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The authors report a family in which two affected first cousins had a severe demyelinating Charcot-Marie-Tooth disease (CMT) phenotype. One had related parents, and there were no other affected relatives, suggesting an autosomal recessive mode of inheritance. Molecular studies showed that a de novo duplication in 17p11.2 and a second mutation in MTMR2 were present.
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The aim of this study was to compare, under different models of gene-environment (G x E) interaction, the power to detect linkage and G x E interaction of different tests using affected sib-pairs. Methods considered were: 1) the maximum likelihood lod-score (MLS), based on the distribution of parental alleles identical by descent (IBD) in affected sibs; 2) the sum of the MLS (sMLS) calculated in affected sib-pairs with 2, 1, or 0 sibs exposed; 3) the predivided sample test (PST), which compares the IBD distribution between affected sib-pairs with 2, 1, or 0 sibs exposed; 4) the triangle test statistic (TTS), which uses the IBD distribution among discordant affected sib-pairs (one exposed, one unexposed); and 5) the mean interaction test (MIT), based on the regression of the proportion of alleles shared IBD among affected sib-pairs on the exposure among sib-pairs. The MLS, sMLS, and MIT allow detection of linkage. However, the sMLS and MIT account for a possible G x E interaction without testing it. In contrast, the PST and the TTS allow detection of both linkage and G x E interaction. Results showed that when exposure cancels the effect of the gene, or changes the direction of this effect (i.e., the protective allele becomes the risk allele), the PST, sMLS, and MIT may provide, under some models, greater power to detect linkage than the MLS. Under models where exposure changes the direction of the effect of the gene, the TTS test may also be more powerful than the other tests accounting for G x E interaction. Under the other models, the MLS remains the most powerful test to detect linkage. However, only the PST and TTS allow the detection of G x E interaction.
OBJECTIVE: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. METHOD: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. RESULTS: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.
Given the enormous progress in the knowledge of the human genome, genetic markers are now available throughout the genome. Haplotype analysis, allowing the simultaneous use of information from several markers, has thus become increasingly popular. However, we often face the problem of missing data and of haplotype identification. We have proposed a haplotype based method for the genetic study of multifactorial diseases in founder populations, the MILC method (Bourgain et al. 2000). MILC is based on the contrast of identity length between haplotypes transmitted to affected offspring and haplotype non-transmitted. In this study, the impact of different strategies, regarding missing data, on the MLIC method are evaluated. A real situation is considered where data are derived from a genome screen for asthma susceptibility alleles in the Hutterites. Results are illustrated on this asthma data set.
A popular method for the analysis of case-control association studies is to compare the frequencies of the alleles between cases and controls by means of Pearson's chi2-statistic. Here, an approach for computing the power of this test is presented, which by computer simulation is shown to be more reliable than a previously published power approximation. Since the test based on Pearson's chi2- statistic can be anti-conservative if there is an excess of homozygotes for the susceptibility allele in the general population, it has been proposed to analyze case-control association studies by means of a trend test based on genotypes instead of alleles. We present an accurate power approximation for the trend test. The power approximations are implemented in an available computer program 'GenOdyPower', which in addition has an option to determine the empirical power of these tests by simulations.
Interleukin 1alpha (IL-1alpha) has been implicated in the pathogenesis of infectious, auto-immune and inflammatory diseases. Polymorphisms in the genes encoding IL-1alpha, IL-1beta and the IL-1 receptor antagonist (ILRN) molecules have been associated with several inflammatory diseases. As the marker D2S160 has been characterized as a candidate locus for Ankylosing Spondylitis (AS) after a genome-wide scan, and since this locus is located approximately 0.3 cM telomeric to the IL-1 gene cluster, we hypothesized that these cytokines might be good candidates for Spondylarthropathies (SpA). Therefore we tested this hypothesis using the transmission disequilibrium test (TDT) in 37 families representing 217 subjects from three intragenic IL-1 gene cluster polymorphisms, the IL1B Taq I, the ILRN 2nd intron, and the IL1A Nco I, taking HLA B27 status into account or not. In conclusion, by means of intra-familial TDT analysis we found no linkage or intra-familial association between SpA and the three IL-1 gene-cluster polymorphisms in SpA multiplex family material.
We report a clinical and genetic study of a French family among whom febrile convulsions (FC) are associated with subsequent temporal lobe epilepsy (TLE) in the same individual, without magnetic resonance imaging-identifiable hippocampal abnormalities. Linkage analyses excluded the loci FEB1 and FEB2, previously implicated in FC; the GEFS+1 locus responsible for generalized epilepsy with febrile seizures plus; and the locus implicated in lateral temporal lobe epilepsy. After scanning the entire genome, significant lod scores (>3) for markers on 18qter and suggestive lod scores (>2) for markers on 1q25-q31 were obtained. An analysis of the haplotypes at these two loci supported the hypothesis that two genes segregated with the phenotype. All patients shared common haplotypes for both 1q25-q31 and 18qter chromosomes. All but one unaffected at-risk individuals carried only one, or none, of the disease haplotypes. Under the assumption of digenic inheritance, haplotype reconstruction defined a 26 cM interval on chromosome 1 and a 10 cM interval on chromosome 18. This family suggests that the association between FC and TLE may be observed in the absence of hippocampal structural abnormalities and that they may have, in some cases, a common genetic basis.
The determination of tetra- to octachlorodibenzo-p-dioxins and tetra- to octachlorodibenzofurans (PCCD/Fs) by high-resolution gas chromatography/tandem mass spectrometry (HRGC/MS/MS) and high-resolution gas chromatography/triple mass spectrometry (HRGC/MS(3)) in a quadrupole ion trap, equipped with an external ion source, is presented. MS/MS involves a typical four-step process, namely ionization, parent ion isolation, collision-induced dissociation (CID) and mass analysis of the daughter ions. For the MS(3) experiment, the MS/MS scan function is used with the addition of selected daughter ion isolation, their CID and the mass analysis of second-generation product ions called 'grand-daughter ions.' For both methods, the energies necessary for the CID of the 17 PCDD/Fs were determined and optimized using multiple scan functions with different CID amplitudes. The CID efficiency, defined as the signal ratio of fragment ions detected from the major dissociation channels to molecular ions isolated, was 1.15-2.40 V for parent ion dissociation (MS/MS) and 1.05-1.50 V for daughter ion dissociation (MS(3)) and for all the chloro congeners. The same sensitivity (1 pg microl(-1)) can be reached with both the MS/MS and MS(3) methods and linear responses were obtained between 1 and 100 pg microl(-1) injected.
Liquid chromatography with photodiode array detection (LC-DAD) and liquid chromatography with mass spectrometry (LC-MS) are two techniques that have been widely used in monitoring pesticides and their degradation products in the environment. However, the application of liquid chromatography with tandem mass spectrometry (LC-MS-MS) for such purposes, once considered too costly, is now gaining considerable ground. In this study, we compare these methods for the multi-residue analysis of pesticides in surface waters collected from the central and southeastern regions of France, and from the St. Lawrence River in Canada. Forty-eight pesticides belonging to eight different classes (triazine, amide, phenylurea, triazole, triazinone, benzimidazole, morpholine, phenoxyalkanoic), along with some of their degradation products, were monitored on a regular basis in the surface waters. For LC-MS, we used the electrospray ionization (ESI) interface in the negative ionization mode on acidic pesticides (phenoxyalkanoic, sulfonylurea), and the atmospheric pressure chemical ionization (APCI) interface in the positive ionization mode on the remaining chemicals. Different extraction techniques were employed, including liquid-liquid extraction with dichloromethane, and solid-phase extraction using C18-bonded silica and graphitized carbon black cartridges. Eleven of the target chemicals (desethylatrazine, desisopropylatrazine, atrazine, simazine, terbuthylazine, metolachlor, carbendazime, bentazone, penconazole, diuron and isoproturon) were detected by LC-MS at concentrations ranging from 20 to 900 ng/l in the surface waters from France, and six pesticides (atrazine, desethylatrazine, desisopropylatrazine, cyanazine, simazine and metolachlor) were detected by LC-MS and LC-MS-MS at concentrations ranging from 3 to 52 ng/l in the samples drawn from the St. Lawrence River. There was good correlation between the LC-DAD and LC-MS techniques for 60 samples. The slope of the curves expressing the relationship between the results obtained with LC-DAD versus those obtained by LC-MS was near 1, with a correlation coefficient (r) of over 0.93. The identification potential of the LC-MS technique, however, was greater than that of the LC-DAD; its mass spectra, mainly reflecting the pseudomolecular ion resulting from a protonation or a deprotonation of the molecule, was rich in information. The LC-MS-MS technique with ion trap detectors, tested against the LC-MS on 10 surface water samples, gave results that correlated well with the LC-MS results, albeit generating mass spectra that yielded far more information about the structure of unknown substances. The sensitivity of the LC-MS-MS was equivalent to the selected ion monitoring (SIM) acquisition mode in LC-MS. The detection limits of the target pesticides ranged from 20 to 100 ng/l for the LC-MS technique (under full scan acquisition), and from 2 to 6 ng/l for LC-MS-MS. These limits were improved by a factor of almost 10 by increasing the sample volume to 10 l.
Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS.
Rheumatoid arthritis is an inflammatory disease for which positive associations have been described with some HLA-DRB1 alleles. The associated alleles share a similar amino acid sequence in the third hypervariable region, the shared epitope, but differ at position 71 and 86. It has been suggested that HLA susceptibility to rheumatoid arthritis could be due not only to the shared epitope but could also be influenced by specific amino acids at positions 71 and 86. In this study, we investigated the role of these amino acids in rheumatoid arthritis on 203 unrelated patients. An involvement of amino acid 71 was detected but no conclusion was possible regarding amino acid 86. A study of the sensitivity of the conclusions to marker allele frequencies was performed. We showed that the results obtained for amino acid 71 are not very sensitive to allele frequencies but those obtained at position 86 are highly sensitive. This emphasizes the importance of studying the robustness of results to variations in allele frequencies before conclusions are drawn.
The current challenge in biomedical research is to detect genetic risk factors involved in common complex diseases. The power to detect their role is generally poor in populations that have been large for a long time. It has been suggested that the power may be increased by taking advantage of the specificity of founder populations: linkage disequilibrium spanning larger regions and kinship coefficients being stronger than in large populations. A new method is proposed here, the Maximum Identity Length Contrast (MILC) which, in contrast with other existing methods, does not make the assumption of unique ancestry for the genetic risk factors. It is thus appropriate for a search for common genetic risk factors for complex diseases. Statistical properties of the method are discussed in realistic contexts.
Mucolipidosis IIIC, or variant pseudo-Hurler polydystrophy, is an autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (N-Acetylglucosamine-1-phosphotransferase [GlcNAc-phosphotransferase]) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Bovine GlcNAc-phosphotransferase has recently been isolated as a multisubunit enzyme with the subunit structure alpha(2)beta(2)gamma(2). We cloned the cDNA for the human gamma-subunit and localized its gene to chromosome 16p. We also showed, in a large multiplex Druze family that exhibits this disorder, that MLIIIC also maps to this chromosomal region. Sequence analysis of the gamma-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the gamma subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase gamma-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.
Meckel syndrome (MKS) is a rare autosomal recessive lethal condition of unknown origin, characterized by (i) an occipital meningo-encephalocele with (ii) enlarged kidneys, with multicystic dysplasia and fibrotic changes in the portal area of the liver and with ductal proliferation, and (iii) postaxial polydactyly. A gene responsible for MKS in Finland has been mapped to chromosome 17q21-q24. Studying a subset of Middle Eastern and northern African MKS families, we have recently excluded the chromosome 17 region and have suggested a genetic heterogeneity. In the present study, we report on the mapping of a second MKS locus (MKS2) to chromosome 11q13, by homozygosity mapping in seven families that do not show linkage to chromosome 17q21-q24 (maximum LOD score 4.41 at recombination fraction .01). Most interestingly, the affected fetuses of southern Tunisian ancestry shared a particular haplotype at loci D11S911 and D11S906, suggesting that a founder effect is involved. Our observation gives support to the clinical and genetic heterogeneity of MKS.
Several mutations in the coding exon of the ACTH receptor (MC2R) gene have been reported in cases of familial glucocorticoid deficiency or FGD. However, many patients with a similar syndrome do not present any mutation in the coding region of this gene. This is the case in 11 families we have investigated. Patients in these families present the typical clinical features of FGD, but no mutation was found in the coding exon of the ACTH receptor. To determine whether mutations on MC2R gene, but outside the coding region, may be involved in FGD in these families, we have performed a linkage analysis. Using three markers flanking MC2R gene on chromosome 18, we were able to exclude linkage in a region of 12 centimorgans around the gene. This result clearly indicates that FGD is genetically heterogeneous. Defects in gene(s) different from MC2R gene are implicated in this syndrome.
A high-performance liquid chromatographic (HPLC) assay method for C60 fullerene, in blood, liver and spleen using photodiode-array detection or mass spectrometric detection (LC-MS) and C70 fullerene, as the internal standard, is described. The recovery from mouse blood and tissues spiked with micronized C60 exceeds 90%. The method is linear from 0.05 to 200 mg of C60 per liter of blood and from 0.05 to 5.00% of C60 per tissue weight. The limit of detection of the method is 0.1 ng of C60 per injection. This method was applied to mouse blood and tissue samples after intraperitoneal administration of a micronized C60 suspension.
Meckel syndrome (MKS) is a lethal, autosomal recessive condition characterised by an occipital meningoencephalocele, enlarged kidneys with multicystic dysplasia, fibrotic changes of the liver in the portal area with ductal proliferation, and postaxial polydactyly. Recently, a MKS gene has been mapped to chromosome 17q21-q24 in Finnish families, with no evidence of locus heterogeneity in this population. Here, we report the exclusion of chromosome 17q21-q24 in eight typical MKS families of North African and Middle Eastern ancestry and provide evidence for genetic heterogeneity of this condition.