Search PubMed⌕ Search

Biomedical subjects

G Thomson

Publications and source records attributed to G Thomson.

At least 19 recordsLinked to original sources
PubMed1991

Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred.

We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA-linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA-DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P less than 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well-established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib-pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA-DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P less than 0.001). The same results were obtained by an independent method which considered HLA-DR transmission from affected parents to their affected children. The affected sib-pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA-linked locus on familiarity accounted for only a 1.61-fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non-HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.

Adult↗
PubMed1991

Affected kin-pair IBD methods: genetic models.

Cases of interest using affected sib-pair methods to distinguish between recessive and additive (dominant) modes of inheritance of a disease-predisposing gene involve goodness-of-fit tests with a small expected number in the "share-zero parental haplotypes" category, as well as an unknown parameter, the frequency of the disease-predisposing allele. Our simulations demonstrate that the real significance level of the chi-square test using the three-haplotype-sharing IBD values (share 2, 1, and 0 parental haplotypes) is close to the assumed (.05) level in these cases, so that the haplotype-sharing classes do not have to be lumped, which would leave no degrees of freedom for a statistical test. The validity of the chi-square approximation in cases of small expected frequencies has previously been described, but the situations that have been considered do not cover the very small values in the share-zero category that are often expected in the affected sib-pair analysis, nor do they involve estimation of an unknown parameter. Although including IBD values from affected kin pairs other than sibs can be a very powerful tool in demonstrating linkage of a marker and disease, these pairs do not add power, in fact they reduce the power, of the chi-square tests of goodness-of-fit of modes of inheritance.

Alleles↗
PubMed1991

HLA population genetics.

The HLA system has been extensively studied from an evolutionary perspective. The region contains a number of closely linked genes whose products control a variety of functions concerned with the regulation of immune responses. In addition, the genetic predisposition to over 40 diseases maps to this region. A number of observations indicate that strong selection is acting on the HLA region, including its extensive polymorphism with very even allele frequencies, the preferential occurrence of high levels of variability at positions critical to antigen recognition, the great age of alleles and the patterns of linkage disequilibrium among loci. The form of the selection is unknown. Although balancing selection is a strong candidate, it seems unlikely that only one selective mechanism is operating in this complex multigene family region. Mutation, recombination and gene conversion all contribute to the generation of HLA variability. The apparent great age of many HLA alleles revealed by phylogenetic analysis suggests that the absolute rate of production of new variants is not high. Detailed studies of population and evolutionary features of the HLA region are necessary for an informed discussion of the evolution of disease predisposing genes and epitopes, and of complex multigene families.

Alleles↗
PubMed1991

Three-locus systems impose additional constraints on pairwise disequilibria.

Combinations of allele frequencies and pairwise linkage disequilibrium terms, each of which is permissible at the two-locus level, may not always be permissible at the three-locus level. These additional constraints on the possible maximum and minimum values for the pairwise disequilibrium terms are formally determined and numerically analyzed. In some cases, the three-locus constraints on a pairwise disequilibrium (D) may be equivalent to the usual two-locus constraints, while in others, the positive or negative range may be restricted. This can result in situations where the allowable values of D are limited to only positive or only negative values up to the extreme case where there is only a single admissible value. No additional restrictions are placed on pairwise disequilibrium values when four loci are considered, other than those imposed by the three-way combinations containing the two loci of interest. A new measure of normalized pairwise linkage disequilibrium, allowing for the three-locus constraints, is defined and illustrated by an application to data from the human histocompatibility antigen (HLA) system. An analogous normalized three-way disequilibrium measure is also formulated.

Alleles↗
PubMed1991

Selection, hitchhiking and disequilibrium analysis at three linked loci with application to HLA data.

The HLA system has been extensively studied from an evolutionary perspective. Although it is clear that selection has acted on the genes in the HLA complex, the nature of this selection has yet to be fully clarified. A study of constrained disequilibrium values is presented that is applicable to HLA and other less polymorphic systems with three or more linked loci, with the purpose of identifying selection events. The method uses the fact that three locus systems impose additional constraints on the range of possible disequilibrium values for any pair of loci. We have thus examined the behavior of the normalized pairwise disequilibrium measures using two locus (D'), and also three locus (D"), constraints on pairwise disequilibria in a three locus system when one of the three loci is under positive selection. The difference between these measures, delta = magnitude of D' - magnitude of D", has a distribution for the two unselected loci differing from that for the selected locus with either of the unselected loci (the hallmark is a high positive value of delta for the two unselected loci). An examination of genetic drift indicates that positive delta values are unlikely to be found in human populations in the absence of selection when recombination is greater than about 0.1%. This measure can thus provide insight into which allele of several linked loci might have been subject to selection. Application of this method to HLA haplotypes from a large French population study (Provinces Francaise) identifies selected alleles on particular haplotypes. Application of a complementary method, disequilibrium pattern analysis also confirms the action of selection on these haplotypes.

Alleles↗
PubMed1990

Gene conversion in the evolution of both the H-2 and Qa class I genes of the murine major histocompatibility complex.

In order to better understand the role of gene conversion in the evolution of the class I gene family of the major histocompatibility complex (MHC), we have used a computer algorithm to detect clustered sequence similarities among 24 class I DNA sequences from the H-2, Qa, and Tla regions of the murine MHC. Thirty-four statistically significant clusters were detected; individual analysis of the clusters suggested at least 25 past gene conversion or recombination events. These clusters are comparable in size to the conversions observed in the spontaneously occurring H-2Kbm and H-2Kkm2 mutations, and are distributed throughout all exons of the class I gene. Thus, gene conversion does not appear to be restricted to the regions of the class I gene encoding their antigen-presentation function. Moreover, both the highly polymorphic H-2 loci and the relatively monomorphic Qa and Tla loci appear to have participated as donors and recipients in conversion events. If gene conversion is not limited to the highly polymorphic loci of the MHC, then another factor, presumably natural selection, must be responsible for maintaining the observed differences in level of variation.

Algorithms↗
PubMed1989

HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients.

We examined the distribution of non-B27 alleles of the HLA-B locus among B27+ patients with ankylosing spondylitis (AS), to detect any additional HLA-B locus allele(s) that may act in conjunction with B27 to increase susceptibility to AS. HLA-Bw60 (or B40 when the Bw60,61 split of B40 was not typed for) was shown to be increased among B27+ AS patients in each of 5 independent data sets. This increase was statistically significant in 4 of the 5 data sets studied, and the overall significance was P less than 0.00001. Susceptibility to AS in B27+ individuals was further increased by a factor of approximately 3 when Bw60 was also present. The distribution of HLA-A alleles on the B27-bearing haplotypes in AS patients was not significantly different from that in normal controls. On the other hand, the distribution of HLA-A alleles on Bw60-bearing haplotypes was significantly different from the distribution of A alleles on Bw60 haplotypes in the general population (P less than 0.0005). Bw60 was not increased in B27- patients with AS. A dominant mode of inheritance generally fits AS; however, our sib pair analysis indicates that the B27,Bw60 disease subgroup follows a more recessive mode of inheritance.

Alleles↗
PubMed1989

Clues to IDDM pathogenesis from genetic and serological traits in multiply affected families.

A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5' insulin locus (INS) in insulin-dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.

Cohort Studies↗
PubMed1989

Autoimmune thyroid disease in type I diabetic families.

The prevalence rate for autoimmune thyroid disease (ATD) is about 30 times higher in the type I diabetic (IDDM) families that were ascertained for Genetic Analysis Workshop 5 (GAW5) than in the general population. Two approaches were used to study the clustering of ATD and IDDM in these families: 1) HLA haplotype sharing in sib pairs in which one has IDDM and the other has ATD was analyzed with the genetic interrelationship method. The hypotheses of different alleles (at the same locus or at different loci) were rejected. Thus there must exist at least one common allele that predisposes to both IDDM and ATD. 2) The DR genotype frequencies suggest that in the GAW5 families two alleles may be predisposing to ATD; a recessive DR3-associated allele and a dominant DR4-associated allele.

Cross-Sectional Studies↗
PubMed1989

HLA and insulin gene associations with IDDM.

The HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene.

Child↗
PubMed1989

Relative predispositional effects (RPEs) of marker alleles with disease: HLA-DR alleles and Graves disease.

A method is described to reveal the relative predispositional effects (RPEs) (predisposing, protective, or neutral) of the HLA alleles or of any other marker system that is associated with a disease. When the disease is associated with two or more alleles of a locus, the RPE method identifies the associations sequentially according to their strength; thus the problem that a strong association with one allele can create misleading deviations in the frequencies of other alleles is alleviated. Using this method, we have examined the relative effects of HLA-DR alleles in susceptibility to Graves disease in the Caucasian population. The well-established positive association with DR3 was confirmed as the strongest effect. In addition, a negative association was found between DR5 and Graves disease. The reduced frequency of DR5 among patients is statistically significant and is not a result of the increase in DR3. Finally, when patients were divided according to the presence or absence of eye disease, the latter showed a significant increase in the frequency of DR4. With family data, linkage to HLA of Graves disease was established in both Caucasian and Chinese families by the sib-pair method.

Alleles↗