotypes associated with hereditary haemochromatosis in populations of predominantly white European origin. Steinberg et al are currently determining transferrin saturation levels (that is, a phenotypic indication of haemochromatosis) in the NHANES III samples, in an attempt to estimate the penetrance of the mutations. However, as the samples have been irrevocably anonymised, it will presumably not be possible to estimate the penetrance of the genotypes in terms of overt disease. 

Sciona Limited, a small company based in Hampshire, is offering, for a subscription fee of £120 a year, to compile an individually-tailored health "Action Plan" based on information from a client's genetic profile. The company claims that by analysing specific polymorphisms in DNA extracted from a mouth swab sample, and combining this with information about lifestyle, it can advise an individual "about their metabolism, how it reacts to different foods, what to eat more of, what to eat less of or what to avoid altogether". The DNA sample will be retained and re-analysed so that the Action Plan can be updated as new information becomes available, the company says. The concept behind Sciona's service - individually tailored healthcare based on an understanding of gene-environment interactions - is the Holy Grail of those who predict a future era in which genetics will make a major contribution both to prevention and to medical care. Most experts, however, think that current knowledge is inadequate to make this vision a reality for at least another 10 years. It would be interesting to know exactly what Sciona's analysis consists of, and what scientific evidence backs it up.

A paper in the BMJ reports the recommendations of a Canadian workshop on the criteria that should be satisfied by genetic screening programmes [Goel, V. (2001) BMJ 322, 1174-1178]. Starting with the classical Wilson and Jungner criteria, the participants adapted and added to them to arrive at an expanded set that they felt were appropriate for screening programmes involving genetic tests. Additions to the Wilson and Jungner criteria include the need to ensure that facilities are available for education, counselling and social support; that these factors are included in the economic analysis of the programme; that screening does not lead to discrimination or violation of confidentiality; and that the test is acceptable to the individual, their family and society. Another important addition is that the target population or population at risk should be identifiable. Although not explicitly stated, the assumption seems to be that identification would usually be on the basis of family history. The paper describes the use of the proposed criteria to assess a hypothetical programme to screen for hereditary colorectal cancer.

Comment: The proposed criteria represent a good starting point for discussion. It could be argued, however, that many of the assumptions that underlie the additional criteria may be appropriate only for the rare highly-penetrant Mendelian (single-gene) subsets of common disease, such as hereditary non-polyposis colorectal cancer. If programmes were ever to be proposed that involved screening for (combinations of) normal polymorphisms involved in susceptibility to common disease, extensive counselling might not be necessary. Another possible weakness of the paper is that it does not define when a test or screening programme should be defined as "genetic".  

Crohn's disease, estimated to affect about 0.1% of people in western populations, is one of the two major types of inflammatory bowel disease. Twin and family studies have suggested that disease is caused by genetic factors interacting with unknown environmental triggers. Now, two papers to be published in Nature on 31 May independently report that alterations in a gene encoding a protein that participates in cell signalling pathways involved in immune responses increase susceptibility to Crohn's disease [Hugot, J-P. et al (2001) Nature 411, 599-603; Ogura, Y. et al (2001) Nature 411, 603-606]. The gene, NOD2, is in a region on chromosome 16 that had previously been shown to be associated with the disease. Both research groups show that various alterations in the sequence of NOD2 are significantly more common in Crohn's disease patients than in controls. In contrast, the NOD2 variants were no more frequent in patients with ulcerative colitis, the other major type of inflammatory bowel disease, than in controls.

Comment: It is important to note that the association between these NOD2 gene variants and Crohn's disease is not absolute: not everyone who has one of the variants will get the disease, and not everyone with Crohn's disease has an alteration in NOD2. It is estimated that at least five additional genes are also involved in susceptibility to Crohn's disease. However, this work is an important advance in understanding the genetic contribution to Crohn's disease. Quite a lot is already known about the function of the NOD2 gene, and the hope is that by studying how this function is affected by the sequence alterations found in some Crohn's disease patients, it will be possible to learn more about the disease process and to design more effective therapies.  

Note added 8/6/01: For a more detailed analysis of this paper, see the new HuGE Net e-journal club, set up by the CDC Office of Genetics and Disease Prevention. Papers chosen for the e-journal club will be abstracted using a standard template, and a one-page summary analysis prepared. Anyone who is interested in the e-journal club can sign up to join the HuGE Net listserv.

Note added 15/6/01: A paper published in the Lancet, reporting the results of family-based association studies and case-control studies in German and British populations, confirms the association between NOD2 variants and susceptibility to Crohn's disease. The authors calculate an odds ratio of about 2.6 for individuals heterozygous for an insertion mutation that is thought to lead to production of a dysfunctional protein. The odds ratio for homozygotes (approximately 0.2% of the population) is estimated to be at least 40 [Hampe, J et al (2001) Lancet 357, 1925-1928].

Leading epidemiologists are concerned that the interpretation of the Data Protection Act by the Department of Health, local health authorities and the General Medical Council is hindering vital research on the causes of death and ill health. Last week a letter in the BMJ stressed the importance of medical information for auditing population screening and health promotion activities. Adding his voice to the debate, Professor Julian Peto of the Institute of Cancer Research has claimed that research funded by the Health and Safety Executive into the association between asbestos exposure and cancer has been held up for well over a year because the relevant authorities claim they cannot provide the researchers with the names of doctors who may have patients eligible for the study, or with information that would enable them to find potential healthy controls (see report in The Times). Without access to medical information about individual patients, research into the genetic and environmental causes of disease cannot go ahead.

A clause in the Health and Social Care Act, which has just received royal assent, enables the Secretary of State for Health to permit the use of patient information for specific purposes if it is in the public interest, but researchers fear that its application may be too cumbersome and that medical research should have a blanket exemption from the provisions of the Data Protection Act. During the passage of the Health and Social Care Bill through Parliament, the House of Lords successfully opposed a clause that would have enabled the Secretary of State to restrict the disclosure and use of anonymised patient information for commercial purposes (for example by the pharmaceutical industry). The Government also agreed to establish a statutory advisory committee to review the Act's provisions on confidential medical information, and the use of these provisions by the Secretary of State

Two recent papers in the journal Family Practice discuss the appropriateness of GP referrals to the Regional Genetics Service because of concerns about a family history of breast cancer. Watson et al found, in a survey of 45 GPs who referred patients to the Oxford Regional Genetics Service, that only about half of referrals clearly met referral criteria that had been sent to GPs two years earlier [Watson, E. et al (2001) Fam Pract 18, 131-134 (Abstract)]. The remainder either did not meet the criteria, or there was insufficient information in the referral letter to determine whether the criteria had been met or not. The study also revealed that GPs had unrealistic expectations about the sorts of advice and interventions that might result from a consultation at the family cancer clinic: in general, GPs overestimated the likelihood that their patients would be offered genetic testing, or advice on prophylactic mastectomy or oral contraceptive use. In an accompanying paper, Lucassen et al analyse GP referrals before and after circulation of referral guidelines [Lucassen, A. et al (2001) Fam Pract 18, 135-140 (Abstract)]. They found that the guidelines did improve the accuracy of genetic risk estimation by GPs and that the informativeness of referral letters improved.

Comment: All Regional Genetics Services in the UK have reported a large increase in the numbers of patients referred to them because of concerns about a family history of breast/ovarian or bowel cancer. In many cases it turns out that the family history does not indicate a significantly increased genetic risk. Various ways of improving the appropriateness of referrals have been investigated, including the issuing of guidelines, and providing GPs with decision-support tools to help them assess genetic risk. Lucassen et al show that guidelines do help, but the study of Watson et al suggests that, unless these guidelines are fresh in GPs' minds, they are likely to be forgotten. Perhaps the solution is regularly-updated web-based information that all GPs know about and can access rapidly.

The Human Genetics Commission (HGC) has recommended that, except in respect of high-value policies (over £500,000), insurance companies should not be permitted to use the results of genetic tests in assessing risk for insurance underwriting purposes, for at least the next three years (see recommendations). Even in the case of high-value policies, the HGC suggests that the only tests whose use should be permitted are those approved by the Genetics and Insurance Committee (currently only Huntington's disease, though tests for a few other rare single-gene disorders are currently under consideration). During the period of the moratorium, which the HGC says should be imposed by legislation, insurers would still be able to use favourable test results submitted to them voluntarily by an applicant for insurance.

The HGC points out the substantial level of public concern over the issue of genetics and insurance, and notes that the House of Commons Select Committee on Science and Technology recently concluded that the current system of self-regulation by the insurance industry was not working satisfactorily. The HGC also calls into question the way family history information is used by insurers, and suggests that during the moratorium period this issue could be investigated. The aim would be to devise a regulatory system for the use of all genetic information in insurance that would have the confidence of both the public and the insurance industry.The Government's response to the HGC's recommendation is awaited.

On the same day that the HGC recommendations were released, the Association of British Insurers announced that its member companies would not use the results of genetic tests in assessing premiums for any type of insurance product, up to a policy value of £300,000. This extends the ABI's former commitment not to use genetic test results for life insurance linked to mortgage applications up to a value of £100,000. For policies over £300,000, only the results of tests approved by GAIC can be used.

As part of a raft of measures aimed at improving maternity and neonatal services, initiatives to offer antenatal serum screening for Down's syndrome to all pregnant women, and to introduce universal neonatal screening for cystic fibrosis, were announced recently by public health minister Yvette Cooper (see Department of Health press release). Current Down's syndrome screening services are patchy and inconsistent (see article in the November 1999 newsletter); beginning in 2001/2 (and assuming, presumably, that a Labour government is returned after the June election), the new UK-wide service would offer serum screening to all pregnant women during the second trimester of pregnancy, with the option of amniocentesis for those who tested positive. A network of regional coordinators has been set up to coordinate services, implement new standards and ensure that counselling services are available to help women consider the antenatal testing options open to them.

Current practice in screening newborns for cystic fibrosis is also very variable: regions offering screening account for only 20% of infants born in the UK. The National Screening Committee (NSC) recently decided that there was insufficient evidence to recommend universal neonatal screening for CF, but new evidence from a large study in Wisconsin has shown that CF children identified by newborn screening have better long-term health outcomes than those identified by other routes [Farrell, P.M. (2001) Pediatrics 107, 1-13 (Abstract)]. During 2001, the NSC will advise on the development and implementation of a neonatal screening programme using the Guthrie bloodspot card.

An international study comparing BRCA1 and BRCA2 mutation carriers with and without ovarian cancer has found that women with a BRCA1 mutation who were free of ovarian cancer were more likely to have had a tubal ligation than were mutation carriers who had suffered invasive ovarian cancer [Narod, S.A. et al (2001) Lancet 357, 1467-1470]. The two groups, each containing 173 women, were matched as far as possible for other relevant factors such as age, year of birth and oral contraceptive use. Tubal ligation appeared to have no effect on the risk of ovarian cancer in a smaller group of women with BRCA2 mutations. Previous studies have suggested that tubal ligation protects against ovarian cancer in the general population of women, but it was not known whether this protective effect applied to women with BRCA1 or BRCA2 mutations. The authors suggest that BRCA1 mutation carriers who have completed their families might be offered tubal ligation to reduce their ovarian cancer risk, followed by oophorectomy at a later age when the menopausal symptoms associated with this procedure might be more acceptable.