RBMS3 versus ZNF516: interaction between SNPs in two genes impacts on BMD.
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PROVIDER: S-EPMC3817972 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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RBMS3 versus ZNF516: interaction between SNPs in two genes impacts on BMD.
BoneKEy reports 20130703
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Project description:Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. Although an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high versus low hip BMD (20% tails of the distributions), in two independent U.S. Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 versus ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two single-nucleotide polymorphisms (SNPs), rs6549904 and rs7640046, both of which had significant interactions with an SNP, rs4891159, located on ZNF516 (p?=?7.04?×?10(-11) and 1.03?×?10(-10) ). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 versus ZNF516, was successfully replicated in the Caucasian sample (p?=?8.07?×?10(-3) and 2.91?×?10(-3) ). For the African sample, a significant interaction was also detected (p?=?0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineates the genetic architecture of osteoporosis.
| S-EPMC4127986 | biostudies-literature
Project description:Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well-established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA, defined as the presence of definite osteophytes with or without joint space narrowing (Kellgren-Lawrence [KL] grade ? 2) and controls were absent for definite radiographic OA in both knees (KL grade ? 1 bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on Illumina 2.5M and 1M arrays in Genetic Components of Knee OA (GeCKO) and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, body mass index (BMI), and sex, and then parameter estimates were combined across the two cohorts by meta-analysis. We identified four SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p?=?0.0009; OR?=?1.22; 95% CI, 1.08-1.37) maps to 12q3, which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5), and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta-analysis demonstrates that several genomewide association studies (GWAS)-identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development. © 2014 American Society for Bone and Mineral Research.
| S-EPMC4080308 | biostudies-literature
Project description:Gene expression is regulated by genetic variants and DNA methylation with evidence from molecular biology studies, as well as expression QTL (eQTL) mapping and methylation QTL (mQTL) mapping. In this study, we explored the interaction between genetic variants and DNA methylation for its influence on gene expression. We analyzed a postmortem brain data and identified 2,768 SNP-methylation interaction (SMI) that can survive Bonferroni correction for the number of tests in cis- region of each gene. Seven SNP-methylation pairs were significant after Bonferroni correction for all the tests, including number of gene expression traits, we performed in this study. Only a small proportion of the SMI had evidence from the exact same SNP-transcript pair in eQTL mapping or SNP-methylation pair in mQTL mapping. This suggested that the interaction analysis could uncover novel regulatory relationships, which would be missed by eQTL or mQTL analyses. Since methylation per se is regulated by both genetic and environmental factors, analysis indicates that the SMI detected in this study may involve both genetic and environmental regulation. A total of 155 postmortem cerebellum brains were used in this study, including 47 bipolar disorder, 46 schizophrenia, 15 depression patients and 47 normal controls. All were of European Ancestry. We also designed 13 random replicates in our experiment. Illumina Infinium HumanMethylation27 BeadChip was used for DNA methylation profiling. The assay was performed at the Genomics Core Facility at Northwestern University.
2013-06-30 | E-GEOD-38873 | biostudies-arrayexpress
Project description:Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the first large scale genome wide association study (GWAS) identified three genomic regions associated with RLS. MEIS1, BTBD9 and MAP2K5/SKOR1 are the only known genes located within these loci and their association with RLS was subsequently confirmed in a number of follow up GWAS. Following this finding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the effect of the risk variants of the three other genes strongly associated with RLS. While these variants had no effect on the mRNA levels of the genes harboring them, we find that the homeobox transcription factor MEIS1 positively regulates the expression of the transcription co-repressor SKOR1. This regulation appears mediated through the binding of MEIS1 at two specific sites located in the SKOR1 promoter region and is modified by an RLS associated SNP in the promoter region of the gene. Our findings directly link MEIS1 and SKOR1, two significantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS.
| S-EPMC6093889 | biostudies-literature
Project description:ObjectiveThis study aimed to explore the associations of genetic variants in the semaphorin 3A (SEMA3A) signaling pathway genes, including SEMA3A, NRP1, PLXNA1, PLXNA2 and PLXNA3 with osteoporosis (OP) risk and bone mineral density (BMD) in a Chinese Han older adult population.Study design and methodA two-stage design was adopted. Total of 47.8kb regions in the 5 genes were sequenced using targeted next-generation sequencing (NGS) technology in the discovery stage, and the discovered OP-related single nucleotide polymorphisms (SNPs) were further genotyped using improved multiple linkage detection reaction technique in the validation stage. Methods of ALP/TRAP staining, real-time fluorescent quantitative PCR, and cell proliferation and apoptosis assays were performed with MC3T3-E1 and RAW 264.7 cell lines to clarify biological effects of observed functional variants in cell lines responsible for bone mass remodeling.ResultsTotal of 400 postmenopausal women (211 OP cases) were involved in the discovery stage, where 6 common and 4 rare genetic variants were found to be associated with OP risk. In the validation stage among another 859 participants (417 women, 270 OP cases), the PLXNA2 rs2274446 T allele was associated with reduced OP risk and increased femoral neck (FN) BMD compared to the C allele. Moreover, significant associations of NRP1 rs2070296 with FN BMD/OP risk and of NRP1 rs180868035 with lumbar spine and FN BMDs were also observed in the combination dataset analysis. Compared to the osteoblasts/osteoclasts transfected with the wild-type NRP1 rs180868035, those transfected with the mutant-type had reduced mRNA expression of osteoblastic genes (i.e., ALP, RUNX2, SP7 and OCN), while elevated mRNA expression of osteoclastic genes (i.e., TRAP, NFATc1 and CTSK). Furthermore, mutant NRP1 rs180868035 transfection inhibited osteoblast proliferation and osteoclast apoptosis, while promoted osteoclast proliferation and osteoblast apoptosis in corresponding cell lines.ConclusionGenetic variants located in NRP1 and PLXNA2 genes were associated with OP risk and BMD. The NRP1 rs180868035 affects bone metabolism by influencing osteoblasts and osteoclasts differentiation, proliferation and apoptosis.
| S-EPMC9679019 | biostudies-literature
Project description:The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5.We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program's Adult Treatment Panel III (NCEP (AIII)) including medication.The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13-0.83) and 0.40 (95% CI = 0.15-1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing.Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome.
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Project description:The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background. We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype.We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls). Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction.An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02-0.5 in the incident study, and AP 0.4, 95% CI 0.1-0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02. Compared with non-smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3-6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5-10.8).The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking. The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease.
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Project description:Hybrids provide an interesting model to study the evolution of sex-determining genes and sex chromosome systems as they offer the opportunity to see how independently evolving sex-determining pathways interact in vivo. In this context, the genus Xenopus represents a stimulating model, since species with non-homologous sex chromosomes and different sex-determining genes have been identified. In addition, the possibility of interspecies breeding is favoured in this group, which arose by alloploidization events, with species ploidy ranging from 2n = 2x = 20 in X. tropicalis (the only diploid representative of the genus) to 2n = 12x = 108 in X. ruwenzoriensis. To study how two sex-determining genes interact in vivo, X. laevis × X. tropicalis hybrids were produced. Gonadal differentiation in these hybrids revealed that the dm-w gene is dominant over X. tropicalis male-determining sex chromosomes (Y or Z), even though the Y chromosome is dominant in X. tropicalis (Y > W>Z). In the absence of the dm-w gene (the Z chromosome from X. laevis is present), the W chromosome from X. tropicalis is able to trigger ovarian development. Testicular differentiation will take place in the absence of W chromosomes from any of the parental species. The dominance/recessivity relationships between these sex-determining loci in the context of either parental genome remains unknown. This article is part of the theme issue 'Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)'.
| S-EPMC8310712 | biostudies-literature
Project description:Genetic variation in the expression of human xenobiotic metabolism enzymes and transporters (XMETs) leads to inter-individual variability in metabolism of therapeutic agents as well as differed susceptibility to various diseases. Recent expression quantitative traits loci (eQTL) mapping in a few human cells/tissues have identified a number of single nucleotide polymorphisms (SNPs) significantly associated with mRNA expression of many XMET genes. These eQTLs are therefore important candidate markers for pharmacogenetic studies. However, questions remain about whether these SNPs are causative and in what mechanism these SNPs may function. Given the important role of microRNAs (miRs) in gene transcription regulation, we hypothesize that those eQTLs or their proxies in strong linkage disequilibrium (LD) altering miR targeting are likely causative SNPs affecting gene expression. The aim of this study is to identify eQTLs potentially regulating major XMETs via interference with miR targeting. To this end, we performed a genome-wide screening for eQTLs for 409 genes encoding major drug metabolism enzymes, transporters and transcription factors, in publically available eQTL datasets generated from the HapMap lymphoblastoid cell lines and human liver and brain tissue. As a result, 308 eQTLs significantly (p?<?10(-5)) associated with mRNA expression of 101 genes were identified. We further identified 7,869 SNPs in strong LD (r(2)???0.8) with these eQTLs using the 1,000 Genome SNP data. Among these 8,177 SNPs, 27 are located in the 3'-UTR of 14 genes. Using two algorithms predicting miR-SNP interaction, we found that almost all these SNPs (26 out of 27) were predicted to create, abolish, or change the target site for miRs in both algorithms. Many of these miRs were also expressed in the same tissue that the eQTL were identified. Our study provides a strong rationale for continued investigation for the functions of these eQTLs in pharmacogenetic settings.
| S-EPMC3502871 | biostudies-literature
Project description:This study evaluates how 2 different total hip arthroplasty (THA) stems compares regarding adaptive bone remodelling. The stems are both proximally porous coated, aiming for proximal fixation, but with different dispersal of the coating. They are also differently designed regarding the distal tip of the stem. We aimed to investigate if there is a difference in periprosthetic adaptive bone remodelling between two different designs. From February 2016 to September 2017, we randomised 62 patients, 1:1 (mean age = 64 years, Female/Male = 28/34), scheduled for an uncemented THA to receive either an EBM or a BM THA stem. We performed dual-energy x-ray absorptiometry (DEXA) scans within a week after surgery and at 3, 6, 12 and 24 months with measurements of bone mineral density (BMD) in the 7 Gruen zones (region of interest (ROI) 1-7). Additionally, Oxford Hip Score and Harris Hip Score were collected at 6, 12 and 24 months. We found a decrease in BMD between the postoperative and the 24-months values in all ROIs for both stems. The greatest decrease over time was seen for both groups in the ROI1 (BM = - 8.4%, p = 0.044, and EBM = - 6.5%, p = 0.001) and ROI7 (BM = - 7%, p = 0.005, and EBM = - 8.6%, p < 0.0005). We found a tendency in ROI2-4 of a higher degree of bone loss in the EBM group. However, this difference only continued beyond 6 months in ROI4 (24 months: BM = - 1.2% and EBM = - 2.8%, p = 0.001). The stems show similar adaptive bone remodelling and are clinically performing well.
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