Current concepts in genetics of nonsyndromic clefts

ABSTRACTNonsyndromic cleft lip and palate is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having certain effects. Numerous genes have been reported in studies demonstrating associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of cleft lip and palate genetics in the past decade, the role of the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype remain to be determined.

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Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Journal of Cancer Epidemiology ◽

10.1155/2008/147905 ◽

2008 ◽

Vol 2008 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Zhibin Hu ◽

Chunying Li ◽

Kexin Chen ◽

Li-E Wang ◽

Erich M. Sturgis ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Statistical Power ◽

Cancer Susceptibility ◽

Nucleotide Polymorphisms ◽

Apoptotic Pathway ◽

Single Nucleotide ◽

Single Locus Analysis ◽

The Common ◽

Apoptotic Pathways

Apoptotic capacity (AC) in primary lymphocytes may be a marker for cancer susceptibility, and functional single nucleotide polymorphisms (SNPs) in genes involved in apoptotic pathways may modulate cellular AC in response to DNA damage. To further examine the correlation between apoptotic genotypes and phenotype, we genotyped 14 published SNPs in 11 apoptosis-related genes (i.e.,p53, Bcl-2, BAX, CASP9, DR4, Fas, FasL, CASP8, CASP10, CASP3, andCASP7) and assessed the AC in response to benzo[a]pyrene-7,8-9,10-diol epoxide (BPDE) in cultured primary lymphocytes from 172 cancer-free subjects. We found that among these 14 SNPs, R72P, intron 3 16-bp del/ins, and intron 6 G>A inp53, −938C>A inBcl-2, and I522L inCASP10were significant predictors of the BPDE-induced lymphocytic AC in single-locus analysis. In the combined analysis of the threep53variants, we found that the individuals with the diplotypes carrying 0-1 copy of the commonp53R-del-G haplotype had higher AC values compared to other genotypes. Although the study size may not have the statistical power to detect the role of other SNPs in AC, our findings suggest that some SNPs in genes involved in the intrinsic apoptotic pathway may modulate lymphocytic AC in response to BPDE exposure in the general population. Larger studies are needed to validate these findings for further studying individual susceptibility to cancer and other apoptosis-related diseases.

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Preliminary Analysis of the Nonsynonymous Polymorphism rs17563 in BMP4 Gene in Brazilian Population Suggests Protection for Nonsyndromic Cleft Lip and Palate

Plastic Surgery International ◽

10.1155/2012/247104 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Tânia Kawasaki Araújo ◽

Milena Simioni ◽

Têmis Maria Félix ◽

Liliane Todeschini de Souza ◽

Marshall Ítalo Barros Fontes ◽

...

Keyword(s):

Logistic Regression ◽

Statistical Power ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Strong Association ◽

Bone Morphogenetic Protein 4 ◽

Brazilian Sample ◽

Morphogenetic Protein ◽

Pcr Rflp

Cleft lip with or without palate (CL±P) is common congenital anomalies in humans. Experimental evidence has demonstrated that bone morphogenetic protein 4 gene (Bmp4) is involved in the etiology of CL±P in animal models. The nonsynonymous polymorphism rs17563 T>C (p.V152A) in the BMP4 gene has been associated to the risk of nonsyndromic CL±P in Chinese population and microforms from different ethnic backgrounds. The aim of this study was to investigate the role of BMP4 gene in CL±P in Brazilian sample using genetic association approach. Our sample was composed by 123 patients with nonsyndromic CL±P and 246 controls, in which absence of CL±P was confirmed in 3 generations. The rs17563 polymorphism was genotyped by PCR-RFLP technique. Logistic regression was performed to evaluate allele and genotype association. Our data showed statistical power to detect association (86.83%) in this sample. Logistic regression results showed significant association between C allele and CL±P (P=0.00018, OR =0.40, and 95% CI = 0.25–0.65), as well as CC genotype and CL±P (P=0.00018, OR =0.35, and 95% CI = 0.19–0.66). So, there is a strong association between nonsyndromic CL±P and BMP4 rs17563 polymorphism in our sample and the C allele had a protective effect against the occurrence of nonsyndromic CL±P.

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DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Non-syndromic Cleft Lip and Palate

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.656865 ◽

2021 ◽

Vol 9 ◽

Author(s):

Juan I. Young ◽

Susan Slifer ◽

Jacqueline T. Hecht ◽

Susan H. Blanton

Keyword(s):

Dna Methylation ◽

Candidate Genes ◽

Dna Sequences ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Differential Methylation ◽

Potential Contribution ◽

Hippo Signaling ◽

Mz Twins

Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in MAFB and ZEB2 in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP.

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Associating Symptom Phenotype and Genotype in Preeclampsia

Biological Research For Nursing ◽

10.1177/1099800417754140 ◽

2018 ◽

Vol 20 (2) ◽

pp. 126-136 ◽

Cited By ~ 3

Author(s):

Sandra A. Founds ◽

Eleni Tsigas ◽

Dianxu Ren ◽

M. Michael Barmada

Keyword(s):

Candidate Genes ◽

Medical Records ◽

Genetic Disorder ◽

Later Life ◽

Small Sample ◽

Nucleotide Polymorphisms ◽

History Of ◽

Complex Genetic Disorder ◽

Symptom Phenotype ◽

Visual Disturbances

Preeclampsia is a complex genetic disorder with an incompletely understood pathogenesis. Its phenotype may be better elucidated by integrating symptoms. This study aimed to identify symptoms by gestational age and associations with novel preeclampsia candidate genes. Women with a history of preeclampsia recruited from The Preeclampsia Registry completed clinical/demographic, symptom surveys and provided medical records. DNA extracted from saliva was processed with multiplexed assays for eight single-nucleotide polymorphisms (SNPs) selected to tag candidate genes and/or located in symptom susceptibility regions. Groups with versus without symptoms were compared using χ2. Associations between SNPs and symptoms were analyzed as genotype categories and presence/absence of the variant allele. Logistic regression modeling was conducted with exploratory p = .05. In 114 participants, 113 reported at least 1 of the 18 symptoms. Symptoms varied by trimester. Nine symptoms were associated with seven SNPs. Visual disturbances were associated with three SNPs and nausea/vomiting with two SNPs. Modeling adjustment for maternal age and parity resulted in 15 associations between 9 symptoms and 8 SNPs. Medical records demonstrated 100% concordance with self-reported diagnosis and 48% concordance with reported severity. Findings indicated novel symptom–genotype associations in preeclampsia. The small sample was self-selected, but results support future studies including medical records review. When validated, these results may lead to holistic phenotyping of women to characterize subsets of preeclampsia. This approach may optimize health in pregnancy and later life for mothers and offspring through prediction, prevention, and precision nursing care.

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Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2020-60-12-898-903 ◽

2020 ◽

Vol 60 (12) ◽

pp. 898-903

Author(s):

Lyudmila P. Kuzmina ◽

Anastasiya G. Khotuleva ◽

Evgeniy V. Kovalevsky ◽

Nikolay N. Anokhin ◽

Iraklij M. Tskhomariya

Keyword(s):

Antioxidant Enzymes ◽

Genetic Polymorphism ◽

Genetic Predisposition ◽

Risk Groups ◽

Dust Exposure ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Gstp1 Gene ◽

Polymorphic Variants

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

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Dementia key gene identification with multi-layered SNP-gene-disease network

Bioinformatics ◽

10.1093/bioinformatics/btaa814 ◽

2020 ◽

Vol 36 (Supplement_2) ◽

pp. i831-i839

Author(s):

Dong-gi Lee ◽

Myungjun Kim ◽

Sang Joon Son ◽

Chang Hyung Hong ◽

Hyunjung Shin

Keyword(s):

Candidate Genes ◽

Learning Algorithm ◽

Search Space ◽

Supplementary Information ◽

Gene Identification ◽

Nucleotide Polymorphisms ◽

Disease Network ◽

Single Nucleotide ◽

Key Genes ◽

Significant Attention

Abstract Motivation Recently, various approaches for diagnosing and treating dementia have received significant attention, especially in identifying key genes that are crucial for dementia. If the mutations of such key genes could be tracked, it would be possible to predict the time of onset of dementia and significantly aid in developing drugs to treat dementia. However, gene finding involves tremendous cost, time and effort. To alleviate these problems, research on utilizing computational biology to decrease the search space of candidate genes is actively conducted. In this study, we propose a framework in which diseases, genes and single-nucleotide polymorphisms are represented by a layered network, and key genes are predicted by a machine learning algorithm. The algorithm utilizes a network-based semi-supervised learning model that can be applied to layered data structures. Results The proposed method was applied to a dataset extracted from public databases related to diseases and genes with data collected from 186 patients. A portion of key genes obtained using the proposed method was verified in silico through PubMed literature, and the remaining genes were left as possible candidate genes. Availability and implementation The code for the framework will be available at http://www.alphaminers.net/. Supplementary information Supplementary data are available at Bioinformatics online.

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The role of 25-hydroxyvitamin-D3 and vitamin D receptor gene in human periodontal ligament fibroblasts as response to orthodontic compressive strain: an in vitro study

BMC Oral Health ◽

10.1186/s12903-021-01740-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Erika Calvano Küchler ◽

Agnes Schröder ◽

Vinicius Broska Teodoro ◽

Ute Nazet ◽

Rafaela Scariot ◽

...

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Single Nucleotide Polymorphisms ◽

Periodontal Ligament ◽

Compressive Strain ◽

Nucleotide Polymorphisms ◽

Periodontal Ligament Fibroblasts ◽

Single Nucleotide ◽

Cox 2

Abstract Background This study aimed to investigate, if different physiological concentrations of vitamin D (25(OH)D3) and single nucleotide polymorphisms in vitamin D receptor (VDR) gene have an impact on gene expression in human periodontal ligament (hPDL) fibroblasts induced by simulated orthodontic compressive strain. Methods A pool of hPDL fibroblasts was treated in absence or presence of 25(OH)D3 in 3 different concentrations (10, 40 and 60 ng/ml). In order to evaluate the role of single nucleotide polymorphisms in the VDR gene, hPDL fibroblasts from 9 patients were used and treated in absence or presence of 40 ng/ml 25(OH)D3. Each experiment was performed with and without simulated orthodontic compressive strain. Real-time PCR was used for gene expression and allelic discrimination analysis. Relative expression of dehydrocholesterol reductase (DHCR7), Sec23 homolog A, amidohydrolase domain containing 1 (AMDHD1), vitamin D 25-hydroxylase (CYP2R1), Hydroxyvitamin D-1-α hydroxylase, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2) and interleukin-6 (IL6) was assessed. Three single nucleotide polymorphisms in VDR were genotyped. Parametric or non-parametric tests were used with an alpha of 5%. Results RANKL, RANKL:OPG ratio, COX-2, IL-6, DHCR7, CYP2R1 and AMDHD1 were differentially expressed during simulated orthodontic compressive strain (p < 0.05). The RANKL:OPG ratio was downregulated by all concentrations (10 ng/ml, 40 ng/ml and 60 ng/ml) of 25(OH)D3 (mean = 0.96 ± 0.68, mean = 1.61 ± 0.66 and mean = 1.86 ± 0.78, respectively) in comparison to the control (mean 2.58 ± 1.16) (p < 0.05). CYP2R1 gene expression was statistically modulated by the different 25(OH)D3 concentrations applied (p = 0.008). Samples from individuals carrying the GG genotype in rs739837 presented lower VDR mRNA expression and samples from individuals carrying the CC genotype in rs7975232 presented higher VDR mRNA expression (p < 0.05). Conclusions Simulated orthodontic compressive strain and physiological concentrations of 25(OH)D3 seem to regulate the expression of orthodontic tooth movement and vitamin-D-related genes in periodontal ligament fibroblasts in the context of orthodontic compressive strain. Our study also suggests that single nucleotide polymorphisms in the VDR gene regulate VDR expression in periodontal ligament fibroblasts in the context of orthodontic compressive strain.

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NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.131243 ◽

2010 ◽

Vol 70 (4) ◽

pp. 668-674 ◽

Cited By ~ 65

Author(s):

P Dieudé ◽

M Guedj ◽

J Wipff ◽

B Ruiz ◽

G Riemekasten ◽

...

Keyword(s):

Innate Immunity ◽

Systemic Sclerosis ◽

Potential Role ◽

Additive Model ◽

Nucleotide Polymorphisms ◽

Fibrosing Alveolitis ◽

Single Nucleotide ◽

Risk Alleles ◽

Caucasian Origin

BackgroundRecent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders.ObjectiveTo study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population.MethodsNLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin.ResultsConditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA.ConclusionsOur results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

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