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Item Analysis of a TNFRSF11A Gene Polymorphism and External Apical Root Resorption During Orthodontic Treatment(2005-07) French, Michael; Hartsfield, James K., Jr.; Al-Qawasmi, Riyad A.; Foroud, Tatiana M.; Roberts, W. Eugene; Shanks, JamesExternal Apical Root Resorption (EARR) can be an undesirable side effect of orthodontic treatment. Several studies have already recognized a genetic predisposition to EARR, and some have suggested possible candidate genes that may be involved. The objective of this prospective study was to explore one possible candidate gene that may predispose individuals to EARR during orthodontic treatment. The TNFRSF11A gene encodes the receptor activator of nuclear factor-kappa β (RANK). Together with the RANK ligand, RANK mediates cell signaling that leads to osteoclastogenesis. A diallelic marker was used to investigate the possible relationship between a nonsynonymous TNFRSF11A (RANK) polymorphism and the individuals' development of EARR concurrent with orthodontic treatment. Buccal swab cells of 112 patients who had completed orthodontic treatment were collected for DNA isolation and analysis. EARR of the maxillary central incisors was calculated based on measurements from pre and post treatment occlusal radiographs. Linear regression analysis indicated that length of treatment, overjet, and molar classification are significant predictors of EARR (p=0.05). Other factors, including age, gender, and overbite, were not found to be significantly associated with EARR. An ANOVA was performed to examine the relationship of the genotyped TNFRSF11A marker with the dependent variable EARR. When individuals having at least one copy of allele 2 (1,2 and 2,3 genotypes) were pooled together, a marginally significant association was found between EARR and the marker. Further analysis using logistic regression revealed that individuals with a (1,1) genotype are 4.3 times more likely to be affected by EARR than a person with a (1,2) or (2,2) genotype. From these findings it was concluded that EARR is a complex condition influenced by several treatment variables with the TNFRSF11A gene and its product (RANK) contributing to the individuals' predisposition.Item EFFECT OF POLYMORPHISM ON EXPRESSION OF THE NEUROPEPTIDE Y GENE IN INBRED ALCOHOL-PREFERRING AND -NONPREFERRING RATS(Elsevier, 2005) SPENCE, J. P.; LIANG, T.; HABEGGER, K.; CARR, L. G.; Department of Psychiatry, IU School of MedicineUsing animal models of alcoholism, previous studies suggest that neuropeptide Y (NPY) may be implicated in alcohol preference and consumption due to its role in the modulation of feeding and anxiety. Quantitative trait loci (QTL) analysis previously identified an interval on rat chromosome 4 that is highly associated with alcohol preference and consumption using an F2 population derived from inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats. NPY mapped to the peak of this QTL region and was prioritized as a candidate gene for alcohol-seeking behavior in the iP and iNP rats. In order to identify a potential mechanism for reduced NPY protein levels documented in the iP rat, genetic and molecular components that influence NPY expression were analyzed between iP and iNP rats. Comparing the iP rat to the iNP rat, quantitative real-time polymerase chain reaction detected significantly decreased levels of NPY mRNA expression in the iP rat in the six brain regions tested: nucleus accumbens, frontal cortex, amygdala, hippocampus, caudate-putamen, and hypothalamus. In addition, the functional significance of three previously identified polymorphisms was assessed using in vitro expression analysis. The polymorphism defined by microsatellite marker D4Mit7 in iP rats reduced luciferase reporter gene expression in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the NPY gene resulting from the D4mit7 marker polymorphism may contribute to reduced levels of NPY in discrete brain regions in the iP rats.Item Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2003-09) Spence, John P.; Liang, Tiebing; Eriksson, C. J. Peter; Taylor, Robert E.; Wall, Tamara L.; Ehlers, Cindy L.; Carr, Lucinda G.; Department of Medicine, IU School of MedicineBACKGROUND: Cytosolic aldehyde dehydrogenase, or ALDH1A1, functions in ethanol detoxification, metabolism of neurotransmitters, and synthesis of retinoic acid. Because the promoter region of a gene can influence gene expression, the ALDH1A1 promoter regions were studied to identify polymorphism, to assess their functional significance, and to determine whether they were associated with a risk for developing alcoholism. METHODS: Sequence analysis was performed in the promoter region by using Asian, Caucasian, and African American subjects. The resulting polymorphisms were assessed for frequency in Asian, Caucasian, Jewish, and African American populations and tested for associations with alcohol dependence in Asian and African American populations of alcoholics and controls. The functional significance of each polymorphism was determined through in vitro expression analysis by using HeLa and HepG2 cells. RESULTS: Two polymorphisms, a 17 base pair (bp) deletion (-416/-432) and a 3 bp insertion (-524), were discovered in the ALDH1A1 promoter region: ALDH1A1*2 and ALDH1A1*3, respectively. ALDH1A1*2 was observed at frequencies of 0.035, 0.023, 0.023, and 0.012 in the Asian, Caucasian, Jewish, and African American populations, respectively. ALDH1A1*3 was observed only in the African American population, at a frequency of 0.029. By using HeLa and HepG2 cells for in vitro expression, the activity of the luciferase reporter gene was significantly decreased after transient transfection of ALDH1A1*3-luciferase compared with the wild-type construct ALDH1A1*1-luciferase. In an African American population, a trend for higher frequencies of the ALDH1A1*2 and ALDH1A1*3 alleles was observed in a population of alcoholics (p = 0.03 and f = 0.12, respectively) compared with the control population. CONCLUSIONS: ALDH1A1*2 and ALDH1A1*3 may influence ALDH1A1 gene expression. Both ALDH1A1*2 and ALDH1A1*3 produce a trend in an African American population that may be indicative of an association with alcoholism; however, more samples are required to validate this observation. The underlying mechanisms contributing to these trends are still unknown.Item Evaluation of IL-1 B (+3954) Gene Polymorphism and External Apical Root Resporption Associated with Orthodontic Treatment(2005) Smith, Elizabeth Dockerty; Hartsfield, James K., Jr.; Al-Qawasmi, Riyad A.; Foroud, Tatiana M.; Roberts, W. Eugene; Shanks, JamesThe purpose of this prospective study was to examine the external apical root resorption (EARR) status and genetic marker composition of 100 Caucasian patients (59 females and 41 males) who have undergone orthodontic treatment at the private practice office of Dr. James V. Macri. A diallelic polymorphism marker for IL-1B +3954 within the candidate gene IL-1B was used to investigate the difference in relative risk for EARR. EARR measurements taken on pre and post treatment occlusal radiographs were then used to determine any association with genotype. Using linear regression analysis, length of treatment, overjet and molar classification were found to be significant predictors of EARR (p<0.05). The findings indicated that increased length of treatment or overjet is associated with increased EARR. Furthermore, those subjects with a class II molar classification were less likely to experience EARR compared to those with either a class I or class III molar classification. An ANOV A test was performed to examine the relationship of the IL-1B marker with the dependent variable EARR. There was no statistically significant association between the IL-1B genotype and EARR (p=0.53). Finally, a chi-square test was used to evaluate the association of the IL-1B genotypes in the affected (>5mm EARR) and unaffected (<5mm EARR) groups. There was no significant association between affection status and the IL-1B genotype (p=0.87).Item Evaluation of the IL-6 Gene in External Apical Root Resorption Associated with Orthodontic Treatment(2003) Harris, Nathan P.; Hartsfield, James K., Jr.; Everett, Eric T.; Foroud, Tatiana M.; Roberts, W. Eugene; Shanks, JamesThe objective of this project is to investigate the possibility that a functional polymorphism of the interleukin-6 (IL-6) gene is associated with external apical root resorption (EARR) during orthodontic tooth movement. If genes that are involved in EARR could be identified and easily screened, the orthodontist could adjust the patient's treatment plan accordingly. Having information about a patient's susceptibility to EARR could help diagnose and treat a patient accordingly. This would allow orthodontists to monitor patients more closely or modify the treatment plan to minimize the amount EARR. The study sample consists of 60 subjects from 36 different families. The siblings had received orthodontic treatment at Indiana University School of Dentistry or in the private practice of Dr. James V. Macri. EARR was not a prerequisite to be included in this sample. Informed consent was obtained for sample collection. This study received Indiana University School of Dentistry Student Research Subcommittee Review and Indiana University Purdue University at Indianapolis Institutional Review Board approval. No significant difference between any of the IL-6 genotypes and EARR could be noted. The hypothesis that individuals with the IL-6 -174 C/C genotype would show a greater amount of EARR during orthodontic treatment could not be supported.Item Subjective response to alcohol and ADH polymorphisms in a select sample of young adult male East Indians and Africans in Trinidad and Tobago(Alcohol Research Documentation, 2014-09) Jaime, Lazara Karelia Montane; Shafe, Samuel; Liang, Tiebing; Wills, Derek N.; Berg, Greta I.; Ehlers, Cindy L.; Department of Medicine, IU School of MedicineOBJECTIVE: Level of response to alcohol has been associated with risk of alcohol dependence in a number of ethnic groups. In the present study, subjective and objective responses to alcohol were evaluated in Indo-Trinidadians (Indo-T) and Afro-Trinidadians (Afro-T). Associations of alcohol dehydrogenase polymorphisms with response to alcohol, using the Subjective High Assessment Scale (SHAS), and breath alcohol concentrations (BrAC) were tested. METHOD: Regular male drinkers without alcohol dependence (n = 112) ages 18-25 years participated in alcohol challenge sessions consisting of placebo and two doses of alcohol (target BrAC: 0 g/dl for placebo, .04 g/dl low dose, and .08 g/dl high dose) and genotyped for variants in ADH1B*3 and ADH1C*2. RESULTS: Indo-T had significantly higher BrAC, pulse rates, and cortisol levels when compared with Afro-T but did not have significantly higher SHAS values. Higher responses on the SHAS items muddle/confused and nauseated were significantly associated with the presence of at least one ADH1B*3 allele following the high dose of alcohol in Afro-T. Indo-T with at least one ADH1C*2 allele displayed significantly different Drug × Time interactions for the SHAS item effects of alcohol at the low dose and for the SHAS items clumsy, muddle/confused, effects of alcohol, floating, drunk, and total at the high dose from Indo-T with two ADH1C*1 alleles. CONCLUSIONS: This is the first study that has investigated individual sensitivity to alcohol in a Caribbean population and in people of East Indian descent. Indo-T with at least one ADH1C*2 allele may be at higher risk for heavy drinking by feeling less of the effects of alcohol, including nausea. In Afro-T, having at least one ADH1B*3 allele appears to exert a protective effect by enhancing the unpleasant effects of alcohol, such as nausea and confusion.Item The Association of Specific EPHX1 and GSTM1 Gene Polymorphisms with Phenytoin- or Smoking-Associated Birth Defects(1998) Hickman, Todd Andrew; Hartsfield, James K., Jr.; Everett, Eric T.; Dean, Jeffrey A.; Shanks, James C.Eleven percent of children exposed in utero to phenytoin show a pattern of fetal hydantoin syndrome (FHS) which may include cleft lip/palate. Also, in utero exposure to the products of cigarette smoke leads to reduced birth weight, prematurity, and small but significant risk of oral clefts. Cleft lip/palate occur at a frequency of 1 per 750 to 1000 livebirths in the United States. Microsomal epoxide hydrolase (mEH) participates in xenobiotic metabolism, including the detoxification of the bioactive arene oxide metabolite of phenytoin and polycyclic hydrocarbons found in cigarette smoke. Another enzyme that accelerates phenytoin arene oxide detoxification is glutathione S-transferase μ (GSTM). Our objective was to study the occurrence of selected DNA polymorphisms in genes encoding the drug metabolism enzymes, mEH and GSTM in individuals affected with FHS, fetal hydantoin effects, oral clefts, congenital heart defect, and other major malformations associated with maternal phenytoin use during the first trimester. We also studied infants born with an orofacial cleft whose mothers smoked tobacco during their pregnancy. The methods included polymerase chain reaction and allele-specific restriction enzyme digest on DNA samples of affected and non-affected individuals. Results: The allele frequencies at EPHX1 codon 113 in the phenytoin exposure population appeared to differ from the reported allele frequencies by Hassett et al. 1994, however statistically there was no significant difference where p = 0.14 . There was no apparent correlation between the EPHX1 and GSTM1 genotypes examined and mEH enzyme activity or phenotype associated with FHS. Our observed allele frequencies at EPHX1 codon 113 for the cigarette smoke exposure population were not comparable to allele frequencies reported by Hassett et al. 1994, where p = 0.0048. Our prevalence of the GSTM1 null genotype for the cigarette smoke exposure population was significantly higher than the prevalence of approximately 50 percent reported by others, where p < 0.0001. Overall these data do not support an association between the EPHX1 or GSTM1 polymorphisms tested and cigarette smoking-induced oral clefting. In conclusion, individual variation in mEH and GSTM activity may depend on factors other than those gene polymorphisms studied to date. Possible undetermined factors include additional 5' polymorphisms, post-transcriptional regulation, gene induction by environmental agents and variation in the levels of transcriptional proteins required for mEH expression. The participation of these factors must be characterized more definitively in order to allow prediction of individual activities on the basis of these integrated phenomena.Item Tissue-specific network-based genome wide study of amygdala imaging phenotypes to identify functional interaction modules(Oxford University Press, 2017-10-15) Yao, Xiaohui; Yan, Jingwen; Liu, Kefei; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Greene, Casey S.; Moore, Jason H.; Saykin, Andrew J.; Shen, Li; Alzheimer’s Disease Neuroimaging Initiative; BioHealth Informatics, School of Informatics and ComputingMotivation: Network-based genome-wide association studies (GWAS) aim to identify functional modules from biological networks that are enriched by top GWAS findings. Although gene functions are relevant to tissue context, most existing methods analyze tissue-free networks without reflecting phenotypic specificity. Results: We propose a novel module identification framework for imaging genetic studies using the tissue-specific functional interaction network. Our method includes three steps: (i) re-prioritize imaging GWAS findings by applying machine learning methods to incorporate network topological information and enhance the connectivity among top genes; (ii) detect densely connected modules based on interactions among top re-prioritized genes; and (iii) identify phenotype-relevant modules enriched by top GWAS findings. We demonstrate our method on the GWAS of [18F]FDG-PET measures in the amygdala region using the imaging genetic data from the Alzheimer's Disease Neuroimaging Initiative, and map the GWAS results onto the amygdala-specific functional interaction network. The proposed network-based GWAS method can effectively detect densely connected modules enriched by top GWAS findings. Tissue-specific functional network can provide precise context to help explore the collective effects of genes with biologically meaningful interactions specific to the studied phenotype.