We identified pepsinogen C (PGC) gene polymorphisms by means of PCR, which amplified DNA in the region within the intron between exons 7 and 8, and by 6% polyacrylamide gel electrophoresis. Six alleles were found in a Japanese population. The frequencies of these alleles in 408 unrelated Japanese individuals were 0·074, 0·026, 0·335, 0·237, 0·016 and 0·314, respectively. The serum pepsinogen II level significantly decreased in the order of the allele 6 homozygote, the allele 6 heterozygote and the other genotypes (χ2=7·850, D.F.=2, p=0·020). These findings indicated that the genetic background of serum pepsinogen should be considered when screening for stomach cancer by this procedure.

Phosphoglucomutase 1 (PGM1) deficiency is a stable characteristic of the erythroleukaemic cell line, K562, whereas the activity of the isozymes of the other two PGM loci (PGM2 and PGM3) is slightly elevated. In this study the molecular basis of PGM1 deficiency was investigated by a combined approach utilising protein electrophoresis, immunodetection, cytogenetic techniques, and DNA and RNA analysis. Isoelectric focusing and activity staining confirmed that K562 has no detectable PGM1 activity. Immunoblot analysis of extracts, separated by isoelectric focusing, starch gel and SDS gel electrophoresis, using monospecific anti-PGM1 antibodies showed that K562 contained no detectable immunoreactive material. Karyotype analysis revealed the presence of two intact chromosomes 1 and a derivative chromosome 1, der(1)t(1; 11), each of which carried a copy of the PGM1 gene as demonstrated by fluorescence in situ hybridization using a PGM1 cosmid as probe. Southern blot analysis using a PGM1 cDNA clone as probe suggested that the PGM1 genes had not been subject to any gross structural rearrangements. We were also able to determine that K562 is type PGM1 2+1+ by restriction endonuclease analysis of genomic DNA. Very low levels of PGM1 mRNA which appeared to be full length transcripts were detected in K562 using a reverse transcriptase PCR technique. We conclude that the most likely cause of PGM1 enzyme deficiency in K562 is abnormal regulation of transcription.

Complex segregation analysis was conducted in a series of patients with hereditary non-polyposis colorectal cancer (HNPCC) ascertained through probands registered in the Cancer Registry of the Health Care District of Modena, Northern Italy. Altogether there were 125 nuclear families segregating for HNPCC, for a total of 672 individuals. The analysis favoured a two-locus model, with both susceptibility genes rare and dominant. The gene frequency of the deleterious allele at the major locus is estimated to be low qm=0·004 and for the second locus the estimate is even lower q=0·00003. Both genes defining the two-locus model seem to be highly penetrant. The lifetime penetrance of the abnormal gene at the major locus is estimated to be 0·73 for female, while the estimation for male is higher, 0·85.

We addressed the question: Is there evidence that allelic variation in a single unmeasured gene that has a large effect on maximal activity of erythrocyte sodium-lithium countertransport (Na-Li CNT) also has pleiotropic effects on variation in plasma triglyceride levels? Complex segregation analysis models that included plasma triglyceride levels as a covariate were considered as explanations for interindividual variation in Na-Li CNT. A sample of 711 healthy adults from 254 pedigrees enrolled in the Rochester Family Heart Study was selected for this study. The majority of the pedigrees supported the hypothesis that variations in a single unmeasured non-transmitted environmental factor have large effects on the Na-Li CNT distribution. Only gender-specific first-order covariate parameters were necessary in the complex segregation models suggesting that the form of the relationship between Na-Li CNT and plasma triglyceride level was not influenced by variation in the inferred environmental factor with large effects. Stratification of the sample by this inferred environmental factor resulted in three classes of individuals with significant differences in the distributions of coronary heart disease risk factor traits, as well as interindividual variation in both Na-Li CNT and plasma triglyceride levels. These results, along with other observations from the Rochester Family Heart Study sample, emphasize the complex and multifactorial nature of the causes of interindividual variation in Na-Li CNT. Our study further suggests that new research strategies are needed for studying the relationships between genetic and environmental variation and variation in quantitative traits such as Na-Li CNT that have been identified as risk factors for hypertension.

We have studied the impact of natural selection through stillbirth on the Italian population, taking into account the socio-economic heterogeneity of the country. The results suggest that older age at delivery and lower cultural level of the mothers, indicators of critical biological and socio-economic conditions, even at present increase stillbirth risk. Moreover, in the less favourable environment of the southern regions, selection is still sex-specific.

As part of the 1990/1991 Pakistan Demographic and Health Survey, data were collected on the outcome of 26408 births to 6611 women, with mortality rates investigated at specific age intervals during the first 5 years of life. Bivariate and multivariate logistic regression analyses were employed to examine the comparative roles of consanguineous marriage and a number of demographic and socioeconomic factors, including the sex of the child, maternal age, maternal education, birth interval and birth order, as determinants of early death. The results indicate that, even after controlling for these non-genetic variables, inbreeding at the level of first cousin exerted a significant adverse effect on survival in four of the five age intervals examined, neonatal, post-neonatal, infant and under 5 years.

The transmission/disequilibrium test (TDT), for evaluation of the null hypothesis of neither linkage nor association between a marker locus and disease, is extended to the more general situation of transmission of two multi-allele marker loci from parents to affected offspring. Transmission probabilities are derived for a generalized single locus disease model, where the disease locus is taken to lie between the two marker loci. There could be unlinked modifier loci for the disease. Examples of the extended TDT are given and it is shown how the contribution from each locus can be evaluated, both separately and jointly.

A score statistic for testing the Hardy–Weinberg law for data sampled from several populations with different allele frequencies is derived assuming a common coefficient of disequilibrium (odds ratio-type) across strata. The assumption can be examined by a chi-square goodness-of-fit test. It is unlikely such a model would be rejected in typical studies involving human populations. Under this model, a Wald-type test has substantially less power than the score test. An approximate formula for the sample size required for a specific power of the stratified score test for detecting departure from equilibrium is given.

Sponsored by the Oasi Institute for Research on Mental Retardation and Brain Aging Genetics is a rapidly growing field of medical science, which reveals molecular mechanisms of biological phenomena in health and disease. For this reason, we selected the topic ‘Neurogenetic Disease: From Molecule to Patient’, for the 4th International Symposium on Brain Dysfunction to be held September 1997. Various aspects of neurogenetic diseases: phenotype, pathology, pharmacology, biochemistry, genetics, animal models, and treatment will be discussed. We hope that this international meeting will further promote research in this field in order to understand pathogenesis as well as to develop new therapeutic approaches to genetic diseases affecting the nervous system.