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Zhao Zhang,
Jackie Quinlan,
David Grote, Mathieu Lemire,
Thomas Hudson,
Alice Benjamin,
Anne Roy,
Elena Pascuet,
Meigan Goodyer,
Chandhana Raju,
Fiona Houghton,
Maxime Bouchard,
Paul Goodyer
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ABSTRACT: Glial cell-derived neurotrophic factor (GDNF) plays an important role in renal development, serving as a trophic factor for outgrowth of the ureteric bud and its continued arborisation. Our previous studies have shown that common variants of the human paired-box 2 (PAX2) gene (a transcriptional activator of GDNF) and rearranged during transfection (RET) gene (encoding the cognate receptor for GDNF) are associated with a subtle reduction in the kidney size of newborns. Since heterozygosity for a mutant GDNF allele causes mild renal hypoplasia and modest hypertension in mice, we considered the possibility that common variants of the GDNF gene might also contribute to renal hypoplasia in humans. We studied the relationship between newborn renal size or umbilical cord cystatin C and 19 common GDNF gene variants [minor allele frequency (MAF) >5%], three single nucleotide polymorphisms (SNPs) related to a putative PAX binding site and one rare SNP (rs36119840 A/G) which changes an amino acid (R93W), based on data from the haplotype map of the human genome (HapMap). However, none of these 23 SNPs was associated with reduced newborn kidney size or function. Among the 163 Caucasians in our cohort, none had the R93W allele.
Pediatric Nephrology 01/2009; 24(6):1151-7. · 2.52 Impact Factor
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Alexandra-Chloe Villani,
Yuri A. Saito, Mathieu Lemire,
Marroon Thabane,
Joseph J. Larson,
Elizabeth J. Atkinson,
Janice Zimmerman,
Ann E. Almazar Elder,
Stephen M. Collins,
Denis Franchimont,
John K. Marshall
Gastroenterology 01/2009; 136(5). · 11.68 Impact Factor
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Alexandra-Chloé Villani, Mathieu Lemire,
Geneviève Fortin,
Edouard Louis,
Mark S Silverberg,
Catherine Collette,
Nobuyasu Baba,
Cécile Libioulle,
Jacques Belaiche,
Alain Bitton, [......],
Albert Cohen,
Diane Langelier,
Paul R Fortin,
Joan E Wither,
Marika Sarfati,
Paul Rutgeerts,
John D Rioux,
Severine Vermeire,
Thomas J Hudson,
Denis Franchimont
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ABSTRACT: We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
Nature Genetics 01/2009; 41(1):71-6. · 35.53 Impact Factor
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Zhao Zhang,
Jackie Quinlan,
Wendy Hoy,
Michael D Hughson, Mathieu Lemire,
Thomas Hudson,
Pierre-Alain Hueber,
Alice Benjamin,
Anne Roy,
Elena Pascuet,
Meigan Goodyer,
Chandhana Raju,
Fiona Houghton,
John Bertram,
Paul Goodyer
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ABSTRACT: Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.
Journal of the American Society of Nephrology 11/2008; 19(10):2027-34. · 9.66 Impact Factor
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Karine Tremblay,
Denise Daley,
Annie Chamberland, Mathieu Lemire,
Alexandre Montpetit,
Michel Laviolette,
Arthur W Musk,
Alan L James,
Moira Chan-Yeung,
Allan Becker,
Anita L Kozyrskyj,
Andrew J Sandford,
Thomas J Hudson,
Peter D Paré,
Catherine Laprise
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ABSTRACT: Eight genes in the immune signaling pathway shown to be differentially expressed in asthmatic lung biopsy specimens in a previous microarray experiment were selected as candidate genes for asthma susceptibility.
We sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and 1 Australian asthma case-control study.
Tagging single nucleotide polymorphisms were selected by using the HapMap public database (r(2) > 0.8; minor allele frequency >0.10) and genotyped with the Illumina platform. Family-based association and trend tests for asthma, atopy, airway hyperresponsiveness, and allergic asthma phenotypes were done in each sample, correcting for multiple testing.
Uncorrected associations with polymorphisms within 7 genes were detected with 1 or more of the phenotypes in 1 or more of the 4 populations (.001 <P < .05). After correction, the 15-lipoxygenase (15-LO) associations with airway hyperresponsiveness and allergic asthma remained significant in 2 Canadian samples (corrected P = .022 and .049, respectively), and the association of the CD14 antigen with asthma remained significant in 1 Canadian sample (corrected P = .042). In both cases a protective effect of the minor alleles was observed.
Expression profiling studies are a useful way to identify candidate genes for asthma because this approach has led to the first report of an association with 15-LO in 2 independent populations. Because 15-LO is involved in anti-inflammatory processes, further functional and clinical investigation of the role of this biologic pathway in asthma is warranted.
The Journal of allergy and clinical immunology 09/2008; 122(3):529-36.e17. · 9.17 Impact Factor
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ABSTRACT: Asthma is a complex trait for which different strategies have been used to identify its environmental and genetic predisposing factors. Here, we describe a novel methodological approach to select candidate genes for asthma genetic association studies. In this regard, the Genes to Diseases (G2D) computational tool has been used in combination with a genome-wide scan performed in a sub-sample of the Saguenay-Lac-St-Jean (SLSJ) asthmatic familial collection (n = 609) to identify candidate genes located in two suggestive loci shown to be linked with asthma (6q26) and atopy (10q26.3), and presenting differential parent-of-origin effects. This approach combined gene selection based on the G2D data mining analysis of the bibliographic and protein public databases, or according to the genes already known to be associated with the same or a similar phenotype. Ten genes (LPA, NOX3, SNX9, VIL2, VIP, ADAM8, DOCK1, FANK1, GPR123 and PTPRE) were selected for a subsequent association study performed in a large SLSJ sample (n = 1167) of individuals tested for asthma and atopy related phenotypes. Single nucleotide polymorphisms (n = 91) within the candidate genes were genotyped and analysed using a family-based association test. The results suggest a protective association to allergic asthma for PTPRE rs7081735 in the SLSJ sample (p = 0.000463; corrected p = 0.0478). This association has not been replicated in the Childhood Asthma Management Program (CAMP) cohort. Sequencing of the regions around rs7081735 revealed additional polymorphisms, but additional genotyping did not yield new associations. These results demonstrate that the G2D tool can be useful in the selection of candidate genes located in chromosomal regions linked to a complex trait.
PLoS ONE 02/2008; 3(8):e2907. · 4.09 Impact Factor
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James C Engert, Mathieu Lemire,
Janet Faith,
Diane Brisson,
T Mary Fujiwara,
Nicole M Roslin,
Carl G Brewer,
Alexandre Montpetit,
Corinne Darmond-Zwaig,
Yannick Renaud, [......],
Swneke D Bailey,
Andrei Verner,
Gérald Tremblay,
Julie St-Pierre,
Christine Bétard,
Jill Platko,
John D Rioux,
Kenneth Morgan,
Thomas J Hudson,
Daniel Gaudet
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ABSTRACT: Susceptibility to coronary heart disease (CHD) has long been known to exhibit familial aggregation, with heritability estimated to be greater than 50%. The French Canadian population of the Saguenay-Lac Saint-Jean region of Quebec, Canada is descended from a founder population that settled this region 300-400 years ago and this may provide increased power to detect genes contributing to complex traits such as CHD. Probands with early-onset CHD, defined by angiographically determined coronary stenosis, and their relatives were recruited from this population (average sibship size of 6.4). Linkage analysis was performed following a genome-wide microsatellite marker scan on 42 families with 284 individuals. Nonparametric linkage (NPL) analysis provided suggestive evidence for a CHD susceptibility locus on chromosome 8 with an NPL score of 3.14 (P=0.001) at D8S1106. Linkage to this locus was verified by fine mapping in an enlarged sample of 50 families with 320 individuals. This analysis provided evidence of linkage at D8S552 (NPL score=3.53, P=0.0003), a marker that maps to the same location as D8S1106. Candidate genes in this region, including macrophage scavenger receptor 1, farnesyl-diphosphate farnesyltransferase 1, fibrinogen-like 1, and GATA-binding protein 4, were resequenced in all coding exons in both affected and unaffected individuals. Association studies with variants in these and five other genes did not identify a disease-associated mutation. In conclusion, a genome-wide scan and additional fine mapping provide evidence for a locus on chromosome 8 that contributes to CHD in a French Canadian population.
European Journal of HumanGenetics 02/2008; 16(1):105-14. · 4.40 Impact Factor
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ABSTRACT: Chronic rhinosinusitis (CRS) is increasingly viewed as an inflammatory condition of the sinonasal mucosa interacting with bacteria and/or fungi. However, factors conferring susceptibility to disease remain unknown. Advances in genomics offer powerful tools to explore this disorder. The goal of this study was to evaluate the effect of single nucleotide polymorphisms (SNP) on CRS in a panel of genes related to cysteinyl leukotriene metabolism.
Severe cases of CRS and postal code match controls were recruited prospectively. A total of 206 cases and 200 controls were available for the present study. Using a candidate gene approach, five genes related to cysteinyl leukotriene metabolism were assessed. For each gene, we selected the maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. These SNPs are in arachidonate 5-lipoxygenase (ALOX5), arachidonate 5-lipoxygenase-activating protein (ALOX5AP), leukotriene C4 synthase (LTC4S), cysteinyl leukotriene receptor 1 (CYSLTR1) and cysteinyl leukotriene receptor 2 (CYSLTR2) genes.
A total of 59 SNPs were genotyped to capture the common genetic variations within these genes. Three SNPs located within the ALOX5, CYSLTR1 and ALOX5AP genes reached the nominal p-value threshold (p < 0.05) for association with CRS. However, none of these SNPs resist multiple testing adjustment.
While these initial results do not support that polymorphsims in genes assessed involved in the leukotriene pathways are contributing to the pathogenesis of CRS, this initial study was not powered to detect polymorphisms with relative risk of 2.0 or less, where we could expect many gene effects for complex diseases to occur. Thus, despite this lack of significant association noted in this study, we believe that validation with external populations and the use of better-powered studies in the future may allow more conclusive findings.
BMC Medical Genetics 01/2008; 9:21. · 2.33 Impact Factor
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Philippe Bégin,
Karine Tremblay,
Denise Daley, Mathieu Lemire,
Sébastien Claveau,
Charleen Salesse,
Sabine Kacel,
Alexandre Montpetit,
Allan Becker,
Moira Chan-Yeung,
Anita L Kozyrskyj,
Thomas J Hudson,
Catherine Laprise
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ABSTRACT: Urokinase plasminogen activator (uPA) interacts with its receptor on inflammatory and migrating cells to regulate extracellular matrix degradation, cell adhesion, and inflammatory cell activation. It is necessary for the development of an appropriate immune response and is involved in tissue remodeling. The PLAU gene codes for this enzyme, and is located on 10q24. This region has demonstrated evidence for linkage in a genome scan for asthma in a sample from northeastern Quebec. Here, we hypothesized that uPA may function as a regulator of asthma susceptibility.
To test for association between asthma and genetic variants of PLAU. Methods: We sequenced PLAU and tested for genetic association between identified variants and asthma-related traits in a French-Canadian familial collection (231 families, 1,139 subjects). Additional association studies were performed in two other family-based Canadian cohorts (Canadian Asthma Primary Prevention Study [CAPPS], 238 trios; and Study of Asthma Genes and the Environment [SAGE], 237 trios).
In the original sample, under the dominant model, the common alleles, rs2227564C (P141) and rs2227566T, were associated with asthma (p = 0.011 and 0.045, respectively) and with airway hyperresponsiveness (AHR) (p = 0.026 and 0.038, respectively). Analysis of the linkage disequilibrium pattern also revealed association of the common haplotype for asthma, atopy, and AHR (p = 0.031, 0.043, and 0.006, respectively). Whereas no significant association was detected for PLAU single-nucleotide polymorphisms in the CAPPS cohort, association was observed in the SAGE cohort between the rs4065C allele and atopy under additive (p = 0.005) and dominant (p = 0.0001) genetic models.
This suggests a role for the uPA pathway in the pathogenesis of the disease.
American Journal of Respiratory and Critical Care Medicine 07/2007; 175(11):1109-16. · 11.08 Impact Factor
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Jacklyn Quinlan, Mathieu Lemire,
Thomas Hudson,
Huiqi Qu,
Alice Benjamin,
Anne Roy,
Elena Pascuet,
Meigan Goodyer,
Chandhana Raju,
Zhao Zhang,
Fiona Houghton,
Paul Goodyer
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ABSTRACT: Congenital nephron number ranges widely in the human population. Suboptimal nephron number may be associated with increased risk for essential hypertension and susceptibility to renal injury, but the factors that set nephron number during kidney development are unknown. In renal-coloboma syndrome, renal hypoplasia and reduced nephron number are due to heterozygous mutations of the PAX2 gene. This study tested for an association between a common haplotype of the PAX2 gene and subtle renal hypoplasia in normal newborns. A PAX2 haplotype was identified to occur in 18.5% of the newborn cohort, which was significantly associated with a 10% reduction in newborn kidney volume adjusted for body surface area. This haplotype was also associated with reduced allele-specific PAX2 mRNA level in a human renal cell carcinoma cell line. Subtle renal hypoplasia in normal newborns may be partially due to a common variant of the PAX2 gene that reduces mRNA expression during kidney development.
Journal of the American Society of Nephrology 07/2007; 18(6):1915-21. · 9.66 Impact Factor
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Mathieu Lemire
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ABSTRACT: With the recent advances in high-throughput genotyping technologies that allow for large-scale association mapping of human complex traits, promising statistical designs and methods have been emerging. Efficient simulation software are key elements for the evaluation of the properties of new statistical tests. SLINK is a flexible simulation tool that has been widely used to generate the segregation and recombination processes of markers linked to, and possibly associated with, a trait locus, conditional on trait values in arbitrary pedigrees. In practice, its most serious limitation is the small number of loci that can be simulated, since the complexity of the algorithm scales exponentially with this number.
I describe the implementation of a two-step algorithm to be used in conjunction with SLINK to enable the simulation of a large number of marker loci linked to a trait locus and conditional on trait values in families, with the possibility for the loci to be in linkage disequilibrium. SLINK is used in the first step to simulate genotypes at the trait locus conditional on the observed trait values, and also to generate an indicator of the descent path of the simulated alleles. In the second step, marker alleles or haplotypes are generated in the founders, conditional on the trait locus genotypes simulated in the first step. Then the recombination process between the marker loci takes place conditionally on the descent path and on the trait locus genotypes. This two-step implementation is often computationally faster than other software that are designed to generate marker data linked to, and possibly associated with, a trait locus.
Because the proposed method uses SLINK to simulate the segregation process, it benefits from its flexibility: the trait may be qualitative with the possibility of defining different liability classes (which allows for the simulation of gene-environment interactions or even the simulation of multi-locus effects between unlinked susceptibility regions) or it may be quantitative and normally distributed. In particular, this implementation is the only one available that can generate a large number of marker loci conditional on the set of observed quantitative trait values in pedigrees.
BMC Genetics 02/2006; 7:40. · 2.47 Impact Factor
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Mathieu Lemire
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ABSTRACT: A simple multipoint procedure to test for parent-of-origin effects in samples of affected siblings is discussed. The procedure consists of artificially changing all full sibs to half-sibs, with distinct mothers or fathers depending on the parental origin to be evaluated, then analyzing these families with commonly used statistics and software. The procedure leads to tests for linkage through mothers or fathers and also leads to a test for imprinting effects in the presence of linkage. Moreover, simulations illustrate that in regions unlinked to susceptibility genes this multipoint procedure does not have an inflated type I error if a sex-averaged genetic map is used, even when large differences exist between male-specific and female-specific maps. In regions linked with susceptibility genes, the test of imprinting is biased under the null hypothesis if differences exist between sex-specific maps, irrespective of the map used in the analysis. The procedure is applied to the Collaborative Study on the Genetics of Alcoholism dataset from the Genetic Analysis Workshop 14. Results indicate that brothers categorized as affected according to the DMS-III-R and Feighner classification show evidence of linkage through fathers to the 6q25 region (p = 0.00038) as well as modest evidence of imprinting (p = 0.018). This region harbors OPRM1, a candidate gene for substance dependence.
BMC Genetics 01/2006; 6 Suppl 1:S159. · 2.47 Impact Factor
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ABSTRACT: Inter-individual variation in gene expression has proven to be in part governed by genetic determinants, which may be trans- or cis-acting. The underlying cause of cis-acting regulatory variation has been identified in only a handful of the hundreds of genes shown to display differential allelic expression. In this report, we describe a systematic effort to map common cis-acting variants in 64 genes, using association methods in HapMap samples. We identified 16 loci (25%), each of which harbors common haplotypes that affect total expression of a gene, and a further 17 loci (27%) with evidence of haplotypes affecting relative allelic expression in heterozygote samples. Our survey suggests that detailed mapping of allele-specific in vivo expression will provide a rich source of regulatory SNPs or haplotypes that should be given high priority in association studies of human phenotypes.
Human Molecular Genetics 01/2006; 14(24):3963-71. · 7.64 Impact Factor
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ABSTRACT: We studied the effect of transmission-ratio distortion (TRD) on tests of linkage based on allele sharing in affected sib pairs. We developed and implemented a discrete-trait allele-sharing test statistic, Sad, analogous to the Spairs test statistic of Whittemore and Halpern, that evaluates an excess sharing of alleles at autosomal loci in pairs of affected siblings, as well as a lack of sharing in phenotypically discordant relative pairs, where available. Under the null hypothesis of no linkage, nuclear families with at least two affected siblings and one unaffected sibling have a contribution to Sad that is unbiased, with respect to the effects of TRD independent of the disease under study. If more distantly related unaffected individuals are studied, the bias of Sad is generally reduced compared with that of Spairs, but not completely. Moreover, Sad has higher power, in some circumstances, because of the availability of unaffected relatives, who are ignored in affected-only analyses. We discuss situations in which it may be an efficient use of resources to genotype unaffected relatives, which would give insights for promising study designs. The method is applied to a sample of pedigrees ascertained for asthma in a chromosomal region in which TRD has been reported. Results are consistent with the presence of transmission distortion in that region.
The American Journal of Human Genetics 11/2004; 75(4):571-86. · 10.60 Impact Factor
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ABSTRACT: Genome scans for asthma have identified suggestive or significant linkages on 17 different chromosomes, including chromosome 12, region q13-23, housing the vitamin D receptor (VDR) gene. Through interaction with VDR, 1,25-dihydroxyvitamin D3 mediates numerous biological activities, such as regulation of helper T-cell development and subsequent cytokine secretion profiles. Variants of the VDR have been found to be associated with immune-mediated diseases that are characterized by an imbalance in helper T-cell development, such as Crohn's disease and tuberculosis. The VDR, hence, is a good candidate to be investigated for association with asthma, which is characterized by enhanced helper T-cell type 2 activity. Here, we examined VDR genetic variants in an asthma family-based cohort from Quebec. We report six variants to be strongly associated with asthma and four with atopy (0.0005 < or = p < or = 0.05). Analysis of the linkage disequilibrium pattern and haplotypes also revealed significant association with both phenotypes (0.0004 < or = p < or = 0.01). The findings have been replicated by another research team in a second but not in a third cohort. These results identify VDR variants as genetic risk factors for asthma/atopy and implicate a non-human leukocyte antigen immunoregulatory molecule in the pathogenesis of asthma and atopy.
American Journal of Respiratory and Critical Care Medicine 11/2004; 170(9):967-73. · 11.08 Impact Factor
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Benjamin A Raby,
Walter T Klimecki,
Catherine Laprise,
Yannick Renaud,
Janet Faith, Mathieu Lemire,
Celia Greenwood,
Katherine M Weiland,
Christoph Lange,
Lyle J Palmer,
Ross Lazarus,
Donata Vercelli,
David J Kwiatkowski,
Edwin K Silverman,
Fernando D Martinez,
Thomas J Hudson,
Scott T Weiss
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ABSTRACT: Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.
American Journal of Respiratory and Critical Care Medicine 01/2003; 166(11):1449-56. · 11.08 Impact Factor
