HLA and disease: the perils of simplification

Article Abstract:

The appearance of two articles in the June 28, 1990 issue of The New England Journal of Medicine concerning genetic predispositions to particular diseases prompted an editorial advising caution in interpreting experimental results. Particular sites (loci) on a chromosome can be occupied by any of several alleles (different forms of a gene). One research paper concerned the tendency for people with primary sclerosing cholangitis (a chronic inflammatory condition of the bile ducts) to possess particular HLA alleles (alleles in the region called HLA on chromosome 6, an area that codes for genes active in the immune response). The other paper noted associations between insulin-dependent diabetes mellitus (IDDM) and particular HLA alleles. When disease susceptibility is inferred from such data, however, several facts must be considered. Relative risk determination was used to evaluate the significance of the occurrence of particular HLA haplotypes (the series of alleles at the HLA locus on a single chromosome) in people with the diseases studied. Certain alleles normally tend to occur more often on a given haplotype; this introduces important statistical concerns when calculating whether people with a particular disease 'really' have an HLA marker more often than would be expected. Disease susceptibility may not be the only reason why such alleles group together. Another recent development that, paradoxically, may lead to incorrect interpretation of experimental results is the determination of the structure of HLA molecules. The lack of a the amino acid aspartate (which is the product of one gene) at position 57 on one of the HLA protein chains was interpreted to mean that this single amino acid is responsible for HLA-induced susceptibility to IDDM. However, several other reports have shown that this amino acid is not the only determinant of susceptibility; other alleles have been implicated. Overall, showing that a particular structural characteristic is associated with a disease is not identical with proving susceptibility to that disease. Considerably more information is required before susceptibility can be definitively described. (Consumer Summary produced by Reliance Medical Information, Inc.)

Methods, Criticism and interpretation, Identification and classification, Immunology, HLA histocompatibility antigens, HLA antigens, Histocompatibility testing

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What drives neonatal screening programs?

Article Abstract:

In the September 12, 1991 issue of The New England Journal of Medicine, researchers report the results of a trial of a new screening program designed for the early detection of cystic fibrosis among infants. The trial was conducted in Colorado, and it seems likely that the adoption of mandatory screening for cystic fibrosis in that state was not a coincidence. However, this adoption of mandatory screening illustrates the irrational basis on which such decisions are made. In Colorado, the screening was made mandatory even before the results of the research were complete. Even now, it is far from certain that the screening will have any beneficial effects for anyone. All infants are tested; many infants, therefore, are tested for the possible benefit of a few. Furthermore, it is not known whether early detection will actually result in better treatment for the few who are discovered to have cystic fibrosis. This can only be determined on the basis of further research, which may never be done. There is a great risk that the health of any child with mild symptoms may be attributed to the early screening program, rather than to improvements in treatment or inherently mild disease. Furthermore, routine testing adds further to the cost of medical care, already pressing the limits of available resources. Unfortunately, with constant improvements in genetic technology, it is likely that the problem of evaluating the practical benefits of neonatal screening programs will become worse. Careful research must establish the costs and benefits of newly developed screening methods. Furthermore, special interest groups must not be permitted to push screening techniques into standard use. Rather, means must be found to enable broad participation in the decisions concerning the practicality and desirability of newborn screening programs. (Consumer Summary produced by Reliance Medical Information, Inc.)

Evaluation, Testing, Infants (Newborn), Newborn infants, Medical screening, Health screening

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Will genetics revolutionize medicine?

Article Abstract:

Doctors should spend more time identifying the social, environmental, and behavioral causes of disease rather than the genetic causes. Most diseases do not have a strong genetic component, even those that tend to run in families. Many diseases are caused by interactions between several genes and the environment. Even when a gene mutation is linked to a disease, it may only account for a few percent of the cases. For this reason, widespread genetic screening may be a waste of time and money. It may also be difficult to develop treatments for genetic diseases, especially if multiple genes are involved.

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