Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22.

We have performed linkage analysis in 186 multiplex families to search for genes that predispose to schizophrenia. Under a model with partially dominant inheritance, moderately broad disease definition and assuming locus homogeneity, a lod score of 3.2 was obtained for D6S260 on chromosome 6p23. A multipoint lod score of 3.9 (P = 2.3 x 10(-5)) was achieved when the F13A1 and D6S260 loci were analysed, allowing for locus heterogeneity. Adjusted for testing of multiple models, the multipoint lod score of 3.9 under heterogeneity has a genome wide significance of between 5-8%. The nonparametric affected pedigree member test provided results (P = 3 x 10(-4)) also supporting this finding. Our findings provide supportive evidence for a susceptibility locus for schizophrenia on distal chromosome 6p, and support a model of locus heterogeneity.

Correlates of anti-EBV EBNA1 IgA positivity among unaffected relatives from nasopharyngeal carcinoma multiplex families.

BACKGROUND: To determine whether non-viral nasopharyngeal carcinoma (NPC) risk factors might be associated with (and mediated through) Epstein-Barr virus (EBV) serological responses linked to NPC risk, we evaluated predictors of risk of anti-EBNA1 IgA seropositivity and other markers among unaffected relatives from a large NPC family study in Taiwan. METHODS: Multivariate logistic regression conditioned on family was used to examine the associations between sociodemographic, dietary, lifestyle, and occupational variables and risk of anti-EBV EBNA1 IgA positivity, anti-VCA IgA, and anti-DNase positivity. RESULTS: Among 2393 unaffected relatives from 319 multiplex families, 1180 (49.3%) were anti-EBV EBNA1 IgA seropositive. None of the associations with anti-EBNA1 IgA were statistically significant, except for being 31-50 years of age (vs <30, adjusted ORs 0.51-0.57). For one or more EBV serological markers, there were suggestive associations for older age, GuangDong firm salted fish, betel use, current alcohol use, and male gender. CONCLUSION: Overall, we found little evidence to suggest that non-viral NPC risk factors significantly alter EBV serological patterns, suggesting that non-viral NPC risk factors act through pathways independent of EBV serological responses.

Linkage analysis localises a Kartagener syndrome gene to a 3.5 cM region on chromosome 15q24-25.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity. METHODS: In a genome-wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction-only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow-up study, 65 additional microsatellite markers encompassing D15S205 were analysed. RESULTS: A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24-25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families. CONCLUSIONS: Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.

Cambridge Healthtech Institute's Third Annual Conference on human genetic variation. 16-18 October 2000, Philadelphia, Pennsylvania, USA.

A major goal of pharmacogenomics is to identify the human genetic variation that influences susceptibility to complex diseases. Recently, theoretical statistical analyses have suggested that genes for complex diseases may be found by linkage disequilibrium (i.e., association). Single nucleotide polymorphism (SNP) susceptibility alleles for common diseases can occur at high frequencies in various populations and, thus, have a major impact on morbidity and mortality. To be successful, SNP mapping studies require successful teamwork, integrating clinicians, epidemiologists, molecular genetics experts, laboratory automation engineers, bioinformatics and database experts. New statistical methods are also developing rapidly and promise to further increase the power of these studies. A recent conference on human genetic variation provided an opportunity for experts in all of these disciplines to exchange ideas. At present, great technological challenges need to be overcome in order to increase the throughput greatly while lowering cost and still maintaining high accuracy for SNP genotyping. Although this approach is relatively new (at least on the scale now being contemplated), the large payoffs anticipated to accrue from the successful mapping of SNPs in disease genes has led the area to be very strongly supported by both public and private funding sources. The potential payoff for improving disease diagnosis and therapeutic efficacy, with better avoidance of adverse events based on SNP associations, is providing a tremendous incentive to move this effort forward at an ever-accelerating pace.

Analysis of variability of clinical manifestations in Waardenburg syndrome.

Expression of clinical findings of Waardenburg syndrome type 1 (WS1) and type 2 (WS2) is extremely variable. Using our collection of 26 WS1 and 8 WS2 families, we analyzed the occurrence, severity, and symmetry of clinical manifestations associated with WS. We found significant differences between WS1 and WS2 in deafness, and in pigmentary and craniofacial anomalies. Factor analysis was used to identify manifestations which covaried, resulting in 2 orthogonal factors. Since mean factor scores were found to differ when compared between WS1 and WS2, we suggest that these factors could be useful in distinguishing WS types. We found that the WS gene was transmitted from mothers more often than from fathers. We also extensively examined the W-Index, a continuous measure of dystopia canthorum. Our data suggest that use of the W-Index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W-Index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum. Misclassification of families may have implications for risk assessment of deafness, since WS2 families have been reported to have greater incidence of deafness, as confirmed in our study.

A method for recovery of high-molecular-weight DNA suitable for field-inversion gel electrophoresis from frozen tumor cells.

We describe a simple method for isolation of high-molecular-weight (high-mol-wt, > 800 kilobases) DNA from tumor cell lines frozen without dimethylsulfoxide (DMSO) or other protective agents. This method should be applicable to most frozen tissues and useful for molecular genetic studies such as field-inversion gel electrophoresis (FIGE), or cloning procedures that require access to intact, high-mol-wt DNA.

The genetics of schizophrenia: a current, genetic-epidemiologic perspective.

In the "Special Report on Schizophrenia" published in the Schizophrenia Bulletin in 1987, the genetic basis of schizophrenia was reviewed. Here, we provide our perspective on the current status of this area of investigation, focusing largely but not exclusively on recent findings. Methodologically rigorous family studies have now clearly shown that schizophrenia substantially aggregates in families. Familial factors that predispose to schizophrenia also increase the risk for certain schizophrenia-related personality disorders and probably for some forms of non-schizophrenic nonaffective psychosis. Results from one new twin study and updates from two ongoing adoption studies continue to support the hypothesis that genetic factors play a major role in the etiology of schizophrenia. Little is known about how genetic liability to schizophrenia is transmitted, although statistical models suggest that transmission is probably not due solely to a single major gene. Schizophrenia is clearly a complex disorder in that gene carriers need not manifest the illness (incomplete penetrance), affected individuals need not have the gene (environmental forms of phenocopies), diagnostic uncertainties cannot be avoided, and different families may carry different susceptibility genes (genetic heterogeneity). Therefore, segregation or linkage analyses are far more difficult to perform with schizophrenia than with Mendelian genetic disorders. Given this complexity, it is not too surprising that no replicated positive evidence for linkage to schizophrenia has been reported to date. However, just as linkage analysis of schizophrenia should not be excessively embraced as the only form of viable genetic research in schizophrenia, it also shouldn't be prematurely spurned. If one or several genes of major effect exist for schizophrenia, large samples using new statistical and laboratory methodologies have a good chance of detecting them. The authors thus recommend a balanced research approach to the genetics of schizophrenia that includes traditional methods of family, twin, and adoption studies as well as a major effort in large-sample linkage studies.

Strategies for linkage studies of schizophrenia: pedigrees, DNA markers, and statistical analyses.

A current overview of the genetics of schizophrenia is presented. Recently reported linkage studies of schizophrenia using polymorphic DNA markers are discussed and critically evaluated. Linkage studies of schizophrenia that we are currently undertaking are described, and the rationale underlying the specific strategies that we are using is explained. Our major focus is on extended pedigrees ascertained in Ireland containing a high density of schizophrenic cases, but we are also planning to use the technique of homozygosity mapping in an attempt to localize a recessively inherited gene that may be segregating in consanguineous families ascertained in Saudi Arabia. Issues relating to diagnostic criteria, the choice of which DNA markers to type with the highest priority, and appropriate statistical methodology are also considered.

Factors associated with delay in the diagnosis of oral cancer.

Early detection and treatment improve the prognosis for oral cancer. Delays from the onset of symptoms to clinical diagnosis are common. Our aim is to identify factors associated with this delay. Between 1995 and 1998, we interviewed 105 consecutive patients with histologically confirmed oral cancer in Greece. If 21 or more days elapsed from the time the patient noticed major symptoms to a definitive diagnosis, we called it a delay (52% of cases). We used logistic and linear regression to estimate odds ratios of delayed diagnosis and to identify correlates of length of delay, respectively. Former smokers had a 4.3 times greater risk of delayed diagnosis compared with current smokers (95% confidence interval: 1.1-17.1). The length of delay was greater among single patients, non-smokers, or those with stage IV tumors. Clinicians should be advised that delay in the diagnosis of oral cancer occurs frequently, even in individuals who do not smoke heavily.

Evidence of a substantial genetic basis for IgG2 levels in families with aggressive periodontitis.

IgG2 is elevated in localized but not in generalized aggressive periodontitis (AgP). Exposure to pathogenic bacteria is essential for disease. Immune responses are dominated by IgG2 reactive with bacterial surface carbohydrates. We used variance component analyses to assess IgG2 heritability and determine whether genes that influence IgG2 are the same genes that influence disease susceptibility. We studied 17 Caucasian and 43 African American families with two or more localized or generalized AgP-affected members (274 subjects with IgG2 measurements). Only 16% of the variance in IgG2 was attributable to age, race, and smoking. Even with the addition of localized AgP, the model still explained only 19% of IgG2 variance. By contrast, heritability of IgG2 levels was estimated to be 38% and highly significant (P = 0.0006), demonstrating a substantial genetic basis. Bi-trait variance component analyses of IgG2 and quantitative measures of AgP indicate that different genes appear to control IgG2 levels and disease susceptibility.

Smoking and alcohol in the etiology of oral cancer: gender-specific risk profiles in the south of Greece.

Oral and pharyngeal cancer (OC) mortality is very low in Greece, especially among men, compared to other European countries. We conducted a case-control study of OC in Athens, and obtained information on tobacco, alcohol use and other potential risk factors and confounding variables for 110 incident cases and 115 hospital-based controls. We used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tobacco smoking (pack years, P(trend)=0.01) and alcohol use (drinks/week, P(trend)=0.07) were independent risk factors, with a multiplicative effect for combined exposures (OR, 8.3; 95% CI, 2.4-29.1, for >28 alcohol drinks/week and >50 pack years of cigarette smoking). The type of alcoholic beverage also seemed important: drinking ouzo and tsipouro (liquors of high ethanol concentration) was associated with greater increased OC risk than drinking comparable amounts of wine, beer or dark spirits. While alcohol drinking is more common for male cases versus controls, few men reported regularly consuming large quantities of ethanol associated with highest risk of OC in other studies. This may partially explain the low rates of male OC mortality in Greece. Among the 38% of our cases who were women, however, neither smoking nor alcohol drinking frequencies were significantly elevated compared to controls, and so the etiology of OC risk in females requires further investigation.

Re-interpretation of the evidence for X-linked dominant inheritance of juvenile periodontitis.

Several studies have provided evidence supporting the inheritance of juvenile periodontitis (JP) in a Mendelian fashion, and both X-linked and autosomal modes of transmission have been proposed. Re-examination of the evidence for the X-linked dominant hypothesis reveals that two assumptions were crucial in favoring the X-linked rather than an autosomal hypothesis of JP transmission. The first assumption was that females are more likely than males to have JP by ratios of approximately 2.5:1. The second key observation was the reported lack of father to son transmission of the trait. However, the data that these assumptions were based on may be interpreted differently. Although the number of females reported to be affected by JP is greater than the number of affected males, this is probably a reflection of the greater number of females incorporated into these studies. When the proportions of affected males and females are examined, rather than total numbers of affected individuals, the proportion of affected males and females is similar. Additionally, the reported lack of father to son transmission for JP appears to be the result of incomplete family data. The female ascertainment bias inherent in many JP studies, compounded by the lack of male participation in such studies, appears to have resulted in the perception of a lack of male to male transmission of JP. This lack of observed father to son transmission of JP in incomplete data sets has been regarded as proof of no male to male transmission for the trait. Studies of more complete family data, however, do document father to son transmission of JP.(ABSTRACT TRUNCATED AT 250 WORDS)

Associations between serum antibody levels to periodontal pathogens and early-onset periodontitis.

BACKGROUND: The role of antibodies to periodontal microorganisms in the development of periodontal tissue destruction is still unclear. The aim of this study was to investigate the association between serum levels of IgG, IgA, and IgM antibodies to 6 periodontal microorganisms and clinical subtypes of varying severity of early-onset periodontitis (EOP) in young African American adults. METHODS: The study group consisted of 159 African Americans aged 19 to 25 years (mean 22 years) and included 97 cases with EOP and 62 controls with no clinical signs of EOP. These subjects were selected from a nationally representative sample of adolescents who received an oral examination as part of the National Survey of Oral Health of United States Children in 1986-1987. The group was examined clinically a second time 6 years later and blood samples were collected. Serum levels of IgG, IgA, and IgM reactive to Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, Eikenella corrodens, and Fusobacterium nucleatum were assessed. RESULTS: Serum levels of IgG and IgA antibody reactive to P. gingivalis and A. actinomycetemcomitans and IgA antibody to P. intermedia were significantly higher in generalized EOP cases compared to healthy controls. IgM antibody levels did not show any significant associations with EOP for any of the 6 bacterial species tested. There were no significant differences in antibody levels between controls and the 13 subjects in our study who were classified with localized EOP. CONCLUSIONS: The findings suggest that antibodies to P. gingivalis, P. intermedia, and A. actinomycetemcomitans may play a significant role in the pathogenesis of EOP. Substantial longitudinal studies that monitor antibody levels and avidity prior to disease onset, during progression, and following clinical intervention will be necessary to fully understand the role of this component of the immune response in protection versus tissue destruction and the potential use in EOP risk assessment and disease management.

No female preponderance in juvenile periodontitis after correction for ascertainment bias.

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.

Linkage disequilibrium of interleukin-1 genetic polymorphisms with early-onset periodontitis.

BACKGROUND: Genetic polymorphisms at interleukin (IL)-1alpha and IL-1beta were recently suggested to be associated with severity of adult periodontitis. We evaluated whether these polymorphisms might also be associated with early-onset periodontitis (EOP) in 28 African American families and 7 Caucasian American families with 2 or more affected members. METHODS: Genomic DNA from peripheral blood was amplified, followed by restriction endonuclease digestion and acrylamide gel electrophoresis to distinguish alleles of different fragment sizes. Genetic epidemiological methods suitable for family data were used that are robust to false-positive findings due to mismatching of cases and controls or mixed subpopulations of different ethnic or geographic origin. The 2 major EOP subtypes, localized juvenile periodontitis (LJP), and generalized early-onset periodontitis (G-EOP, encompassing rapidly progressive periodontitis and generalized juvenile periodontitis), were analyzed both separately and together. RESULTS: We obtained highly significant evidence of linkage disequilibrium for both African American and Caucasian G-EOP subjects. A similar trend was noted for LJP. The IL- alleles associated with high risk of EOP had been suggested previously to be correlated with low risk for severe adult periodontitis. Disequilibrium with G-EOP was equally strong for smoking and non-smoking subjects. IL-1alpha and IL-1beta polymorphisms were in strong disequilibrium with each other in Caucasians, but not in African Americans. Haplotype analyses evaluating both polymorphisms simultaneously indicated that the IL-1beta variant is likely to be most important for EOP risk. Sibpair linkage analyses, by contrast, provided only marginal support for a gene of very major effect on EOP risk attributable to these IL-1 polymorphisms. CONCLUSIONS: Recent theoretical analyses indicate that our findings are most consistent with an interpretation of EOP as a complex, oligogenic disorder, with IL-1 genetic variation contributing an important but not exclusive influence on disease risk.

Evidence of a substantial genetic basis for risk of adult periodontitis.

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 > or = 2, AL > or = 3, PD > or = 4, or PD > or = 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.

Scientific progress in understanding oral and pharyngeal cancers.

Oral and pharyngeal cancers result from a complex interaction between genetic susceptibility and behavioral factors. Improved understanding of the underlying genetic events has led to insights about how oral and pharyngeal cancers develop and suggests promising new treatments. Tobacco and alcohol consumption are associated with most oral and pharyngeal cancers. Dental professionals' efforts to modify their patients' tobacco and alcohol use and to detect oral lesions at an early stage, together with scientific advances, will help reduce the impact of these cancers.

Reducing the burden of oral and pharyngeal cancers.

In the United States, oral and pharyngeal cancers continue to result in significant morbidity and mortality. Dental professionals play a pivotal role in all facets of controlling the burden of oral and pharyngeal cancer-from efforts to prevent its occurrence, to ensuring that oral cancers are detected at the earliest possible stage, to treating these cancers, and to ensuring maximum quality of life and function for oral and pharyngeal cancer survivors. Individually and by making linkages within the community and beyond, dentists can help patients modify their risk of these cancers and can take steps to screen for them, thereby potentially improving survival and function of those who develop oral cancer. Creative partnerships between community dentists and academic and other research centers will help move knowledge of the biological processes involved in carcinogenesis and innovations in treatment into clinical practice. Partnerships between dental and medical professionals may also help efforts to reduce the morbidity related to oral and pharyngeal cancers. Local, state and national multidisciplinary initiatives are emerging that focus more broadly on risk factor control or oral and pharyngeal cancer issues. These many forms of cooperative approaches offer excellent opportunities to make a significant impact on reducing the incidence of and in treating these debilitating and disfiguring malignancies.