PubMed · 8706952
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J Dausset. 1996. Predictive medicine.. https://doi.org/10.1016/0028-2243(95)02299-8
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Schizophrenia is generally thought to arise as a result of interactions between genetic vulnerability and environmental risk factors. However, research methods to actually investigate the pattern of hypothesized interactions have only recently been developed. In this article, we review the evidence that genes increase the risk for schizophrenia by making individuals more sensitive to environmental risk factors (genotype-environment interaction), or by making individuals more likely to select high-risk environments (genotype-environment correlation). It is likely that at least some of the impact of genes on the occurrence of schizophrenia is mediated through (sensitivity for) environmental risk factors such as a dysfunctional early family rearing environment, cannabis, viral infections, complications of birth and pregnancy, stressful life events and unknown environmental risk factors associated with urban birth or residence and membership of certain ethnic groups. With the advent of molecular genetics, further knowledge about possible genotype-environment interactions is urgently required in order to develop and improve strategies for the prevention and early treatment of schizophrenia.
IFN-gamma is critical in the immune response to mycobacterial infections, and deficits in IFN-gamma production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN-gamma receptor ligand-binding chain (IFNgammaR1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-gamma receptor signal-transducing chain (IFNgammaR2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-gamma signaling due to a mutation in the extracellular domain of IFNgammaR2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-gamma production than in normal cells, while patient PHA-induced TNF-alpha production was normal. The normal augmentation of TNF-alpha production when IFN-gamma was added to endotoxin was absent from patient cells. Expression of IFNgammaR1 was normal, but there was no phosphorylation of Stat1 in response to IFN-gamma stimulation. DNA sequence analysis of the gene for IFNgammaR2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN-gamma plays in host defense against mycobacteria.
Studies of molecular genetic changes in prostate carcinomas are slowly improving our understanding of the biological process which leads to a normal prostate epithelial cell becoming an adenocarcinoma cell with invasive and metastatic properties. Carriers of germ-line mutations in still unidentified prostate cancer susceptibility genes, one of which has been localised to chromosome arm lq, seem to be particularly prone to develop the disease. The susceptibility genes have to be identified and the effects of carrier detection evaluated before genetic testing for prostate cancer predisposition can be performed in a clinical setting. The identification of specific molecular genetic changes in prostate carcinomas may become clinically useful diagnostic and prognostic tools. An improved understanding of the molecular genetic mechanisms underlying the development of prostate cancer may eventually yield novel therapeutic strategies, attacking specific genetic changes in the prostate carcinomas.