Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2336-2341 ◽  
Author(s):  
Ulrike Nowak-Göttl ◽  
Birgit Fröhlich ◽  
Sabine Thedieck ◽  
Andreas Huge ◽  
Monika Stoll
Keyword(s):  
Genetic Variation ◽  
Linkage Disequilibrium ◽  
Multiple Testing ◽  
Risk Haplotype ◽  
Nucleotide Polymorphisms ◽  
Permutation Testing ◽  
Protein Z ◽  
White Children ◽  
German Children ◽  
Family Based

Abstract To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)–based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, χ2 = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.

Epistatic Interaction between Fibrinogen alpha and gamma Genes and Factor V Leiden in Children with Venous Thrombosis: Results from a Family-Based Association Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1640-1640
Author(s):  
Ulrike Nowak-Gottl ◽  
Hartmut Weiler ◽  
Tanja Seehafer ◽  
Sabine Thedieck ◽  
Monika Stoll
Keyword(s):  
Genetic Variation ◽  
Epistatic Interaction ◽  
Association Studies ◽  
Factor V Leiden ◽  
Complex Nature ◽  
Factor V ◽  
Nucleotide Polymorphisms ◽  
Permutation Testing ◽  
Factor V Leiden Mutation ◽  
Family Based

Abstract Background: Fibrinogen, the precursor of fibrin, is an essential component of the hemostatic system. A previous large case-control study showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for VT in adults. Here we investigated the association of haplotypes comprising the fibrinogen alpha (FGA) and gamma (FGG) genes, carriership of the Factor V Leiden mutation and risk for VT in a large family-based study sample for pediatric VT. Methods: We genotyped 188 pediatric VT families for seven single nucleotide polymorphisms (SNPs) (rs6050, rs2070016, rs2070014 and rs2070011, rs1049636, rs2066861, rs2066860) as well as the G1691A Factor V Leiden (FV) polymorphism. Association was assessed using the Transmission Disequilibrium Test (TDT) and corrected for multiple testing using permutation testing as implemented in HAPLOVIEW. Interaction between FV and FGA and FGG, respectively, was assessed by TDT in families stratified for presence or absence of the FV mutation in the affected child. Results: rs6050, rs2070016, rs2070014 and rs2070011 located in the FGA gene are in tight linkage disequilibrium (LD) and define 5 common haplotypes (HT) and are linked with the neighboring FGG gene (q= 0.91). rs1049636, rs2066861, rs2066860 located in FGG are in tight LD and define 4 HTs. HTs in both, FGA and FGG are significantly overtransmitted from parents to affected offspring (FGA: HT1 (AACT), HT frequency 0.32, T:U 62: 32, p=0.0025; FGG: HT2 (ATC), HT frequency 0.32, T:U 60:32, p=0.0035). When stratifying for FV status, it became apparent that the association between FGA and FGG and VT was more pronounced in FV-negative families (FGA, HT1, T:U 55:24, p=0.0006; FGG, HT2, T:U 55:24, p=0.0005), while absent in FV-positive families. Conclusion: Our results indicate that genetic variation in FGA and FGG are risk factors for VT in children, and further that an epistatic interaction between FGA/FGG and FV Leiden influences the risk of FGG and FGA on pediatric VT. Our study highlights the complex nature of VT and the necessity to evaluate gene-gene interactions in association studies of complex, polygenic diseases.

Fibrinogen Alpha and Gamma Genes and Factor VLeiden in Children with Thromboembolism: Results from Two Family-Based Association Studies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3816-3816
Author(s):  
Ulrike Nowak-Gottl ◽  
Hartmut Weiler ◽  
Sabine Thedieck ◽  
Tanja Seehafer ◽  
Monika Stoll
Keyword(s):  
Multiple Testing ◽  
Genetic Interaction ◽  
Association Studies ◽  
Large Family ◽  
Independent Study ◽  
Risk Haplotype ◽  
Nucleotide Polymorphisms ◽  
System A ◽  
Protective Haplotype ◽  
Family Based

Abstract Background: Fibrinogen, the precursor of fibrin, is an essential component of the hemostatic system. A previous large case-control study showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for VT in adults. We investigated the association of haplotypes comprising the fibrinogen alpha (FGA) and gamma (FGG) genes, carriership of the Factor VLeiden-mutation and risk for VT in two large family-based study samples for pediatric thromboembolism. Methods: We genotyped 7 single nucleotide polymorphisms in FGA and FGG, and the G1691A Factor VLeiden polymorphism in 244 pediatric VT and 268 thrombo-embolic stroke families. Association was assessed using the Transmission Disequilibrium Test (TDT) and corrected for multiple testing. Results: Association analysis revealed that the FGA-H1 haplotype, and the FGG-H2 and -H3 haplotypes, were significantly associated with VT (FGA-H1, P=0.05; FGG: H2, P=0.032; H3, P=0.0216). In an independent study sample, FGA-H1 (P=0.0085) and FGG-H2 (P=0.05) were significantly associated with TS. When stratifying for FVLeiden carriership, the association between FGA and FGG and VT was more pronounced in FVLeiden-negative families (FGA-H1, P=0.0006; FGG-H2, P=0.0005). Homozygous carriership of the FGG-H2 risk haplotype resulted in the lowest fibrinogen γ′ content (γ′ levels: 22.7±13.7 vs. 26.8±12.0, P=0.013; % γ′: 7.63±3.05 vs. 9.46±3.17, P=2.3×10−5), with increasing concentrations of fibrinogen γ′ in heterozygote H2 carriers. Compound heterozygote carriers of one FGG-H2 risk and one FGG-H3 protective haplotype, showed significant increase in fibrinogen γ′ (P=0.000032), while fibrinogen levels remained unchanged. In contrast, homozygote carriers of the protective FGG-H3 haplotype showed the highest concentration of fibrinogen γ′ content (% γ′: 9.21±3.09, P=0.0031) with decreased total fibrinogen levels. Conclusion: Our results support an important role of genetic variants in FGA and FGG in thromboembolism in children and adults. Our data further suggest that the genetic architecture of VT is complex and involves subtle influences through susceptibility and protective haplotypes in FGG and a genetic interaction with the FVLeiden-mutation.

scholarly journals Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness

2016 ◽  
Vol 47 (4) ◽  
pp. 1072-1081 ◽  
Author(s):  
Marie-Hélène Dizier ◽  
Rachel Nadif ◽  
Patricia Margaritte-Jeannin ◽  
Sheila J. Barton ◽  
Chloé Sarnowski ◽  
...  
Keyword(s):  
Significant Interaction ◽  
Multiple Testing ◽  
Bronchial Hyperresponsiveness ◽  
Homogeneity Test ◽  
Nucleotide Polymorphisms ◽  
Linear Interaction ◽  
Genome Wide ◽  
Respiratory Cilia ◽  
Family Based ◽  
Log Linear

A previous genome-wide linkage scan of bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families, performed in the presence of a gene×early-life environmental tobacco smoke (ETS) exposure interaction, showed the strongest interaction in the 17p11 region where linkage was detected only among unexposed siblings. Our goal was to conduct fine-scale mapping of 17p11 to identify single nucleotide polymorphisms (SNPs) interacting with ETS that influence BHR.Analyses were performed in 388 French EGEA asthmatic families, using a two-step strategy: 1) selection of SNPs displaying family-based association test (FBAT) association signals (p≤0.01) with BHR in unexposed siblings, and 2) a FBAT homogeneity test between exposed and unexposed siblings plus a robust log-linear interaction test.A single SNP reached the threshold (p≤3×10−3) for significant interaction with ETS using both interaction tests, after accounting for multiple testing. Results were replicated in 253 French-Canadian families, but not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs to DNAH9 (dynein, axonemal, heavy chain 9), a promising candidate gene involved in respiratory cilia mobility and associated with primary ciliary dyskinesia, a disease associated with abnormalities of pulmonary function.

Linkage disequilibrium analyses within chromosome 19p in multiple sclerosis

2008 ◽  
Vol 14 (4) ◽  
pp. 433-439
Author(s):  
T. Vyshkina ◽  
B. Kalman
Keyword(s):  
Multiple Sclerosis ◽  
Linkage Disequilibrium ◽  
Multiple Testing ◽  
Potential Candidate ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pedigree Disequilibrium Test ◽  
The Family ◽  
Chromosome 19P

Objective The aim of this study was to determine if multiple sclerosis (MS) shows association with variants of single nucleotide polymorphisms (SNP) within chromosome 19p, where previous studies resulted in conflicting observations. Subjects and methods The transmissions of 569 SNP variants and 608 haplotypes from unaffected parents to their affected children were tested in 257 Caucasian families by using the pedigree disequilibrium test (PDT), the TRANSMIT version 2.5 program and the family- and haplotype-based association tests (FBAT and HBAT). The distribution of linkage disequilibrium (LD) among SNPs in 19p was assessed by ldmax and correlated with the location of MS-associated haplotypes. Results Individual SNP alleles did not show association after correction for multiple testing in PDT. Several marker haplotypes within potential candidate genes of intracellular enzymes, transmembrane proteins and receptors and signaling and adhesion molecules appeared to be weakly associated with the disease in both TRANSMIT and HBAT. However, none of the associations was strong enough to survive correction for multiple testing. Conclusions The present study is in the line of previous studies with negative conclusions concerning the role of the 19p region in MS. Multiple Sclerosis 2008; 14: 433—439. http://msj.sagepub.com

Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene QPC with low radial BMD in adult women.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Linkage Disequilibrium ◽  
Multiple Regression ◽  
Genetic Variations ◽  
Strong Linkage Disequilibrium ◽  
Adult Women ◽  
Nucleotide Polymorphisms ◽  
Haplotype Estimation ◽  
Factors Affecting ◽  
Glutaminyl Cyclase ◽  
Strong Linkage

Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene andadjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium,R54W showed a prominent association (p ? 0.0003), which was more striking when examined among 309 eldersubjects (>50 years; p ? 0.0001). Contribution for postmenopausal bone loss was suggested.Introduction: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis(HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have beenproposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene(GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essentialmodifier of pituitary peptide hormones, including GnRH.Materials and Methods: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locuswith adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) wasanalyzed by haplotype estimation and calculation of D? and r2. Multiple regression analysis was applied forevaluating the combined effects of the variations.Results and Conclusions: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of theQPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD,among which R54W (nt ? 160C?T) presented the most prominent association (p ? 0.0003). Striking associationwas observed for these SNPs among the 309 subjects ?50 years of age (R54W, p ? 0.0001; ?1095T?C, p ?0.0002; ?1844C?T, p ? 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might actin combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are theimportant factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The datashould provide new insight into the etiology of the disease and may suggest a new target to be considered duringtreatment.J Bone Miner

Protein Variation in ADH and ADH-RELATED in Drosophila pseudoobscura: Linkage Disequilibrium Between Single Nucleotide Polymorphisms and Protein Alleles

Genetics ◽  
2001 ◽  
Vol 159 (2) ◽  
pp. 673-687
Author(s):  
Stephen W Schaeffer ◽  
C Scott Walthour ◽  
Donna M Toleno ◽  
Anna T Olek ◽  
Ellen L Miller
Keyword(s):  
Linkage Disequilibrium ◽  
Single Nucleotide Polymorphisms ◽  
Drosophila Pseudoobscura ◽  
Linkage Disequilibrium Mapping ◽  
Nucleotide Polymorphisms ◽  
Neutral Model ◽  
Significant Linkage Disequilibrium ◽  
Single Nucleotide ◽  
Synonymous Sites ◽  
Significant Linkage

Abstract A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes the Adh and Adh-related genes was sequenced in 139 Drosophila pseudoobscura strains collected from 13 populations. The Adh gene encodes four protein alleles and rejects a neutral model of protein evolution with the McDonald-Kreitman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene encodes 18 protein haplotypes and fails to reject an equilibrium neutral model. The populations fail to show significant geographic differentiation of the Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SNPs) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations with and without recombination were used to derive the expected levels of significant linkage disequilibrium between SNPs and 18 protein haplotypes. Maximum levels of linkage disequilibrium are expected for protein alleles at moderate frequencies. In coalescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplotypes that are rare or that reach moderate frequency. The implication of this study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%.

scholarly journals Genomic Analyses of Globodera pallida, A Quarantine Agricultural Pathogen in Idaho

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 363
Author(s):  
Sulochana K. Wasala ◽  
Dana K. Howe ◽  
Louise-Marie Dandurand ◽  
Inga A. Zasada ◽  
Dee R. Denver
Keyword(s):  
Genetic Variation ◽  
Potato Production ◽  
Globodera Pallida ◽  
Fixation Index ◽  
Parasitic Nematodes ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Field Samples ◽  
Multiple Introduction

Globodera pallida is among the most significant plant-parasitic nematodes worldwide, causing major damage to potato production. Since it was discovered in Idaho in 2006, eradication efforts have aimed to contain and eradicate G. pallida through phytosanitary action and soil fumigation. In this study, we investigated genome-wide patterns of G. pallida genetic variation across Idaho fields to evaluate whether the infestation resulted from a single or multiple introduction(s) and to investigate potential evolutionary responses since the time of infestation. A total of 53 G. pallida samples (~1,042,000 individuals) were collected and analyzed, representing five different fields in Idaho, a greenhouse population, and a field in Scotland that was used for external comparison. According to genome-wide allele frequency and fixation index (Fst) analyses, most of the genetic variation was shared among the G. pallida populations in Idaho fields pre-fumigation, indicating that the infestation likely resulted from a single introduction. Temporal patterns of genome-wide polymorphisms involving (1) pre-fumigation field samples collected in 2007 and 2014 and (2) pre- and post-fumigation samples revealed nucleotide variants (SNPs, single-nucleotide polymorphisms) with significantly differentiated allele frequencies indicating genetic differentiation. This study provides insights into the genetic origins and adaptive potential of G. pallida invading new environments.

scholarly journals Pleiotropy and multilocus polymorphisms.

Genetics ◽  
1992 ◽  
Vol 130 (1) ◽  
pp. 223-227
Author(s):  
A Gimelfarb
Keyword(s):  
Genetic Variation ◽  
Linkage Disequilibrium ◽  
Stabilizing Selection ◽  
Additive Genetic Variation ◽  
Very High

Abstract It is demonstrated that systems of two pleiotropically related characters controlled by additive diallelic loci can maintain under Gaussian stabilizing selection a stable polymorphism in more than two loci. It is also shown that such systems may have multiple stable polymorphic equilibria. Stabilizing selection generates negative linkage disequilibrium, as a result of which the equilibrium phenotypic variances are quite low, even though the level of allelic polymorphisms can be very high. Consequently, large amounts of additive genetic variation can be hidden in populations at equilibrium under stabilizing selection on pleiotropically related characters.

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