Observational study on primary and secondary stability of two current bone level implant designs.

Objective: Achieving high levels of primary implant stability is considered to be desirable, despite some studies warning of the risk of bone damage. It was the goal of this observational clinical study to compare two current bone level implant systems with respect to primary and secondary stability. Method and materials: Data on bone quality, insertion torque, implant stability at insertion and after healing, as well as number of implants lost during healing were obtained from two centers either placing BLT (Bone Level Tapered, Straumann) or Nobel Parallel CC (Nobel Biocare) implants. Statistical analysis was based on Spearman rank correlation tests, analysis of variance, and t tests with the level of significance set at α = .05. Results: A total of 312 BLT and 92 Nobel Parallel CC implants were placed. Ten BLT and two Nobel Parallel CC implants failed resulting in survival rates of 96.79% and 97.83%, respectively. Mean insertion torque recorded in the different bone classes showed large standard deviations, and only torque values for BLT implants recorded in type 3 bone differed significantly from type 2 bone and type 1 bone (P = .024). For BLT implants, bone quality and insertion torque correlated (Spearman rho = -.3326; P = .0023) as did ISQ at insertion (Spearman rho = -.2241; P = .0429). Implant diameter significantly affected primary (P = .0013) and secondary (P = .0050) stability of Nobel Parallel CC implants while for BLT implants a significant effect was only seen for secondary stability (P = .0000). Bone quality had a significant effect on implant insertion torque for BLT implants (P = .0059). Bone quality had no general effect on ISQ changes during healing but 3.3-mm BLT implants showed significantly (P = .0005) lower stability after healing. Conclusion: Huge variation with respect to primary and secondary stability seems to exist among similar looking implant systems clinically used for identical indications.

Students at Saarland University dental school-A survey on their background and curriculum perception.

INTRODUCTION: With the aim of optimising dental education without overburdening students, new legislation restructuring the undergraduate dental curriculum in German is under way. The goal of this study was to survey the current situation of dental students at one specific university with respect to their socio-economic background, admission to dental school, curriculum perception and work-life balance. MATERIALS AND METHODS: An online questionnaire was presented to all undergraduate students enrolled at Saarland University who had at least completed the first preclinical practical course in dentistry. RESULTS: A response rate of 85% was reached with two-thirds of the student body being females. The profession of 40% of students' parents either was physicians or dentist. Students reported a slight reduction in time spent for leisure activities during their studies, however, with sports activities hardly being affected. With respect to a proper work-life balance, almost 50% of respondents considered their clinical workload as being too high. Students did not express a clear opinion regarding curriculum structure, whilst the content mostly satisfied their expectations (59%). The majority (71%) of students considered their preclinical training as being demanding whilst less than 3% fully agreed that preclinical training provided an optimal background for patient treatment. The learning modules in the first clinical semester were considered as being adequate by 56% of students. Examinations during courses were seen as properly reflecting the students' knowledge by 79% of students. DISCUSSION: The status quo of German dental students is characterised by a high workload affecting the students' work-life balance and by a transition between preclinical and clinical education which only about half the student body perceives as being adequate. Patient-based examinations obviously are not considered as being problematic.

Short-term induction of assimilation and accommodation.

The dual-process model of developmental regulation distinguishes two processes of self-regulation (assimilation = tenacious goal pursuit, and accommodation = flexible goal adjustment) that depend on differing conditions, but both contribute to successful development. Four experiments were conducted to investigate whether assimilation and accommodation can be induced or at least shifted by sensorimotor and cognitive manipulations. Experiment 1 investigated the relation between body manipulation and self-regulation. It was shown that assimilation could be triggered when participants were asked to hold on to golf balls as compared to being asked to drop them. Experiment 2 showed that a semantic priming of "let go" or "hold on" via instructions influenced the processes of self-regulation. Experiment 3 and Experiment 4 investigated the role of cognitive sets (divergent thinking) and motivational processes (thinking about one's action resources) in enhancing accommodation or assimilation. As expected, accommodation was triggered by an intervention activating divergent thought, and participants were more assimilative when they thought about their action resources. In sum, the results indicate that assimilation and accommodation can be induced experimentally; they were systematically dependent on physical, cognitive, and motivational states. The implications of the findings were discussed in the light of the dual-process model.

Lytic Epstein-Barr virus infection in epithelial cells but not in B-lymphocytes is dependent on Blimp1.

Epstein-Barr virus (EBV) replicates in superficial differentiated cells of oral hairy leukoplakia (OHL). Differentiation of squamous epithelial cells depends on B-lymphocyte-induced maturation protein 1 (Blimp1). Here we show that expression of the EBV immediate-early protein BZLF1 is restricted to Blimp1-positive epithelial cells in OHL. Luciferase assays revealed Blimp1-dependent induction of the BZLF1 promoter Zp in epithelial cell lines. Expression of ZEB1, a negative regulator of Zp, and of Xbp-1, which mediates the Blimp1 effect on Zp in B-cells, was not affected by enforced Blimp1 expression. Moreover, Xbp-1 protein expression was not detected in differentiated epithelial cells of OHL. Thus, Blimp1 induces BZLF1 expression in epithelial cells independently of ZEB1 and Xbp-1. In contrast to epithelial cells of OHL, BZLF1 expression was also observed in Blimp1-negative lymphoid cells in infectious mononucleosis tonsils, suggesting that EBV replication in B-cells may be induced independently of terminal differentiation.

[Contract focused short-term group therapy--results of an evaluation]. / Auftragsfokussierende Gruppenkurztherapie--Ergebnisse einer Evaluation.

A short description outlines the development of commission focused short-term therapy (AFoG) for children and adolescents. Subsequently the generic principles of psychotherapy are applied to AFoG in order to underline the basic assumptions of this variation of systemic group therapy. Behavioural changes arising in different contexts (school, family, group therapy) show the need for an appropriate flexibility of group therapy techniques. The evaluation was accomplished using the Child Behaviour Checklist (CBCL 4-18) at the beginning and 3 month after the end of the group therapy. The results show positive effects which finally are discussed critically.

Dispersal capacity and diet breadth modify the response of wild bees to habitat loss.

Habitat loss poses a major threat to biodiversity, and species-specific extinction risks are inextricably linked to life-history characteristics. This relationship is still poorly documented for many functionally important taxa, and at larger continental scales. With data from five replicated field studies from three countries, we examined how species richness of wild bees varies with habitat patch size. We hypothesized that the form of this relationship is affected by body size, degree of host plant specialization and sociality. Across all species, we found a positive species-area slope (z = 0.19), and species traits modified this relationship. Large-bodied generalists had a lower z value than small generalists. Contrary to predictions, small specialists had similar or slightly lower z value compared with large specialists, and small generalists also tended to be more strongly affected by habitat loss as compared with small specialists. Social bees were negatively affected by habitat loss (z = 0.11) irrespective of body size. We conclude that habitat loss leads to clear shifts in the species composition of wild bee communities.

Reasons patients with a positive fecal occult blood test result do not undergo complete diagnostic evaluation.

PURPOSE: Screening for fecal occult blood reduces colorectal cancer mortality by identifying patients with positive results for complete diagnostic evaluation (CDE). CDE rates are suboptimal, however. We sought to determine common reasons for nonperformance of a CDE as recorded by the primary care physician. METHODS: We undertook a descriptive analysis of reasons reported by physicians for nonperformance of CDE in a nested sample of patients with positive fecal occult blood test (FOBT) results from a randomized controlled trial designed to evaluate the impact of a physician intervention (CDE reminder-feedback and educational outreach) on recommendation and performance rates in primary care practices. Inspection of administrative data for 1,468 patients with positive results showed that 661 (45%) did not undergo CDE. We reviewed patient follow-up forms, which were completed by physicians for patients who did not have a CDE, to identify reasons for nonperformance. RESULTS: Nonperformance of CDE was due to physician decision for 217 patients (33%). In 123 patients (19%), reasons for nonperformance were compatible with the guidelines, and in 94 patients (14%), they were not. Reasons wholly or partially due to factors other than physician decision were noted in 212 patients (32%); physician action was considered to be appropriate in these patients. For the 232 patients (35%) without a clearly documented reason for CDE nonperformance, the appropriateness of the physicians' action could not be determined. CONCLUSIONS: Decision making by primary care physicians had a major effect on nonperformance of CDE after a positive FOBT result. Colorectal cancer screening programs should include guidance for physicians about when a CDE should and should not be performed.

Comparison of lipooligosaccharide biosynthesis genes of Campylobacter jejuni strains with varying abilities to colonize the chicken gut and to invade Caco-2 cells.

Campylobacter jejuni strains develop a high variability of lipooligosaccharide (LOS) structures on the cell surface based on variations in the genetic content of the LOS biosynthesis locus. While the importance of these variations for ganglioside mimicry as a critical factor in the triggering of Guillain-Barré syndrome has already been shown, little work has been done on the investigation of LOS structures and their function in the pathogenesis of gastrointestinal disease. In this study, the presence of several LOS genes in 40 C. jejuni strains with different abilities to colonize the chicken gut and to invade Caco-2 cells was investigated by PCR. Two genes, cgtB and wlaN, encoding putative beta-1,3-galactosyltransferases were detected in most strongly invasive strains and rarely in non-invasive strains. A homopolymeric tract within the wlaN gene resulted in an intact gene product only in strongly invasive strains. The specific function of these genes during LOS biosynthesis is still unknown. cgtB and wlaN gene products are suggested to be involved in development of the colonization and invasion ability of C. jejuni. After a classification of the complete LOS loci, an association between a particular LOS class and colonization and invasion ability of the C. jejuni strain could not be detected. Lack of the pglB gene involved in protein glycosylation in one strain could be responsible for the weak colonization and invasion ability of this strain. There is some evidence that different genetic characteristics were responsible for strong or weak colonization and the invasion ability of C. jejuni strains.

Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40.

Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-kappaB dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-kappaB. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment.

Effectiveness of complete diagnostic examination in clinical practice settings.

BACKGROUND: Thorough follow-up of a positive fecal occult blood test (FOBT) result, or a complete diagnostic evaluation (CDE), is recommended as routine care on the basis of findings from colorectal cancer (CRC) screening trials. CDE involves either colonoscopy or the combination of flexible sigmoidoscopy and double contrast barium enema X-ray. However, little evidence outside clinical screening trial settings has been reported in the literature to support CDE performance. The focus of this study was to determine the impact of CDE in primary care practice settings. METHODS: We determined diagnostic outcomes for 461 adult patients with a positive FOBT result in 318 primary care practices in southeastern Pennsylvania and southern New Jersey. Sociodemographic data were collected and CDE status was ascertained for these patients. Polytomous logistic models were used to identify whether having CDE was associated with subsequently being diagnosed with lower gastrointestinal "neoplastic disease" or "other gastrointestinal disease" as compared to "normal findings. RESULTS: Patients who underwent CDE were significantly more likely to have a reported diagnosis of colorectal neoplasia than normal findings (adjusted odds ratio = 3.65, 95% confidence interval = 1.58-8.39, p = 0.02). CDE performance did not result in the differential diagnosis of other gastrointestinal disease. CONCLUSIONS: Patients with a positive screening FOBT who underwent CDE were more likely to be diagnosed with colorectal neoplasia than with less serious conditions or have normal findings. Results support the use of CDE in CRC screening.

Three novel Pax6 alleles in the mouse leading to the same small-eye phenotype caused by different consequences at target promoters.

PURPOSE: To characterize three new mouse small-eye mutants detected during ethylnitrosourea mutagenesis programs. METHODS: Three new mouse small-eye mutants were morphologically characterized, particularly by in situ hybridization. The mutations were mapped, and the candidate gene was sequenced. The relative amount of Pax6-specific mRNA was determined by real-time PCR. Reporter gene analysis used Crygf and Six3 promoter fragments in front of a luciferase gene and HEK293 cells as recipients. RESULTS: The new mutations--ADD4802, Aey11, and Aey18--were mapped to chromosome 2; causative mutations have been characterized in Pax6 (Aey11: C-->T substitution in exon 8, creating a stop codon just in front of the homeobox; ADD4802: G-->A substitution at the beginning of intron 8 changes splicing and leads to an altered open reading frame and then to a premature stop codon; Aey18: G-->A exchange in the last base of intron 5a leads also to a splice defect, skipping exons 5a and 6). Real-time PCR indicated nonsense-mediated decay in Pax6Aey11 and Pax6Aey18 mutants but not in Pax6ADD4802. This result is supported by the functional analysis of corresponding expression constructs in cell culture, where the Aey11 and Aey18 alleles did not show a stimulation of the Six3 promotor or an inhibition of the Crygf promoter (as wild-type constructs do). However, the Pax6ADD4802 allele stimulated both promoters. CONCLUSIONS: Together with functional analysis in a reporter gene assay and immunohistochemistry using Pax6 antibodies, it is suggested that the Pax6Aey11 and Pax6Aey18 alleles act through a loss of function, whereas ADD4802 represents a gain-of-function allele.

A region on human chromosome 4 (q35.1-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis.

Human papillomavirus (HPV) types 16 and 18 are known to play a major role in cervical carcinogenesis. Additional genetic alterations are required for the development and progression of cervical cancer. Previously, we showed that the introduction of an entire human chromosome 4 into HPV-immortalized cells by microcell-mediated chromosome transfer (MMCT) can induce senescence in cell hybrids. In the present study, we established eight new murine donor cell lines harboring different fragments of the human chromosome 4. These were tested for their ability to induce senescence by MMCT into HPV16-immortalized keratinocytes (HPK II) and cervical carcinoma cells (HeLa). By exclusion, we could identify a region for a putative senescence gene or genes at 4q35.1-->qter. Further evidence that this locus may be involved in cervical carcinogenesis was obtained by studying sections of high-grade cervical intraepithelial neoplasias (CIN2/3) and cervical cancers from 87 women using a combination of interphase fluorescence in situ hybridization (I-FISH) and microsatellite PCR. I-FISH indicated copy number loss at 4q34-->qter. Microsatellite analysis showed that loss of one or more alleles at chromosome 4 was more frequent in the cervical carcinomas than in the CINs. Loss of heterozygosity (LOH) affected four areas, D4S412 (4p16.3), D4S2394 (4q28.2), D4S3041 (4q32.3), and D4S408 (4q35.1), and was highest at D4S408. LOH at terminal 4q has been reported previously for cervical carcinomas and other human malignancies. This is the first report associating allelic loss at 4q34-->qter with high-grade intraepithelial neoplasia and cervical carcinoma, and the first experimental evidence that this locus or these loci can induce senescence in cervical carcinoma cells and HPV16-immortalized cells.

Expression of the interferon-inducible chemokine IP-10 (CXCL10), a chemokine with proposed anti-neoplastic functions, in Hodgkin lymphoma and nasopharyngeal carcinoma.

Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) are characterized by their association with Epstein-Barr virus (EBV) and an abundant infiltrate of reactive lymphoid cells. The presence of this lymphoid stroma may influence the effect of anti-viral immunotherapy. The interferon-inducible chemokine IP-10 has anti-neoplastic effects in several model systems mediated by T-cells expressing the CXCR3 chemokine receptor. Using in situ hybridization, it is shown that IP-10 is expressed in neoplastic cells of HL and correlates both with the mixed cellularity histotype and with EBV infection. IP-10 expression was also detected in tumour cells of most NPCs as well as in EBV-negative squamous cell carcinomas of the tongue. Thus, in carcinomas, IP-10 expression showed no correlation with EBV infection. Numerous CXCR3-positive lymphocytes were detected in the lymphoid stroma of HL and NPC, raising the possibility of a Th1-predominant immune response in these cases. In view of the proposed anti-neoplastic functions of IP-10 and CXCR3-positive lymphocytes, these findings are unexpected and raise the possibility that endogenous IP-10 expression in the context of human tumours may not exert the anti-tumour effects ascribed to it by in vitro experiments.

Genomewide linkage analysis identifies novel genetic Loci for lung function in mice.

RATIONALE: Pulmonary function, including lung volumes and compliance, may be genetically determined, but few genetic polymorphisms have been identified that control these traits. We used an experimental approach and performed the first whole genome scan for pulmonary function in mice. OBJECTIVES AND METHODS: To identify novel chromosomal regions contributing to lung function, quantitative trait locus linkage analysis was applied in N(2) backcross and F(2) intercross mice derived from two inbred strains-C3H/HeJ and JF1/Msf-with extremely divergent phenotypes. MAIN RESULTS: Significant linkages to total lung capacity with LOD (logarithm of the odds) scores up to 6.0 were detected on chromosomes 15 and 17, to dead space volume and lung compliance on chromosomes 5 and 15 (LOD scores higher than 4.0), to lung compliance also on chromosome 19 (LOD score of 5.8), and to diffusing capacity on chromosomes 15 and 17 (LOD scores up to 5.0). The region of interest on chromosome 17 near D17Mit133 contains a syntenic region to human chromosome 6q27, which was recently identified to be linked to lung function in humans. The identified intervals harbor valuable candidate genes, such as the relaxin1 and transforming growth factor beta receptor 3 gene, which revealed missense polymorphisms between the parental strains. CONCLUSION: The study provides evidence for linkage of different measures of lung function on murine chromosomes 5, 15, 17, and 19 and suggests novel candidate genes that may also affect the expression of human pulmonary function.

A spontaneous mutation in the desmoglein 4 gene underlies hypotrichosis in a new lanceolate hair rat model.

A recessive hairless mutation arose spontaneously in a congenic line of spontaneously hypertensive rats SHR.BN-(D1Mit3-Igf2)/Ipcv. The mutant rats develop generalized alopecia except for partial hair growth on their heads. Affected animals of the congenic line were crossed with LEW rats and randomly bred for several generations. A genome scan in 74 affected and 75 unaffected offspring localized the mutant gene on rat chromosome 18p12, near the marker D18Rat107, which is closely linked to the desmosomal cadherin gene cluster, syntenic to mouse chromosome 18 and human chromosome 18q12. Recently, the mouse and rat phenotypes lah/lah (lanceolate hair) and lah(J)/lah(J)(lanceolate hair-J) were found to be caused by mutations in the desmoglein 4 (Dsg4) gene. Direct sequencing of the Dsg4 gene in the SHR revealed a homozygous C-to-T transition generating a premature termination codon within exon 8 in the affected animals. Further studies on the skin histology in affected rats demonstrated features consistent with a lanceolate hair mutation, providing further support for the crucial role of desmoglein 4 in hair shaft differentiation.

Expression of tumor necrosis factor receptor-associated factor 1 in nasopharyngeal carcinoma: possible upregulation by Epstein-Barr virus latent membrane protein 1.

EBV infection is associated with virtually all cases of undifferentiated NPC, and the EBV-encoded LMP1 is expressed in a proportion of cases. LMP1 has transforming functions similar to members of the TNF receptor family and activates intracellular signaling cascades through interaction with TRAFs. In B cells, expression of TRAF1 is in turn upregulated by LMP1. LMP1 signaling in epithelial cells may be affected by the presence or absence of TRAF1. By immunohistochemistry, we detected TRAF1 expression in 17 of 42 (40%) EBV+ undifferentiated NPCs. All 7 LMP1+ NPC biopsies were also TRAF1+. Using an RNAse protection assay, high-level TRAF1 expression was detected in an LMP1-expressing NPC-derived cell line (C15) and expression was weaker in 2 LMP1- cell lines (C17, C19). Finally, LMP1 upregulated TRAF1 expression in an EBV- keratinocyte cell line. Our results demonstrate that TRAF1 is expressed in NPC tumor cells in vivo and suggest that TRAF1 expression may be upregulated by LMP1 in NPC. An antiapoptotic function has been proposed for TRAF1, and this may be relevant for the pathogenesis of NPC.

Genome-wide linkage analysis reveals evidence for four new susceptibility loci for familial euthyroid goiter.

Euthyroid goiter is characterized by diffuse or nodular enlargement of the thyroid gland. Iodine deficiency and cigarette smoking have been identified as important environmental factors. However, family and twin pair studies suggest a strong genetic predisposition. Therefore, we performed the first extended genome-wide scan to identify susceptibility loci that predispose for euthyroid goiter using 450 microsatellite markers in 18 extended Danish, German, and Slovakian families. Parametric and nonparametric multipoint linkage analyses were performed. The highest nonparametric LOD scores were obtained for chromosomes 2q and 3p with values of 2.54 at D2S1363 and 2.25 at D3S3038, respectively. Assuming heterogeneity and dominant inheritance, heterogeneity LOD scores (HLOD) of 2.71 and 1.94 were calculated for 2q and 3p, respectively. Furthermore, nonparametric LOD scores of 1.87 (HLOD 1.39) at D7S1808 on 7q and 1.79 (HLOD 1.80) at D8S264 on 8p were obtained. Haplotyping of families contributing to the linkage signals revealed four families compatible with a putative locus on 3p and one family each showing strict cosegregation with the loci on 2q, 7q, and 8p. The four novel candidate loci corroborate the assumed heterogeneity in the etiology of euthyroid familial goiter. For the first time, a more prevalent putative locus, present in 20% of the families investigated, was identified.

Behaviors used by men to protect themselves against prostate cancer.

This paper reports on behaviors men use to protect themselves against prostate cancer. Data were collected via a telephone or mailed survey from 353 men enrolled in two studies of prostate cancer screening. Respondents reported behaviors they used to protect themselves against prostate cancer, and responses were coded as conventional care, self-care, or nothing. Men who reported using both conventional care and self-care were categorized as conventional care users. Polytomous logistic regression was conducted to evaluate the association between sociodemographic background, prior prostate screening, and cognitive, affective, and social support and influence factors with protective behavior type. The distribution of protective behaviors was as follows: conventional care, 63%; self-care only, 19%; and nothing, 18%. In multivariable analyses, higher education level was found to be positively associated with conventional care use. Perceived salience and coherence of prostate cancer screening was positively associated with conventional care use among men in one of the two studies. Low concern about screening was positively associated with self-care use, as was mailed survey completion. This study presents self-report data regarding prostate cancer protection behaviors. Most men in the study reported using some type of prostate cancer protective behavior. Decision-making about whether or not to take protective action and what type of behavior to use may be influenced by socioeconomic background, cognitive perceptions related to behavioral options, and concern about risk.

Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.

Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.

Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p.

Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 "unknown." Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod = 2.1) and central q-arm (lod = 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P = 0.00028). The region around this marker was further investigated by using anonymous SNPs. An associated haplotype containing three SNPs was identified (peak significance P = 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P = 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.