Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate.

The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity.

Loss of calcitonin receptors: a genetically transmitted defect in rats with high incidence of C-cell tumors.

C-cell tumors (medullary thyroid carcinoma) occur in humans and several other mammalian species. This tumor develops spontaneously with a high incidence (50%) in old Wag/Rij (Wistar-derived strain) rats. We have recently shown that calcitonin binding sites, which are present in the Wistar rats, are lost from renal medulla of the Wag/Rij rats before they reach the age of 1 month. In the present work, we investigated the distribution of calcitonin binding sites in the kidneys of first and second generation hybrids of Wistar x Wag/Rij rats. The absence of calcitonin binding sites from the renal medullas of 25% of F2 hybrids indicates that the deficiency is inherited in a Mendelian fashion and opens the way to establishing inbred strains lacking renal medullary calcitonin binding sites.

Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association.

A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 phenotypes was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.

[HLA system and malignant diseases (author's transl)]. / Complexe HLA et tumeurs malignes.

Since ten years, there is an extensive search for association between antigens of the major histocompatibility system HLA and malignant diseases. Data show only weak associations with Hodgkin disease and acute lymphocyte leukemia. For studies of a variety of solid tumours the difference between patients and controls do not attain statistical significance, except for nasopharyngeal carcinoma. According to the gene frequency variations in populations and the ethnic differences in some cancers, inter-population studies are possible. Significant geographic associations between some cancers and HLA antigens have been found. They give evidence for a genetic background of susceptibility or resistance to cancer.

[Comparative study of anti EBV antibodies in non-Hodgkin's lymphomams and angio-immunoblastic lymphadenopathies (author's transl)]. / Anticorps dirigés contre le virus d'Epstein Barr. Etude comparative au cours des lymphosarcomes et des adénopathies angio-immunoblastiques.

Antibody titers to Epstein-Barr virus (EBV)--related antigens (viral capsid antigen : VCA; early antigen : EA; and EBV associated nuclear antigen : EBNA) were determined in the sera of 86 patients and 150 matched control subjects. The patients belonged to four histological groups : diffuse and nodular non-hodgkin's lymphomas angio-immunoblastic lymphadenopathies and apparented syndroms. The incidence of antibodies to other herpes-viruses (cytomégalovirus, herpes simplex virus, and varicella zoster virus) was compared. There was a significantly higher incidence of anti VCA and anti EA titers in some patients, not associated with an increase in titres of antibodies to other herpes viruses.

[Geographical pathology and genetic markers: detection of associations (author's transl)]. / Pathologie géographique et marqueurs génétiques: détection des associations.

The study of potential associations between genetic markers and various diseases is an important approach in epidemiology. With such studies it is possible to reveal an hereditary component for multifactorial diseases. There are three kinds of analyses: --comparisons of the frequency of the marker in patients and in a control group; --investigations of genetic markers in families with high incidence of disease; --studies of geographical clines between the incidence of the disease and the marker frequency. The interpretation of such geographical associations is difficult. These associations can be the reflect of the migration of susceptibility genes with genetic markers. The HLA system is the better for this kind of approach.

[Spina-bifida and anencephaly. Geographic distribution, correlation with HLA system (author's transl)]. / Spina-bifida et anencéphalie. Répartition géograhique, corrélation avec le système HLA.

Geographical variation in the incidence of an Anencephaly and Spina-Bifida is well documented. The highest rates for these malformations were found in Ireland, Wales, Scotland and in Western regions of England. These rates decrease progressively towards eastern Europe. In France the highest rates were found in some regions of Brittany. The geographical correlations between the mortality rates of Spina-Bifida and incidence of Spina-Bifida and Anencephaly and the HLA antigen frequencies are studied. There is a positive correlation with A1 and B8 and a negative one with B5 and BW35. The role of the HLA system in these associations is discussed.

[Interaction between HLA and Gm for susceptibility to insulin-dependent diabetes]. / Interaction entre HLA et Gm pour la susceptibilité au diabète insulino-dépendant.

It is now well established that HLA system is involved in the susceptibility to Type 1 diabetes mellitus. In this study we look for a possible effect of the Gm system. A first study (cases-controls) suggests that among individuals who had HLA-DR3 but not HLA-DR4 or HLA-DR4 without HLA-DR3, there is a possible effect of the phenotype Gm3,23,5 or Gm3,-5 in the susceptibility to IDDM. Moreover, we have tested by the sibpair method whether HLA and Gm are transmitted independently from IDDM: an unaffected sib, sharing the same HLA haplotypes than an affected individual, seems to be more often phenotypically different at the Gm loci.

[Endocrine polyadenomatosis of 2a type (MEN 2a). Clinical and genetic study of a family]. / Polyadénomatose endocrinienne de type 2a (MEN 2a). Etude clinique et génétique d'une famille (GETC).

In a large kindred with multiple endocrine neoplasia type 2a (MEN 2a) (137 members, 5 generations), bilateral thyroid medullary carcinoma was found in all affected members. Pheochromocytoma was present in 59% of the cases, and was responsible at least for 4 out the 5 deaths related to MEN 2a. Hyperparathyroidism was less frequent (41%). Family screening leads to a reduction in age for diagnosis and to an improvement in the prevalence of complete healing after surgery. Linkage between HLA loci and a dominant gene for MEN 2a was investigated in this kindred. Lod scores for recombination fraction were all negative (-0.47 for a recombination fraction of 0.05). These results comfort the lack of linkage between MEN 2a and the HLA complex.

[Multiple endocrine neoplasms type 2. Recent aspects]. / Néoplasies endocriniennes multiples de type 2. Aspects récents.

Multiple endocrine neoplasia type 2 (MEN 2) is transmitted as an autosomal dominant trait, with 3 different forms. MEN 2a consists of medullary thyroid carcinoma, phaeochromocytoma(s) and hyperparathyroidism. In MEN 2b, parathyroid hyperplasia is absent, but a Marfan-like syndrome and neuromas of the mucosae are present. In some families, the only manifestation of MEN 2 is a medullary thyroid carcinoma. These 3 forms seem to related to one or several gene(s) located in the pericentromeric region of chromosome 10. The histological lesions of MEN 2a are multifocal, bilateral and associated with hyperplasia (which affects C-cells in the thyroid gland). Screening for familial medullary thyroid carcinoma is based upon plasma calcitonin levels measured before and after a pentagastrin stimulation test. The demonstration of DNA markers near the gene(s) of the disease in chromosome 10 pericentromeric region makes it possible to identify, with good probability, the subjects at risk for the disease. It is only by determining the responsible gene(s) that subjects carrying the hereditary anomaly will be identified directly, without marker assays.

[Linkage disequilibrium]. / Déséquilibre de linkage.

The linkage disequilibrium which measures the association between linked genes is a temporary phenomenon in a population because of crossing over. But such associations persist in HLA system. These persistent linkage disequilibria may be due to the very small fraction of recombinaison between the loci but other explanations are possible: selection or migration. A linkage disequilibrium produces a phenotypic correlation in a population. A phenotypic correlation may be due to pleiotropic effect of a gene, or epistasie of two genes, or population stratification... On the same hand, if a correlation appears in an inter population study, it may be due to a migration or a subdivided population. In medical genetics the research of such association intra or inter population studies may permit to point out a defect gene. In particular, HLA system study has proved that many susceptibility genes of various diseases are linked to B or D alleles.

[HLA and leprosy]. / HLA et lèpre.

Although there is now accumulating evidence that the host response to Mycobacterium leprae is genetically controlled, the nature of the genetic component is still imprecise. Case-control studies as well as family studies, in various populations, have shown that HLA linked factors confer susceptibility to tuberculoid leprosy and lepromatous leprosy respectively. Recently, associations between Gm allotypes and the disease have also been reported. Further studies of the familial cosegregation of the different forms of leprosy together with the HLA and Gm markers may permit a better understanding of the underlying genetic mechanisms.

Spina bifida and anencephaly. Geographic correlation with the HLA system.

The geographical correlation between the incidence of spina bifida and anencephaly and the HLA and ABO antigen frequencies are studied. There is a positive correlation between these malformations and A1 and B8, and a negative correlation with B5 and Bw35. The role of the HLA system itself, or of a human T-like locus, is discussed. This study provides evidence of a possible genetic background of susceptibility to these malformations.

HLA in populations: an approach for genetical susceptibility to cancer.

The geographical correlations between the incidence of various cancers and the HLA and ABO antigen frequencies are studied. There is, for example, a positive correlation between breast and colorectal carcinoma and AI, B8 and B12 antigens, and a negative one between prostate carcinoma and B12. The role of the HLA system itself or other genes involved in these associations is discussed. This study gives some evidence of a possible genetic background of susceptibility or resistance to cancer.

HLA and susceptibility to multiple sclerosis.

The study of the joint segregation of multiple sclerosis and HLA, using affected sib pairs as well as whole pedigrees, shows that these two traits are not independently transmitted. The hypothesis of a single susceptibility locus inside HLA region could explain all the observed data, only if a high gene frequency, a very low penetrance, and some environmental correlation between relatives are assumed. Linkage analysis performed on the basis of this hypothesis for 58 multiple sclerosis families concludes to a strict linkage. We obtained a maximum score of 3.11 at theta = 0.00 for a dominant gene of frequency 0.18 and penetrance of 0.02. This result contrasts with the large recombination fraction obtained by other authors and the discrepancy is explained by the very low gene frequency used in their analysis. Some environmental correlation, in addition to the genetic determinant in HLA region, may explain the overall familial aggregation, but an alternative is the existence of additional genetic determinants.