Electrotypes and formal genetics of red cell glutathione peroxidase (GPX1) in the Djuka of Surinam.

Samples of venous blood from 239 male and 476 female adults including 41 pairs of parents and 123 of their children belonging to a Surinam population called the Djuka or Bush Negroes of West African origin were screened for electrophoretic variants of red cell glutathione peroxidase (GPX1) in Cellogel. The results confirmed an earlier hypothesis that at least a part of the GPX1 variation mainly, if not exclusively, observed in the Africans and people of African origin living elsewhere, is determined by two codominant alleles (called GPX1*1 and GPX1*2), at an autosomal locus. The frequency of GPX1*2 allele in the Djuka was estimated to be .054. A rare variant provisionally designed as GPX1 Djuka (thought to be a heterozygote due to a third allele called GPX1*3 and the GPX1*1) was found in two apparently unrelated individuals. Catalytically, the product of GPX1*2 appears to be about twice more active than that of GPX1*1. For heuristic purposes, it was proposed and discussed that GPX1*2 is a South-Saharan African allele and is amenable for natural selection.

Homozygosity for a Y/22 chromosome translocation: t(Y;22) (q12;p12/13).

A newborn girl, homozygous for a balanced Y/22 chromosome translocation is described. This unique karyotype was detected during prenatal chromosome studies in the first pregnancy of a 26-year-old woman. Amniocentesis was performed because of clinical evaluation of severe fetal growth retardation in the 28th week of gestation. The cytogenetic results were confirmed using a lymphocyte culture after birth in the 30th week. Subsequent chromosome studies of the parents were hampered by the fact that the pregnancy was thought to be the result of artificial insemination with donorsperm. Nevertheless both, consanguineous, parents were shown to be carriers of the same, singular, chromosome translocation and the spermdonor could be excluded from paternity by bloodgroup- and HLA studies. Distamycin-A-DAPI chromosome staining and DNA studies of the mother were used to confirm the involvement of the Y-chromosome in this translocation. The probanda is developing quite normally at the age of 21 months.

Paradoxical inheritance of HLA-linked susceptibility to rheumatoid arthritis.

In order to clarify the discrepancy between population studies showing association of rheumatoid arthritis (RA) with HLA-DR4/Dw4 and family studies failing to show linkage with HLA, we analysed 16 multicase families in which RA and DR4 status of both parents was known. 120 HLA-haplotypes of affected and unaffected children could be analysed for co-segregation with RA. In a combined analysis of both affected and unaffected children co-segregation of RA with the DR4 carrying haplotype was observed when both parents were unaffected (p = 0.001). Co-Segregation of RA with one of the two haplotypes of affected parents was observed (p = 0.01), but in this case there was no preference for the DR4 carrying haplotype. In both cases preferential inheritance of the other (not associated with RA) haplotype was observed in unaffected siblings. These data indicate that susceptibility to RA is controlled by an HLA-linked gene. This gene is often but not always identical to the gene coding for a product carrying the DR4 epitope or in strong linkage disequilibrium with it. Combined with previous population data, the present data provide evidence for genetic heterogeneity of RA. Finally, they contain a paradox, based on which a new hypothesis for HLA-linked susceptibility to RA is formulated.

Three-locus haplotype interactions in the analysis of linkage disequilibrium.

We have shown that the application of Piazza's formula for the estimation of the "three-locus interaction delta" should not be used for that purpose. In addition, the method of Porta & McHugh, for the demonstration of haplotype interaction in associations between HLA and disease, leads to completely erroneous conclusions. Other methods of calculation that have been used to analyse haplotype interactions also appear to be based on erroneous concepts. We suggest that nothing more than the estimation of heterogeneity in simple 2 X 2 contingency tables should be used for the analysis of linkage disequilibria. This principle is applied to the HLA-A, -B and -C haplotype frequency tables of Baur & Danilovs. For the greater part of the HLA-B alleles, three-locus haplotype frequencies can be explained from the A, B and the B, C disequilibria, without any further haplotype interactions. The predominant exceptions in that respect are haplotypes containing the B44 allele, which has been shown to contain two subgroups and therefore, we are not justified to conclude that this exceptional behaviour of haplotypes with B44 should be attributed to three-locus haplotype interactions.

Immunoglobulin allotypes in Hungarian Gypsies. Relationship to populations from India.

The allotypic markers of immunoglobulin heavy chains (Gm, Am and Em allotypes) provide important contributions to the differentiation between populations, and they are informative for tracing racial origin, migration and admixture of isolates and stray groups. The combined G1m; G2m; G3m; A2m; Em haplotypes are a highly polymorphic system that is a powerful tool in population genetics because of the existence of haplotypes that are unique for a particular race. In this paper, data on Gypsies living in Hungary are compared with those obtained in other populations, in particular Hindus and non-Hindus from India. The analysis agrees with anthropological and philological evidence for population movements from Asia to Europe.

Two different T-cell systems in humans, one of which is probably equivalent to Qa or Tla in mice.

Two different alloantigenic systems, expressed mainly on TG and TM lymphocytes and called TCA and TCB, respectively, are described. Alloantisera from parous women are absorbed with Epstein-Barr virus-transformed B cell lines from the husband of the serum producer to remove all anti HLA-A,B,C and DR antibodies. The absorbed sera are tested against a random panel and against lymphocytes from families. Family studies indicate that the TCA system might be encoded by a gene linked to HLA and located on the telomeric side of HLA-A. The total lod scores for the material of 15 informative families is +3.301 at a recombination fraction of 15%. Furthermore we can show that the TCA molecule is associated with beta 2-microglobulin by blocking with turkey anti-beta 2 microglobulin. The antigens are dimers of peptides with a molecular weight of approximately equal to 42,000 daltons and 12,000 daltons, respectively. This implies that TCA might be equivalent to either Qa or Tla in the mouse. For the TCB system no evidence is found for linkage with any known genetic marker. Only in random population studies is an association seen between TCB and Gm.

Linkage studies in autosomal dominant facioscapulohumeral muscular dystrophy.

Linkage studies were undertaken in 120 individuals from 10 kindreds with autosomal dominant facioscapulohumeral muscular dystrophy using 35 different marker genes. No linkage was found. The highest lod score was 1.438 for the immunoglobulin heavy chain gene cluster (IGH) at a recombination fraction of 0.2. IGH is located on the long arm of chromosome 14. Based on scores of other marker genes and on a recombination map of chromosome 14, the probability that the gene for facioscapulohumeral muscular dystrophy is located on chromosome 14 is estimated to be approximately 6%.

How to select a satisfying typing program for paternity testing.

The efficiency of a typing program for paternity testing concerns three specific aspects: first, what is the percentage of non-fathers that cannot be excluded from paternity; second, what is the percentage of true fathers that cannot be recognized as probable fathers, and third, what is the percentage of non-fathers that will be assigned as probable fathers. When extensive materials for observation with any specific typing program are not directly available, only the chance of non-exclusion of non-fathers can be calculated in a relatively simple way. The aim of the present study was to find a relationship between this and the other two criteria. It was found that the variance of the distribution of natural logarithms of paternity index values is approximated rather well by the formula var. ln I = 0.65 X (n(ln 1/ne)2) (n = the number of genetic systems of the typing program and ne = the chance of non-exclusion of non-fathers). This allows the estimation of the two other critical percentages: the percentage of true fathers that cannot be assigned, and the percentage of non-fathers that will be assigned as probably true fathers.

Linkage and segregation analysis of HLA and congenital hypoaldosteronism due to corticosterone methyl-oxydase deficiency type I and type II.

To determine the genetic relations between HLA and deficiencies of steroidogenic enzymes other than 21-hydroxylase, we investigated HLA and congenital hypoaldosteronism in two families with corticosterone methyl-oxidase type 2 (CMO2) and one family with type 1 (CMO1) deficiency, respectively. Apart from a first documentation of HLA in CMO1 deficiency, our results, combined with those reported previously, excluded close linkage of HLA and CMO2 deficiency. However, loose linkage could not be encluded and the segregation of HLA haplotypes in sibships with CMO2 deficiency deviated significantly from random segregation. We suggest that HLA and CMO2 deficiency may not be independent.

Genetic linkage between erythrokeratodermia variabilis and Rh locus.

A genetic linkage study was performed in a large Dutch kindred with erythrokeratodermia variabilis (EKV, McKusick no. 13320). The autosomal-dominant trait appeared to segregate rather consistently with the cde (r) gene complex of the Rh system. Only one recombinant was found amongst 27 informative individuals. Lod score calculations gave strong evidence for close linkage between the loci for EKV and Rh (with a maximum lod score of 5.55 at a recombination fraction of 0.044).

Familial benign hypercalcaemia (FBH; McK. No. 14598, 1983): linkage studies in a large Dutch family.

By screening 27 hypercalcaemic and 21 normocalcaemic subjects in a large Dutch pedigree with familial benign hypercalcaemia (FBH; McK. No. 14598) (McKusick 1983) for more than 35 genetic markers, it was found that linkage of FBH can be excluded at about 25 centimorgans (cM) from GM, 20 cM from ABO, 15 cM from MNS and HLA, 10 cM from JK and PI, and 5 cM each from ACP1, AK1, ADA, GPT1, and PGP.

Absence of close linkage between Hereditary spherocytosis (SPH) and 24 genetic marker systems including HLA and GM.

A total of 250 individuals belonging to 19 different families, identified through established propositi were simultaneously screened for hereditary spherocytosis (SPH), using stringent criteria, and 27 well-known polymorphic genetic marker systems. The segregation analysis indicated that the pattern of inheritance of SPH in these families, being autosomal and dominant, had a 100% penetrance. A statistical analysis, using the LIPED computer program of Ott (1974), revealed the absence of close linkage between SPH and ABO, ACP1, ADA, AK1, C3, DIA2, ESD, FY, GC, GLO1, GM, GPT1, HLA, HPA, JK, K, KM, MNS, P, PGD, PGM1, PGP, PI, and RH. Since an earlier study by other investigators had convincingly suggested a linkage between SPH and GM, we subjected the data to further analysis and found no significant heterogeneity in our recombination values of linkage between SPH and GM, or any of the other informative loci.

HLA antigens in idiopathic thrombocytopenic purpura.

The lymphocytes of 52 patients with the clinical diagnosis of idiopathic thrombocytopenic purpura (ITP) were typed for the HLA-A, -B and -C antigens, and of 27 of those patients also for the DR antigens. ITP proved not to be significantly associated with any of the HLA-A, -C or -DR antigens tested for. On the platelets of 35 of these 52 patients autoantibodies were detected in the direct immunofluorescence test. In these 35 patients with autoimmune thrombocytopenia (AITP), an increased frequency of HLA-Bw38 was found (14.3% versus 2.6% in controls). The frequency of none of the HLA antigens was significantly increased in the group of 17 ITP patients without demonstrable autoantibodies. The difference in association with HLA-Bw38 between AITP and ITP without demonstrable autoantibodies was not significant.

Human IgG allotypes co-occurring in more than one IgG subclass.

Inheritance of an excess of immunoglobulin allotypes in one haplotype was encountered which could not be explained by the assumption of a duplicated locus. The surplus of allotypes was related to markers on the CH3 domain of gamma 3 chains. Two such cases were investigated extensively. The IgG3 molecules were isolated by gel filtration and by absorption on protein A. Only the usual combination of allotypes appeared to be present on the IgG3 molecules. The supernumerary markers were found in one case on IgG2 molecules and in the other case on IgG1 molecules. This followed from investigations of eluates after separation of the subclasses by immune absorptions. A hypothesis was proposed to explain these events by mutation of a particular position of an otherwise homologous stretch of gamma-subclass DNA.

Mathematical aspects of the paternity index I = X/Y, especially in relation to the chance of non-exclusion of non-fathers.

In a previous paper the author mentioned some aspects of the paternity index I (= X/Y): Among false triplets the frequency of those with I equal to or higher than an (observed) I value of Ix is considerably lower than 1/Ix; among false triplets the mean value of I is equal to 1, and among non-excluded non-fathers it is equal to the inverse of the chance of non-exclusion; among true triplets the mean value of 1/I (= i) is equal to the chance of non-exclusion of non-fathers. In a statistical material rather strong deviations from some of these expectations were observed. In the present paper further characteristics of the distribution of I values were taken into consideration, and especially those that should hold if lnI would fit in with a normal distribution. It was supposed that with the aid of such a distribution the deviations mentioned above could be recognized as chance variability. It appears, however, that neither the logarithms of the paternity index, nor those of the zygosity index of twins (chosen as an analogous model that is more easily analysable than the paternity index) are really normally distributed. This, in turn, makes that estimates of probability of paternity, based on such a supposition, are of doubtful reliability. Besides it is concluded that also for other reasons other estimates than Essen-Möller's W (or I or i), as probability of first type errors, lead in practice to conclusions that are equally subdue to a priori suppositions as are W values and may be, in fact, much more erroneous than those. Special attention is paid to the statistical analysis of paternity studies with more than one alleged father, and it is concluded that in such cases the general formula that may be considered to be equivalent with Essen-Möller's formula for one-man paternity cases, i.e., W = X/(X + Y) or I/(I + 1), must be W1 = I1/(sigma I + n); W2 = I2/(sigma I + n) etc. and certainly not W1 = I1/(sigma I + 1); W2 = I2/(sigma + 1) etc.

Absence of platelet-specific alloantigens in Glanzmann's thrombasthenia.

The platelets of 11 patients with Glanzmann's thrombasthenia and their nearest family members were studied for the expression of the platelet-specific alloantigens of the Zw-, Ko- and Bak systems. The strength of the expression of the Zwa antigen was diminished on the platelets of 3 patients, and the antigen was absent from the platelets of the other 8. The platelets of none of the patients reacted with anti-Zwb serum. Therefore, Glanzmann's thrombasthenia is probably a "Zw-null disease." The expression of the Zwa antigen on the platelets of all the relatives was normal, as indicated on the cytoflurograph. Investigations on the expression of the Koa antigen were complicated by agglutinations of the platelets from genetically Koa-negative thrombasthenic patients with the anti-Koa serum. The Kob antigen was normally expressed. The Baka antigen was absent from the platelets of all thrombasthenic patients and a relatively high percentage of the relatives. A close association between the Glanzmann gene and the Bak(a-) gene is assumed on statistical grounds. Thrombasthenic platelets showed no reaction with EDTA-dependent antibodies, which are reactive with all normal platelets. Owing to immunization by multiple blood and platelet transfusions, serum samples of most patients studied contained HLA antibodies and platelet-specific alloantibodies. However, antibodies directed against the Zw-antigen-bearing glycoproteins were detected in the serum of only one patient and, therefore, seem to be rare.