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PubMed2004

Aldose reductase gene polymorphisms and susceptibility to microvascular complications in Type 2 diabetes.

AIMS: The gene encoding the human aldose reductase, the first and rate-limiting enzyme of the polyol pathway of glucose metabolism, is a promising candidate gene which may contribute to diabetic microvascular complications. We investigated the association of two previously reported DNA sequence variants of this gene, the C-106T polymorphism and the (CA)(n) dinucleotide repeat marker, with the risk of albuminuria and retinopathy in Finnish Type 2 diabetic patients and non-diabetic control subjects. METHODS: The study population included 85 Finnish, middle-aged, newly diagnosed Type 2 diabetic patients and 126 non-diabetic control subjects. Genetic analyses were performed using the polymerase chain reaction, restriction fragment length polymorphism, and automated laser fluorescence scanning analyses. Microvascular complications were determined using 10-year follow-up data of urinary albumin excretion measurements and ophthalmological examinations. RESULTS: The C and Z-2 alleles of the C-106T polymorphism and the (CA)(n) repeat marker, respectively, were found to be more frequent in Type 2 diabetic subjects than in non-diabetic subjects. The C and Z-2 alleles were in 60% linkage disequilibrium in diabetic subjects. At the time of diagnosis, diabetic subjects with the T allele of the C-106T polymorphism had significantly higher urinary albumin excretion rate and prevalence of albuminuria than subjects with the C-106C genotype (prevalence of albuminuria: 33.3 vs. 13.8%, P = 0.036, odds ratio = 3.9, 95% confidence interval 1.1, 14.7). The Z-2 allele of the (CA)(n) repeat marker was not consistently associated with the prevalence of albuminuria. No associations were observed between the polymorphisms examined and the prevalence of retinopathy at any point of the follow-up. CONCLUSIONS: The present study suggests that the C-106T polymorphism of the aldose reductase gene could be involved in the early development of microalbuminuria in Finnish Type 2 diabetic patients.

Aldehyde Reductase↗
PubMed1978

An incorrect definition of fitness revisited.

I have attempted to show that a certain mistaken definition of fitness, which surfaces occasionally, may turn out to have some merit. No claim is made that it is an improvement on, or should replace, the conventional definition of fitness; but it is different and has its own validity. Its generality is intriguing, its application is not limited either to selection or one locus models, and it may be easier to measure experimentally.

Biological Evolution↗
PubMed1985

The affected sib method. IV. Sib trios.

The classical sib pair method uses the expected and observed HLA (human leukocyte antigen) haplotype sharing distribution in sib pairs, who are affected with an HLA associated disease, to make inferences about the inheritance of the disease. In this paper we present the expected HLA haplotype sharing distributions in affected sib trios, and sib pairs, from families with three or more affected sibs. The underlying model for both distributions, as for the classical sib pair method, is that disease predisposition is determined by a single allele at an HLA-linked locus. The sib trio tests of hypotheses (additive and recessive), and disease parameter estimates (additive, recessive and intermediate), can be compared with those obtained from the classical sib pair analysis. In addition, the sib trio data allow parameter estimation for a general disease model to be made, if the data fall within the bounds of the expectation. This study forms the basis of later investigations which show that haplotype sharing of affected sib trios for two susceptibility alleles (negative complementation) model, which appears appropriate for insulin dependent diabetes mellitus (IDDM), moves outside the bound of the single susceptibility expectations outlined here, whereas haplotype sharing values for sib pairs are bound by the single susceptibility allele expectations. Available Caucasian IDDM data have been analysed. The results support genetic heterogeneity of IDDM.

Diabetes Mellitus, Type 1↗
PubMed1987

The locus ordering problem.

Studies of phenotypes defined by codominant alleles at two or more loci in three-generation families allow haplotypes to be deduced. These data are easily summarized by the Mendelian convention of upper and lower case, with case defining phase rather than nature. In two-generation families haplotypes may be inferred with high precision for closely linked loci even if an allele at one locus is recessive. Coding procedures are discussed and a simple solution to inferring the most likely order of three or more loci, and defining its likelihood compared with other orders, is presented.

Chromosome Mapping↗
PubMed1988

A new method to test genetic models in HLA associated diseases: the MASC method.

We propose a new method to analyse data on HLA associated diseases. The method uses the simultaneous information on the marker associations and segregation with the disease. It may also take into account the differential risk of being affected for specific relatives of a patient as well as the differential HLA haplotype sharing according to the marker genotype of the patient. It is based on the principle of minimization of a sum of independent chi-squares. It allows us to test the goodness-of-fit of various models in an easy and economical way. The method is applied to a sample of 269 French IDDM patients and their relatives leading to the rejection of models with one locus closely linked to HLA with two and three alleles.

Alleles↗
PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗
PubMed2006

Genome-wide scan for loci influencing quantitative immune response traits in the Belém family study: comparison of methods and summary of results.

Here we report the results from a genome-wide linkage scan to identify genes and chromosomal regions that influence quantitative immune response traits, using multi-case leprosy and tuberculosis families from north-eastern Brazil. Total plasma IgE, antigen-specific IgG to Mycobacterium leprae soluble antigen (MLSA), M. tuberculosis soluble antigen (MTSA) and M. tuberculosis purified protein derivative (PPD), and antigen-specific lymphocyte proliferation (stimulation index or SI) and interferon-gamma (IFN-gamma) release to MLSA and PPD, were measured in 16 tuberculosis (184 individuals) and 21 leprosy (177 individuals) families. The individuals were genotyped at 382 autosomal microsatellite markers across the genome. The adjusted immune-response phenotypes were analysed using a variety of variance components and regression-based methods. These analyses highlighted a number of practical issues and problems with regard to implementation of the methods and, interestingly, differences were observed between several standard statistical and genetic analysis packages used. From this we determined that, for this set of traits in these pedigrees, significant p values for linkage using variance components analysis, supported by significance using the Visscher-Hopper modification of the Haseman-Elston method, provided the most compelling evidence for linkage. Using these criteria, linkage (5.8 x 10(-5) < p < 0.008) was seen for: total plasma IgE on chromosome 2; IgG to MLSA on chromosomes 8, 17 and 21; IgG to PPD on chromosome 12; SI to PPD on chromosome 1; IFN-gamma to MLSA on chromosomes 6, 7, 10, 12 and 14; and IFN-gamma to PPD on chromosomes 1, 16 and 19.

Analysis of Variance↗
PubMed2005

A likelihood approach for quantitative-trait-locus mapping with selected pedigrees.

Selective sampling is a cost-effective design for mapping quantitative trait loci (QTLs). A unified framework, which naturally combines two complementary sources of linkage information in the data, is proposed for the mapping of QTLs using selected pedigrees. Score statistics for detecting linkage are introduced for single-locus models (univariate or bivariate phenotypes) and two-locus epistasis models. A computer implementation of the methods for single-locus univariate-phenotype models is provided for nuclear families with arbitrary number of sibs and is freely available.

Algorithms↗
PubMed1983

HLA and susceptibility to Hodgkin's disease.

Strong arguments supporting a genetic linkage between susceptibility to HD and HLA are reported. These observations are based on data from 33 multiplex case families, gathered from international series and from our own studies. They confirm the disturbed segregation of HLA haplotypes among pairs of affected siblings (P less than 0.0005). An excess of a shared haplotype among first cousin pairs of patients is also observed (P less than 0.05). When both sib pairs and cousins are taken together, the segregation distortion is even greater (P less than 0.0002). Although the excess of HLA-identical affected sib pairs would favor a recessive mode of transmission of the disease, the lod score analyses do not allow one to conclude a simple genetic pattern. A two-gene model, based on epistatic cooperation, is discussed and could fit with an intermediate mode of transmission. The review of population data confirms the generally admitted trend of higher susceptibility borne by HLA-A1. There are converging arguments in favor of the prevalence of A1, B5, B18 in HD, and in particular A1 in the mixed cellularity form, while the haplotype, A1, B8, predominant in long survivors seems to possess a protective effect. It is expected that more data from multiplex families and prospective series of unrelated patients, fully HLA typed, may help to bring about a better understanding of the first reported HLA linkage with malignancy.

Disease Susceptibility↗
PubMed1999

Temporal and spatial variation of inversion polymorphism in two natural populations of Drosophila buzzatii.

The inversion polymorphism of the cactophilic fly Drosophila buzzatii was studied in two natural populations. We assessed the temporal changes and microspatial population structure. We observed a significant increase in the frequency of arrangement 2J at the expense of 2ST in both populations. These gene arrangements appear to affect the life-history of flies differently. Environmental heterogeneity explains the karyotype coexistence in nature. The analysis of population structure showed that differentiation of inversion frequencies among individual breeding sites, the rotting clacodes of Opuntia vulgaris, was highly significant. The karyotypic frequencies did not depart significantly from Hardy-Weinberg expectations, neither in individual rots nor in the total population. These results suggest that the observed population structure can be easily accounted by random genetic drift.

Animals↗