Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal porti... more Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG ar...
Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growt... more Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growth factor II receptor gene (IGF2R) in oral cancer risk. The 197 individuals that consented to participate in a hospital-based, case-control study were interviewed with a structured questionnaire and provided blood and saliva. DNA was extracted for genotyping using a PCR-based method. Odds ratios were calculated using multivariate logistic regression. Subjects carrying the heterozygous 167-bp IGF2R genotype had a 2.7-fold higher risk of oral cancer compared with subjects with other genotypes (odds ratio = 2.7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer.
Annals of the Entomological Society of America, 1986
... Most plants were pruned to a uniform height of 2.5 m, except for huckle-berry (ca. 0.5 m) and... more ... Most plants were pruned to a uniform height of 2.5 m, except for huckle-berry (ca. 0.5 m) and lowbush blueberry (ca. ... Significance levels: *,P< 0.005; NS, P > 0.05. dax, while the opposite was true in tests conducted with highbush and lowbush blueberry and huckle-berry fruit. ...
This chapter is dedicated to chronic neuropathic pain, the most perplexing pain condition. This d... more This chapter is dedicated to chronic neuropathic pain, the most perplexing pain condition. This disorder is used as an example to illustrate how nature and nurture interact to produce pain as well as to better understand the inter-individual variability in chronic pain. Growing data from the Human Genome Project, and its application to pain research, indicate that a comprehensive assessment of the phenomic and genomic risk and protective factors of pain will provide knowledge critically needed when clinicians administer personalized pain management. The chapter explains the modification of the heritable risk for CNP by certain personality traits. It is generally accepted that personality, like pain, is a collection of complex traits controlled by genetic and nongenetic determinants. The chapter illustrates a number of nongenetic factors and suggests future clinical research studies that appear promising based on findings in animal models of painful neuropathies.
Proceedings of the National Academy of Sciences, 1997
Nonsyndromic clefting of the lip and palate in humans has a highly complex etiology, with both mu... more Nonsyndromic clefting of the lip and palate in humans has a highly complex etiology, with both multiple genetic loci and exposure to teratogens influencing susceptibility. Previous studies using mouse models have examined only very small portions of the genome. Here we report the findings of a genome-wide search for susceptibility genes for teratogen-induced clefting in the AXB and BXA set of recombinant inbred mouse strains. We compare results obtained using phenytoin (which induces cleft lip) and 6-aminonicotinamide (which induces cleft palate). We use a new statistical approach based on logistic regression suitable for these categorical data to identify several chromosomal regions as possible locations of clefting susceptibility loci, and we review candidate genes located within each region. Because cleft lip and cleft palate do not frequently co-aggregate in human families and because these structures arise semi-independently during development, these disorders are usually consi...
Objectives and methods Risks of oral cancer related to a CA microsatellite repeat polymorphism in... more Objectives and methods Risks of oral cancer related to a CA microsatellite repeat polymorphism in intron 1 of the epidermal growth factor receptor (EGFR) gene and a TaqI polymorphism in the transforming growth factor-a (TGFA) gene were evaluated in a population-based case-control study consisting of 157 cases and 149 controls recruited in Puerto Rico. Results Carriers of Z 16 CA repeats in EGFR showed a 1.9-fold increased risk for oral cancer (OR = 1.9, 95% CI = 1.0-3.5). Risks also tended to increase with decreasing number of alleles with Z 16 CA repeats (P for trend = 0.06). Our data suggested a non-significant reduction in risk for subjects heterozygous for the TGFA polymorphism (OR = 0.6, 95% CI = 0.2-1.3). Conclusions The EGFR-associated risk appeared to be independent of tobacco and alcohol use and may be restricted primarily to subjects who consumed low amounts of fresh fruits and vegetables (OR = 5.9, 95%CI: 2.3-15.2). These data implicate dietary and molecular targets for oral cancer prevention. Pharmacogenetics and Genomics 15:343-347 c 2005 Lippincott Williams & Wilkins.
Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self... more Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self-injury of the anesthetic limb (`autotomy'). Since the same denervation produces phantom limb pain and anesthesia dolorosa in humans, autotomy has been used as a model of human neuropathic pain. Autotomy is an inherited trait in rodents, attributable to a few genes of major effect. Here we used recombinant inbred (RI) mouse lines of the AXB-BXA RI set to map a gene for autotomy. Autotomy levels following unilateral sciatic and saphenous nerve section were scored daily for 36 days, using a standardized scale, in all 23 RI lines available for this set. We used a genetic map of 395 marker loci and a permutation-based statistical method for categorical data to assess the statistical signi®cance of mapping results. We identi®ed a marker on chromosome 15 with statistical support (P 0:0003) in the range considered signi®cant for genome-wide scans in the mouse. Several genes located in this chromosomal region encode for neural functions related to neuropathic pain and may indicate targets for development of novel analgesics.
Juvenile Periodontitis (JP) is generally recognized to exist in 2 clinical forms: localized and g... more Juvenile Periodontitis (JP) is generally recognized to exist in 2 clinical forms: localized and generalized. Historically, females have been reported to be affected by both forms of JP at rates of 2 to 10 times greater than males. However, evidence suggests that females are more likely than males to seek dental care. If this is true, females will be diagnosed with JP more often than males even if juvenile Periodontitis is equally prevalent among males and females in the general population. Thus, previous reports of a female predominance for JP may simply reflect this selection bias. The purpose of this study was to test our hypothesis that juvenile Periodontitis occurs with equal frequency in males and females after correcting for selection bias. Twenty-four juvenile Periodontitis probands were ascertained from the VCU/MCV dental clinics. The families of these individuals were examined to determine the relative prevalence of JP among male and female relatives of these probands. Our results indicate that while females are 3 times more likely than males to be initially ascertained as juvenile Periodontitis probands, among relatives of probands the proportion of affected males and females is equal. J
Background: A few previous studies have suggested that risk for adult periodontitis (AP) has a ge... more Background: A few previous studies have suggested that risk for adult periodontitis (AP) has a genetic (heritable) component. We estimated genetic and environmental variances and heritability for gingivitis and adult periodontitis using data from twins reared together. Methods: One hundred seventeen (117) pairs of adult twins (64 monozygotic [MZ] and 53 dizygotic [DZ] pairs) were recruited. Probing depth (PD), attachment loss (AL), plaque, and gingivitis (GI) were assessed on all teeth by two examiners. Measurements were averaged over all sites, teeth, and examiners. Extent of disease in subjects was defined at four thresholds: the percentage of teeth with AL ≥2, AL ≥3, PD ≥4, or PD ≥5 mm. Genetic and environmental variances and heritability were estimated using path models with maximum likelihood estimation techniques. Results: MZ twins were more similar than DZ twins for all clinical measures. Statistically significant genetic variance was found for both the severity and extent of disease. AP was estimated to have approximately 50% heritability, which was unaltered following adjustments for behavioral variables including smoking. In contrast, while MZ twins were also more similar than DZ twins for gingivitis scores, there was no evidence of heritability for gingivitis after behavioral covariates such as utilization of dental care and smoking were incorporated into the analyses. Conclusions: These results confirm previous studies and indicate that approximately half of the variance in disease in the population is attributed to genetic variance. The basis for the heritability of periodontitis appears to be biological and not behavioral in nature.
We show that for all reals c and d such that c 2 d < 4 there exists a positive real e such that t... more We show that for all reals c and d such that c 2 d < 4 there exists a positive real e such that tautologies of length n cannot be decided by both a nondeterministic algorithm that runs in time n c , and a nondeterministic algorithm that runs in time n d and space n e. In particular, for every d < 3 √ 4 there exists a positive e such that tautologies cannot be decided by a nondeterministic algorithm that runs in time n d and space n e .
The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests tha... more The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests that it might also serve as a screening test for individuals who are at high risk for developing NPC. We previously demonstrated that unaffected individuals from high-risk families had elevated anti-EBV antibody levels compared to community controls. In this study, we measured EBV load using 2 different real-time PCR assays (targeting BamH1W and polymerase gene sequences, respectively) carried out in 2 independent research labs in serum samples from 19 untreated NPC cases, 11 healthy community controls and 100 unaffected individuals from families in which 2 or more individuals were affected with NPC. EBV genomes were detectable in 68% of NPC cases by the EBV BamH1W assay and in 74% by the EBV polymerase assay (kappa = 0.64). Patients with stage III or IV disease had significantly higher EBV load compared to those with stage I or II disease (p = 0.008). EBV DNA was detected in a single community control sample by the EBV BamH1W assay and in none of the samples by the EBV polymerase assay. Only one of 100 unaffected family members tested positive by both assays. An additional 14 were positive by only one of the 2 EBV load assays used and usually in only one of the duplicate wells tested, all with very low viral loads (3-50 copies/ml). In addition, EBV load did not correlate with EBV serology results (anti-VCA, anti-DNase, anti-EBNA-1) among these unaffected family members. In conclusion, our study suggests limited clinical utility of the EBV load test, in its current configuration, to screen individuals from high-risk families. Should a more sensitive or specific molecular assay be developed that is capable of detecting and distinguishing tumor-derived EBV genomes or gene products from true negatives, it could be evaluated as a possible screening tool for asymptomatic and early-stage NPC.
Most adults have been infected with EBV. Many studies have indicated that antibodies against spec... more Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.
We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syn... more We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.
Association between specific human leukocyte antigens (HLA) alleles and NPC have been reported fo... more Association between specific human leukocyte antigens (HLA) alleles and NPC have been reported for sporadic NPC but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol. Allele frequencies between case and control groups were compared by chi-square or exact tests. For alleles associated with NPC, odds ratios (OR) and 95% confidence intervals (CI) were calculated. Similar allelic frequency distribution and HLA associations were found as those previously reported for sporadic NPC: protective effect for HLA-A*1101 and increased risk for HLA-A*0207, HLA-A*3303, HLA-B*3802, and HLA-B*5801. Overall, the magnitude of observed associations was weakest when cases were compared to sibling controls and strongest when compared to unrelated community controls. Evaluating the joint effect of HLAA*0207 and HLA-B*4601, individuals who were carriers of HLA-A*0207 with or without the presence of HLA-B*4601 had a 1.9-fold (95% CI = 1.0-3.4) and 2.1fold (95% CI = 0.83-5.3) risk of NPC, respectively. Conversely, carriers of HLA-B*4601 in the absence of HLA-A*0207 had a 50% reduction in NPC risk (95% CI = 0.27-0.93). Comparable
Malignant schwannomas are soft-tissue neoplasms that occur at increased frequency with germline a... more Malignant schwannomas are soft-tissue neoplasms that occur at increased frequency with germline alterations of the neurofibromatosis-1 (NF1) gene at 17q11.2. We report molecular and cytogenetic characterization of a malignant schwannoma cell line established from an individual affected with NF1. This cell line has a complex hyperdiploid karyotype with two cytogenetically identical der(13) t(13;17) (pl 1 ,ql 1.2) chromosomes. Using somatic cell hybrids, we mapped twelve chromosome-17 probes to either the der(13)t(13;17) chromosome or a small der(17) chromosome. Two chromosome-17p loci, including the p53 tumor suppressor gene, were present in the schwannoma cell line, but did not map to either of these chromosomes. Loss of heterozygosity studies indicated that the two der(13)t(13;17) chromosomes arose by duplication, presumably after the translocation event. The 17q11.2 translocation breakpoint maps distal to the NF1 gene, and may not disrupt its functioning. Although NF1 mRNA was detected in this cell line by polymerase chain reaction, Northern blot analysis revealed very little or none of the 13-kb mature NF1 transcript. This suggests that the single remaining allele of the NFI gene contains a mutation that results in either greatly reduced transcription or message instability.
Chip and Microarray technology covered the latest advances in this technology and applications in... more Chip and Microarray technology covered the latest advances in this technology and applications in life sciences. Highlights of the meetings are reported briefly with emphasis on applications in genomics, drug discovery and molecular diagnostics. There was an emphasis on microfluidics because of the wide applications in laboratory and drug discovery. The lab-on-a-chip provides the facilities of a complete laboratory in a hand-held miniature device. Several microarray systems have been used for hybridisation and detection techniques. Oligonucleotide scanning arrays provide a versatile tool for the analysis of nucleic acid interactions and provide a platform for improving the array-based methods for investigation of antisense therapeutics. A method for analysing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional scanner has considerable potential in molecular diagnostics. Various applications of microarray technology for high-throughput screening in drug discovery and single nucleotide polymorphisms (SNP) analysis were discussed. Protein chips have important applications in proteomics. With the considerable amount of data generated by the different technologies using microarrays, it is obvious that the reading of the information and its interpretation and management through the use of bioinformatics is essential. Various techniques for data analysis were presented. Biochip and microarray technology has an essential role to play in the evolving trends in healthcare, which integrate diagnosis with prevention/treatment and emphasise personalised medicines.
Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal porti... more Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG ar...
Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growt... more Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growth factor II receptor gene (IGF2R) in oral cancer risk. The 197 individuals that consented to participate in a hospital-based, case-control study were interviewed with a structured questionnaire and provided blood and saliva. DNA was extracted for genotyping using a PCR-based method. Odds ratios were calculated using multivariate logistic regression. Subjects carrying the heterozygous 167-bp IGF2R genotype had a 2.7-fold higher risk of oral cancer compared with subjects with other genotypes (odds ratio = 2.7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer.
Annals of the Entomological Society of America, 1986
... Most plants were pruned to a uniform height of 2.5 m, except for huckle-berry (ca. 0.5 m) and... more ... Most plants were pruned to a uniform height of 2.5 m, except for huckle-berry (ca. 0.5 m) and lowbush blueberry (ca. ... Significance levels: *,P&lt; 0.005; NS, P &gt; 0.05. dax, while the opposite was true in tests conducted with highbush and lowbush blueberry and huckle-berry fruit. ...
This chapter is dedicated to chronic neuropathic pain, the most perplexing pain condition. This d... more This chapter is dedicated to chronic neuropathic pain, the most perplexing pain condition. This disorder is used as an example to illustrate how nature and nurture interact to produce pain as well as to better understand the inter-individual variability in chronic pain. Growing data from the Human Genome Project, and its application to pain research, indicate that a comprehensive assessment of the phenomic and genomic risk and protective factors of pain will provide knowledge critically needed when clinicians administer personalized pain management. The chapter explains the modification of the heritable risk for CNP by certain personality traits. It is generally accepted that personality, like pain, is a collection of complex traits controlled by genetic and nongenetic determinants. The chapter illustrates a number of nongenetic factors and suggests future clinical research studies that appear promising based on findings in animal models of painful neuropathies.
Proceedings of the National Academy of Sciences, 1997
Nonsyndromic clefting of the lip and palate in humans has a highly complex etiology, with both mu... more Nonsyndromic clefting of the lip and palate in humans has a highly complex etiology, with both multiple genetic loci and exposure to teratogens influencing susceptibility. Previous studies using mouse models have examined only very small portions of the genome. Here we report the findings of a genome-wide search for susceptibility genes for teratogen-induced clefting in the AXB and BXA set of recombinant inbred mouse strains. We compare results obtained using phenytoin (which induces cleft lip) and 6-aminonicotinamide (which induces cleft palate). We use a new statistical approach based on logistic regression suitable for these categorical data to identify several chromosomal regions as possible locations of clefting susceptibility loci, and we review candidate genes located within each region. Because cleft lip and cleft palate do not frequently co-aggregate in human families and because these structures arise semi-independently during development, these disorders are usually consi...
Objectives and methods Risks of oral cancer related to a CA microsatellite repeat polymorphism in... more Objectives and methods Risks of oral cancer related to a CA microsatellite repeat polymorphism in intron 1 of the epidermal growth factor receptor (EGFR) gene and a TaqI polymorphism in the transforming growth factor-a (TGFA) gene were evaluated in a population-based case-control study consisting of 157 cases and 149 controls recruited in Puerto Rico. Results Carriers of Z 16 CA repeats in EGFR showed a 1.9-fold increased risk for oral cancer (OR = 1.9, 95% CI = 1.0-3.5). Risks also tended to increase with decreasing number of alleles with Z 16 CA repeats (P for trend = 0.06). Our data suggested a non-significant reduction in risk for subjects heterozygous for the TGFA polymorphism (OR = 0.6, 95% CI = 0.2-1.3). Conclusions The EGFR-associated risk appeared to be independent of tobacco and alcohol use and may be restricted primarily to subjects who consumed low amounts of fresh fruits and vegetables (OR = 5.9, 95%CI: 2.3-15.2). These data implicate dietary and molecular targets for oral cancer prevention. Pharmacogenetics and Genomics 15:343-347 c 2005 Lippincott Williams & Wilkins.
Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self... more Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self-injury of the anesthetic limb (`autotomy'). Since the same denervation produces phantom limb pain and anesthesia dolorosa in humans, autotomy has been used as a model of human neuropathic pain. Autotomy is an inherited trait in rodents, attributable to a few genes of major effect. Here we used recombinant inbred (RI) mouse lines of the AXB-BXA RI set to map a gene for autotomy. Autotomy levels following unilateral sciatic and saphenous nerve section were scored daily for 36 days, using a standardized scale, in all 23 RI lines available for this set. We used a genetic map of 395 marker loci and a permutation-based statistical method for categorical data to assess the statistical signi®cance of mapping results. We identi®ed a marker on chromosome 15 with statistical support (P 0:0003) in the range considered signi®cant for genome-wide scans in the mouse. Several genes located in this chromosomal region encode for neural functions related to neuropathic pain and may indicate targets for development of novel analgesics.
Juvenile Periodontitis (JP) is generally recognized to exist in 2 clinical forms: localized and g... more Juvenile Periodontitis (JP) is generally recognized to exist in 2 clinical forms: localized and generalized. Historically, females have been reported to be affected by both forms of JP at rates of 2 to 10 times greater than males. However, evidence suggests that females are more likely than males to seek dental care. If this is true, females will be diagnosed with JP more often than males even if juvenile Periodontitis is equally prevalent among males and females in the general population. Thus, previous reports of a female predominance for JP may simply reflect this selection bias. The purpose of this study was to test our hypothesis that juvenile Periodontitis occurs with equal frequency in males and females after correcting for selection bias. Twenty-four juvenile Periodontitis probands were ascertained from the VCU/MCV dental clinics. The families of these individuals were examined to determine the relative prevalence of JP among male and female relatives of these probands. Our results indicate that while females are 3 times more likely than males to be initially ascertained as juvenile Periodontitis probands, among relatives of probands the proportion of affected males and females is equal. J
Background: A few previous studies have suggested that risk for adult periodontitis (AP) has a ge... more Background: A few previous studies have suggested that risk for adult periodontitis (AP) has a genetic (heritable) component. We estimated genetic and environmental variances and heritability for gingivitis and adult periodontitis using data from twins reared together. Methods: One hundred seventeen (117) pairs of adult twins (64 monozygotic [MZ] and 53 dizygotic [DZ] pairs) were recruited. Probing depth (PD), attachment loss (AL), plaque, and gingivitis (GI) were assessed on all teeth by two examiners. Measurements were averaged over all sites, teeth, and examiners. Extent of disease in subjects was defined at four thresholds: the percentage of teeth with AL ≥2, AL ≥3, PD ≥4, or PD ≥5 mm. Genetic and environmental variances and heritability were estimated using path models with maximum likelihood estimation techniques. Results: MZ twins were more similar than DZ twins for all clinical measures. Statistically significant genetic variance was found for both the severity and extent of disease. AP was estimated to have approximately 50% heritability, which was unaltered following adjustments for behavioral variables including smoking. In contrast, while MZ twins were also more similar than DZ twins for gingivitis scores, there was no evidence of heritability for gingivitis after behavioral covariates such as utilization of dental care and smoking were incorporated into the analyses. Conclusions: These results confirm previous studies and indicate that approximately half of the variance in disease in the population is attributed to genetic variance. The basis for the heritability of periodontitis appears to be biological and not behavioral in nature.
We show that for all reals c and d such that c 2 d < 4 there exists a positive real e such that t... more We show that for all reals c and d such that c 2 d < 4 there exists a positive real e such that tautologies of length n cannot be decided by both a nondeterministic algorithm that runs in time n c , and a nondeterministic algorithm that runs in time n d and space n e. In particular, for every d < 3 √ 4 there exists a positive e such that tautologies cannot be decided by a nondeterministic algorithm that runs in time n d and space n e .
The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests tha... more The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests that it might also serve as a screening test for individuals who are at high risk for developing NPC. We previously demonstrated that unaffected individuals from high-risk families had elevated anti-EBV antibody levels compared to community controls. In this study, we measured EBV load using 2 different real-time PCR assays (targeting BamH1W and polymerase gene sequences, respectively) carried out in 2 independent research labs in serum samples from 19 untreated NPC cases, 11 healthy community controls and 100 unaffected individuals from families in which 2 or more individuals were affected with NPC. EBV genomes were detectable in 68% of NPC cases by the EBV BamH1W assay and in 74% by the EBV polymerase assay (kappa = 0.64). Patients with stage III or IV disease had significantly higher EBV load compared to those with stage I or II disease (p = 0.008). EBV DNA was detected in a single community control sample by the EBV BamH1W assay and in none of the samples by the EBV polymerase assay. Only one of 100 unaffected family members tested positive by both assays. An additional 14 were positive by only one of the 2 EBV load assays used and usually in only one of the duplicate wells tested, all with very low viral loads (3-50 copies/ml). In addition, EBV load did not correlate with EBV serology results (anti-VCA, anti-DNase, anti-EBNA-1) among these unaffected family members. In conclusion, our study suggests limited clinical utility of the EBV load test, in its current configuration, to screen individuals from high-risk families. Should a more sensitive or specific molecular assay be developed that is capable of detecting and distinguishing tumor-derived EBV genomes or gene products from true negatives, it could be evaluated as a possible screening tool for asymptomatic and early-stage NPC.
Most adults have been infected with EBV. Many studies have indicated that antibodies against spec... more Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.
We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syn... more We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.
Association between specific human leukocyte antigens (HLA) alleles and NPC have been reported fo... more Association between specific human leukocyte antigens (HLA) alleles and NPC have been reported for sporadic NPC but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol. Allele frequencies between case and control groups were compared by chi-square or exact tests. For alleles associated with NPC, odds ratios (OR) and 95% confidence intervals (CI) were calculated. Similar allelic frequency distribution and HLA associations were found as those previously reported for sporadic NPC: protective effect for HLA-A*1101 and increased risk for HLA-A*0207, HLA-A*3303, HLA-B*3802, and HLA-B*5801. Overall, the magnitude of observed associations was weakest when cases were compared to sibling controls and strongest when compared to unrelated community controls. Evaluating the joint effect of HLAA*0207 and HLA-B*4601, individuals who were carriers of HLA-A*0207 with or without the presence of HLA-B*4601 had a 1.9-fold (95% CI = 1.0-3.4) and 2.1fold (95% CI = 0.83-5.3) risk of NPC, respectively. Conversely, carriers of HLA-B*4601 in the absence of HLA-A*0207 had a 50% reduction in NPC risk (95% CI = 0.27-0.93). Comparable
Malignant schwannomas are soft-tissue neoplasms that occur at increased frequency with germline a... more Malignant schwannomas are soft-tissue neoplasms that occur at increased frequency with germline alterations of the neurofibromatosis-1 (NF1) gene at 17q11.2. We report molecular and cytogenetic characterization of a malignant schwannoma cell line established from an individual affected with NF1. This cell line has a complex hyperdiploid karyotype with two cytogenetically identical der(13) t(13;17) (pl 1 ,ql 1.2) chromosomes. Using somatic cell hybrids, we mapped twelve chromosome-17 probes to either the der(13)t(13;17) chromosome or a small der(17) chromosome. Two chromosome-17p loci, including the p53 tumor suppressor gene, were present in the schwannoma cell line, but did not map to either of these chromosomes. Loss of heterozygosity studies indicated that the two der(13)t(13;17) chromosomes arose by duplication, presumably after the translocation event. The 17q11.2 translocation breakpoint maps distal to the NF1 gene, and may not disrupt its functioning. Although NF1 mRNA was detected in this cell line by polymerase chain reaction, Northern blot analysis revealed very little or none of the 13-kb mature NF1 transcript. This suggests that the single remaining allele of the NFI gene contains a mutation that results in either greatly reduced transcription or message instability.
Chip and Microarray technology covered the latest advances in this technology and applications in... more Chip and Microarray technology covered the latest advances in this technology and applications in life sciences. Highlights of the meetings are reported briefly with emphasis on applications in genomics, drug discovery and molecular diagnostics. There was an emphasis on microfluidics because of the wide applications in laboratory and drug discovery. The lab-on-a-chip provides the facilities of a complete laboratory in a hand-held miniature device. Several microarray systems have been used for hybridisation and detection techniques. Oligonucleotide scanning arrays provide a versatile tool for the analysis of nucleic acid interactions and provide a platform for improving the array-based methods for investigation of antisense therapeutics. A method for analysing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional scanner has considerable potential in molecular diagnostics. Various applications of microarray technology for high-throughput screening in drug discovery and single nucleotide polymorphisms (SNP) analysis were discussed. Protein chips have important applications in proteomics. With the considerable amount of data generated by the different technologies using microarrays, it is obvious that the reading of the information and its interpretation and management through the use of bioinformatics is essential. Various techniques for data analysis were presented. Biochip and microarray technology has an essential role to play in the evolving trends in healthcare, which integrate diagnosis with prevention/treatment and emphasise personalised medicines.
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Papers by Scott Diehl