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Biomedical subjects

G Thomson

Publications and source records attributed to G Thomson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Paternally transmitted IDDM2 influences diabetes susceptibility despite biallelic expression of the insulin gene in human pancreas.

Whereas it is well known that the insulin gene (INS) region at 11p15.5 (IDDM2) confers susceptibility to insulin-dependent diabetes mellitus (IDDM), it is still controversial whether the parental origin of IDDM2 influences IDDM susceptibility. We have analysed the Pst I + 1127 polymorphism in 123 USA multiplex families and detected linkage only in male meioses using the affected sibpair analysis (P = 0.009). Application of the transmission/disequilibrium test (TDT) found significantly increased transmission of the IDDM-associated INS allele from fathers heterozygous for INS to their diabetic offspring (P = 0.00002), but the transmission from heterozygous mothers was not significantly different from random expectation. In non-diabetic families, the transmission from parents heterozygous for INS was not significantly different from random expectation in either paternal or maternal meioses. Maternal imprinting of the INS gene in pancreatic islets was originally considered the most favorable explanation for the observed gender-related difference. However, our study has demonstrated biallelic expression of INS in pancreatic tissues from the human fetuses and thus suggests that INS is probably not imprinted in the pancreatic islets.

Alleles↗
PubMed1996

On distinguishing unique combinations in biological sequences.

The problem of defining combinations of variants unique to a sequence is efficiently addressed as a set covering computation. The unique-combinations method is introduced, which identifies patterns in biological sequence data that distinguish a sequence from a group of other sequences. This method is further developed to describe features consistently present in one group of sequences but not in a second group. The approach is incorporated into a novel analytical tool, designed for use in studies of polymorphic sequence data, such as mitochondrial, human leukocyte antigen (HLA), or viral pathogen sequences. The unique combinations method is well suited to applications in medical genetics and evolutionary genetics. An example implementation of the unique-combinations method yields greatly improved risk assessment for insulin-dependent diabetes mellitus (IDDM) from amino acid patterns isolated in an analysis of HLA class II DQA1-DQB1 patient and control genotypes.

Algorithms↗
PubMed1996

Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8.

Previous genome-wide mapping studies have provided suggestive linkage evidence for several novel susceptibility loci responsible for insulin-dependent diabetes mellitus (IDDM); however, the evidence was not sufficient to confirm the existence of these genes. We analyzed 265 Caucasian families with IDDM and report the first evidence that meets the standard for confirmed linkage for three susceptibility loci. The maximum LOD scores (MLS) were 3.9, 4.5 and 3.6 in our data set, and 5.0, 4.6 and 5.0 for our data combined with non-overlapping data from the literature, for IDDM4 on chromosome 11q13, IDDM5 on 6q25, and IDDM8 on 6q27, respectively. However, we could not confirm linkage for IDDM3 on 15q26 and IDDM7 on 2q31-q33, or linkage disequilibrium between D2S152 and IDDM7.

Adult↗
PubMed1996

African-American HLA class II allele and haplotype diversity.

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB1*1501) and some haplotypes of DRB1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.

Alleles↗
PubMed1996

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families.

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.

Adolescent↗
PubMed1995

Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control.

Neutrophil bactericidal activity was assessed in patients with type 1 (n = 45) and Type 2 diabetes mellitus (n = 68) and non-diabetic control subjects (n = 40) by measurement of whole blood chemiluminescence. Though chemiluminescence values tended to be highest in the non-diabetic subjects these differences were not statistically significant (mean +/- SD) (2.73 +/- 1.65 mV (controls), 2.33 +/- 1.41 mV (Type 1 diabetes) and 2.38 +/- 1.12 mv (Type 2 diabetes), F = 1.12, p = 0.33). Significant negative correlations were evident, however, in patients with both Type 1 and Type 2 diabetes between chemiluminescence and glycated haemoglobin (rs = -0.35, p = 0.005 (Type 1), rs = -0.45, p = 0.002 (Type 2), fructosamine (rs = -0.36, p = 0.003 (Type 1), r = -0.42, p = 0.004 (Type 2)), and random blood glucose (rs 0 -0.25, p = 0.04 (Type 1), rs = -0.48, p = 0.001 (Type 2)). Changes in whole blood chemiluminescence in a further group of 10 patients with Type 2 diabetes mellitus commenced on insulin therapy were followed for 21 days. Serum fructosamine concentrations fell significantly over this time (524 +/- 58 mumol l-1 to 405 +/- 47 mumol l-1, p < 0.001), however, although chemiluminescence values tended to rise these changes were not statistically significant (1.01 +/- 0.38 mV to 1.60 +/- 0.91 mV, S = 4.24, df = 5, p = 0.52). These results suggested that impaired neutrophil bactericidal function is associated with poor blood glucose control. While it is likely that neutrophil bactericidal function will improve as blood glucose control improves, further studies are required both to confirm this and to demonstrate a reduction in the incidence of clinical bacterial infection.

Adult↗
PubMed1995

Evidence that oilseed rape (Brassica napus ssp. oleifera) causes respiratory illness in rural dwellers.

A study of 25 residents in a small Scottish village over a two-year period investigated respiratory symptom reporting in the presence or absence of oilseed rape. Symptom reporting in the year when oilseed rape virtually surrounded the village, varied during the growing season of the crop and was at its highest coincident with peak flowering. At the same period of the following year when the crop was absent, symptom reporting was significantly lower. The symptoms which correlated most strongly with peak oilseed rape flowering were sneezing, cough, headache, eye irritation and the total of these and other symptoms. Increased symptoms were reported by 12 of the participants though only seven of these were judged to be atopic. The symptoms did not correlate with levels of oilseed rape pollen but there is no clear evidence as to which of the other factors associated with the crop might be the cause.

Adult↗
PubMed1995

HLA disease associations: models for the study of complex human genetic disorders.

The genes of the human leukocyte antigen (HLA) region, the major histocompatibility complex (MHC) of humans, control a variety of functions involved in immune response and influence susceptibility to over 40 diseases. Theoretical studies in the development of models to determine the modes of inheritance of the HLA-associated diseases have led to a better understanding of the inheritance patterns in insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hemochromatosis, celiac disease, and others. It is now clear that many of the HLA-associated diseases involve heterogeneity in their HLA components, as well as non-HLA genetic factors. This review is presented using HLA-associated diseases, and in particular IDDM, as the example of interest, but the observations and techniques presented have direct relevance to the study of all human diseases with a complex genetic component. Three methods for localizing disease-predisposing genes are presented: (1) association studies, including population, family, and relative predispositional effects, (2) affected sib pair and other affected-relative methods, and (3) lod score analysis. A variety of complementary methods for studying the mode(s) of inheritance of the alleles at the disease-predisposing locus and for identifying the alleles and amino acids directly involved in the disease process also are presented.

Arthritis, Rheumatoid↗
PubMed1995

Tests of random mating for a highly polymorphic locus: application to HLA data.

Testing for random mating at an HLA locus is a difficult problem because of the highly polymorphic nature of the HLA loci. We discuss some methodological issues and propose several tests. A simulation study is conducted to evaluate these tests. The single allele test and the shared allele test deal with small sample sizes by aggregating the data in different ways. The shared allele test is found to be a more powerful method of detecting non-random mating patterns involving a deficiency or an excess of similar genotypes than the single allele test. We show that random mating of couple at the genotype level implies the random mating of couple at the allele level. Several multi-allele approaches are proposed for large population-based data sets. Among them, the corrected allele-table test performs better than the generalized Wald test in terms of power and size. These methods are then applied to an HLA data set of Caucasian couples, and no solid evidence for non-random mating at the HLA A, B, and DR loci is found.

Alleles↗
PubMed1995

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27.

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.

Chromosome Mapping↗
PubMed1995

Analysis of complex human genetic traits: an ordered-notation method and new tests for mode of inheritance.

A novel ordered notation is introduced that allows description and calculation of the probability of any nuclear-pedigree configuration of disease status and marker-allele information. Algorithms are given that allow for complex models of disease predisposition, a highly polymorphic or less polymorphic marker locus, gametic disequilibrium between the marker and disease loci (marker association with disease), recombination between the marker and disease loci, and different ascertainment schemes. The theoretical foundation is presented for a series of new tests to identify modes of inheritance and genetic heterogeneity. These use marker-locus data in nuclear families from four ascertainment schemes: simplex (S), multiplex parent-child (MPC), multiplex sibs (MS), and multiplex parent-sibs (MPS). The tests are (1) extension of the antigen-geno-type-frequencies-among-patients method to MPC, MS, and MPS pedigrees; (2) determination of the expected rates of transmission, or not, of marker alleles from parents to an affected child, for all pedigree types; (3) determination of expected identity by descent (IBD) values for affected sib pairs when a parent is affected (MPS pedigrees); and (4) determination of the expected marker-allele frequencies in affected-sib-pair IBD categories (MS and MPS pedigrees). A sampling strategy that includes the four pedigree types S, MPC, MS, and MPS is recommended for complex diseases once linkage and/or association of a marker with disease has been established. The full array of new and old tests that can be applied to these pedigrees provides a complementary suite of methods that can facilitate the mapping and characterization of complex human genetic traits.

Alleles↗
PubMed1995

Mapping disease genes: family-based association studies.

With recent rapid advances in mapping of the human genome, including highly polymorphic and closely linked markers, studies of marker associations with disease are increasingly relevant for mapping disease genes. The use of nuclear-family data in association studies was initially developed to avoid possible ethnic mismatching between patients and randomly ascertained controls. The parental marker alleles not transmitted to an affected child or never transmitted to an affected sib pair form the so-called AFBAC (affected family-based controls) population. In this paper, the theoretical foundation of the AFBAC method is proved for any single-locus model of disease and for any nuclear family-based ascertainment scheme. In a random-mating population, when there is a marker association with disease, the AFBAC population provides an unbiased estimate of the overall population (control) marker alleles when the recombination fraction (theta) between the marker and disease genes is sufficiently small that it can be taken as zero (theta = 0). With population stratification, only marker associations present in the subpopulations will be detected with family-based analyses. Of more importance, however, is the fact that, when theta not equal to 0, differences between transmitted parental (patient) marker allele frequencies and non- or never-transmitted parental marker allele frequencies (implying a marker association with disease) can only be observed for marker genes linked to a disease gene (theta < 1/2). Thus, associations of unlinked marker loci with disease at the population level, caused by population stratification, migration, or admixture, are eliminated. This validates the use of family-based association tests as an appropriate strategy for mapping disease genes.

Chromosome Mapping↗
PubMed1994

Affected sib pair identity by state analyses.

Four methods using identity by state (IBS) data from affected sib pairs are compared for their ability to detect linkage between a diallelic marker and disease. A joint null hypothesis of no linkage and no linkage disequilibrium between the marker and disease must be considered. Two tests have undesirable properties in the case of linkage disequilibrium. Which of the other two tests has more power is dependent on the presence or not of linkage disequilibrium. The procedure of choice when possible is to type parents of affected sib pairs: the null hypothesis of no linkage can then be tested using identity by descent (IBD) values from informative parents, and the null hypothesis of no marker association with disease (linkage equilibrium) can be tested independently using the marker allele frequencies in the affected sib pairs.

Gene Frequency↗