Oral health-related quality of life (OHRQoL) and implant therapy: A prospective multicenter study of preoperative, intermediate, and posttreatment assessment.

The purpose of this multicenter continuation study was to use high patient numbers in order to generate reliable statements regarding the association between different implant indications and OHRQoL. Patients with various types of indication for dental implants, ranging from single tooth loss to edentulous jaws, were included. Quality of life relating to dental implants was assessed through the oral health impact profile (OHIP-G-21), which has a summary score from 0 to 20 in healthy patients. In total, 16 253 patients from 29 centers (European Centers for Dental Implantology (ECDI)) were involved in the study between 2009 and 2021.8251 patients (50.7%) completed the questionnaire after implant insertion, and 4996 patients (30.7%) after prosthodontic treatment. The average age was 54 years (range 18-88 years). Posterior single-tooth gap (28.5%) and free-end gap (27.8%) were the most frequent indications. The preoperative OHIP-G-21 score for all patients was 32.81 (SD 11.92), while the score during the healing period was 30.00 (SD 10.72), and after completion of treatment 27.24 (SD 9.26) (p < 0.001). The most significant improvements in OHIP-G-21 scores were in the indication of edentulous jaw (phase 1, 41.81 (SD 15.53); phase 2, 35.39 (SD 14.22); phase 3, 29.60 (SD 10.12) (p < 0.001). The study revealed significant improvements in the most frequently reported problems (chewing, serious concerns, appearance) (p < 0.001). Insertion of dental implants and prosthodontic rehabilitation led to an improved OHRQoL for patients with all indications for dental implants. Special attention should be paid to patients with edentulous jaw, since in comparison with other indications it had the greatest impact on improving OHRQoL. The psychological dissatisfaction scale of the OHIP-G-21 represented the most important factors for patients, and these scores were substantially influenced by implant therapy. Thus, treating physicians should increase their focus on these factors, in order to avoid dissatisfaction and increase the likelihood of complete implant therapy success.

Digitally designed, personalized bone cement spacer for staged TMJ and mandibular reconstruction - Introduction of a new technique.

The aim of this paper is to introduce an innovative workflow for staged reconstruction of the mandible, including the temporomandibular joint (TMJ), using a temporary, patient-specific spacer. In cases of partial mandibular resection including disarticulation, sometimes needed to treat inflammatory bone disease, the spacer is intended to retain symmetry of the hard tissues, to preserve the soft tissues, and to act as a bactericidal agent. When complete healing of the affected surrounding tissues has occurred, final reconstruction using a patient-matched total TMJ endoprosthesis, in combination with an autogenous free bone flap, can be performed as a second-stage procedure. The crucial steps of the workflow are virtual surgical planning, manufacturing of a two-part silicone mold, and chairside manufacturing of the spacer using an established bone cement with gentamycin. The method was first introduced in two patients suffering from therapy-resistant chronic osteomyelitis. The presented protocol of staged surgery allows a much safer and predictable reconstruction compared with immediate reconstruction. The workflow also minimizes the potential risk of endoprosthesis infection - one of the major risks of implant failure.

A matched-pair analysis on survival and response rates between German and non-German cancer patients treated at a Comprehensive Cancer Center.

BACKGROUND: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016. METHODS: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment. RESULTS: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis. CONCLUSIONS: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.

The role of immediate versus secondary removal of the odontogenic focus in treatment of deep head and neck space infections. A retrospective analysis of 248 patients.

OBJECTIVES: Aim of this study was to investigate conditions and predisposing factors for head and neck infection progress regarding the length of stay (LOS) in hospital, with special emphasis on the time of removal of the odontogenic infection focus. MATERIAL AND METHODS: A 3-year retrospective study reviewed hospital records of 248 subjects who were treated under inpatient conditions with severe odontogenic infections who received surgical incisions, drainage, and intravenous (IV) antibiotics. Outcomes measured included age, gender, involved fascial spaces, LOS, number of infected spaces, antibiotics administered, and comorbidities. We precisely recorded the time between abscess incision and focus extraction. RESULTS: Removal of infection focus (tooth) in the same stay (1 stay, n = 106; group 1; mean 6.5 days ± 3) showed significantly higher (p = 0.042) LOS than extraction in a second stay (2 stays, n = 46; group 2; 5.3 ± 3.1). Group 3 patients showed infection after removal of teeth in outpatient management (1 stay ex-op, n = 96) and presented significantly lower LOS (5.6 ± 2.5) compared to group 1 (p = 0.0216). LOS of group 3 to group 2 patients showed no significance (p = 0.668). Infection expansion and diabetes showed a significant increase of LOS. CONCLUSION: Simultaneous removal of infection focus and abscess incision leads to the lowest LOS. If tooth extraction is performed after incision, subsequent focus extraction performed in a second stay shows lower overall-LOS than extraction at the same stay at later stage. CLINICAL RELEVANCE: Multiple factors tend to increase the LOS of patients with severe head and neck infections of odontogenic origin. Our data reveals the role of removal of odontogenic focus and additionally ranks further parameters that influence the LOS. Based on our findings, decisions regarding the surgical treatment can be recommended.

The role of C-reactive protein and white blood cell count in the prediction of length of stay in hospital and severity of odontogenic abscess.

INTRODUCTION: Odontogenic infections and subsequent developing abscess remain to be a potentially life-threatening event, due to septicemia, airway compression and spreading into sensitive anatomic tissues. C-reactive proten (CRP) and white blood cell (WBC) count are routinely blood-measured indicators for inflammation. Are CRP-levels and WBC-count predictive factors of the developement of odontogenic abscess? METHODS: A 4-year retrospective study evaluated hospital records of 218 patients, diagnosed and inpatiently treated for acute odontogenic abscess. They received surgical incision, drainage and intravenous antibiotics. CRP-levels and WBC-counts were measured preoperativly. RESULTS: 218 subjects were enrolled in this study. Patients hospitalized 10 days or more showed significantly higher CRP-levels (p = < 0.001) and WBC-counts (p = 0.006) on admission day than patients with lower LOS. CRP-levels of patients with LOS from 7-9 days were significantly lower (p = 0.47) than in people hospitalized 10 days or more. Abscess focus in the mandible shows significantly higher WBC-counts (p = 0.014). Multiple space infections present a significantly higher CRP (p = 0.003) and WBC (p < 0.001) on admission day. DISCUSSION: According to the presented data, CRP-levels and WBC-count can be regarded as predictive factors for LOS (length of stay in hospital) in patients with long term hospitalization (CRP:7-9 days and > 10 days; WBC: > 10 days). Further WBC and CRP are suitable to predict multiple space infections and localisation of the abscess (WBC) in certain limits. CONCLUSION: In predicting the developement of odontogenic abscess, CRP is more capable in providing exact statements regarding the LOS. However, WBC-counts are more suitable in predicting multiple space infections and localization of infection.

The prevalence of pneumatized articular eminence in the temporal bone. Do we need a high resolution computed tomography-based novel risk classification for eminectomy?

INTRODUCTION: Besides mastoid air filled cells, pneumatizations (PN) occasionally occur in the articular eminence (AE) of the temporomandibular joint (TMJ). These findings represent no pathological character but may increase the risk of perforating the AE during eminectomy with potential harming the skull base. Various classifications catagorize the degree of temporal PN without focussing solely on the AE. Panoramic radiograph (PR) and computed tomographie (CT) are both described as suitable for diagnosing PNs. Are the common ways of imaging capable for precise diagnosis and do we need a risk pattern for eminectomy? METHODS: A 4-year retrospective study evaluated high resolution computed tomographie (HRCTs) of 300 patients. We screened digitalized skull images for PN of the AE. The frankfort horizontal was determined as the reference mark for measurements. Images were assessed by a craniomaxillofacial surgeon and a radiologist. RESULTS: 300 patients (600 AEs) were investigated. We detected 60 PNs (10% of all AEs) in 44 patients (14.7%). We subdevided the findings according to the extent of PN. 10 AEs showed PNs of less than 20% (type 1); n=18: 21-40% (type 2); n=18: 41-70% (type 3). n=14: 71 to 100% (type 4). In 32 cases (72.7%) with 42 PNs a PR existed. Of the 42 AEs, corresponding PN could be detected in 21 cases (50%). DISCUSSION: PNs are a potential threat when performing TMJ surgery. Sufficient preoperative imaging is required to avoid severe endangerment for the patient. CT imaging is most suitable detecting PNs. PR seem to fail in diagnosing PNs of different degree. Our novel HRCT-based classification shows the distribution of PNs and provides a risk pattern. CONCLUSION: HRCT exceeds the diagnostic accuracy of PR in detecting pneumatized AEs. PR is not capable for detecting PNs of different degree. A novel classification may increase the prediction of perforation risk. Restricting eminectomy to reduce height only to a certain amount reduces the risk of complications.

Current concepts in cleft care: A multicenter analysis.

The current surgical techniques used in cleft repair are well established, but different centers use different approaches. To determine the best treatment for patients, a multi-center comparative study is required. In this study, we surveyed all craniofacial departments registered with the German Society of Maxillofacial Surgery to determine which cleft repair techniques are currently in use. Our findings revealed much variation in cleft repair between different centers. Although most centers did use a two-stage approach, the operative techniques and timing of lip and palate closure were different in every center. This shows that a retrospective comparative analysis of patient outcome between the participating centers is not possible and illustrates the need for prospective comparative studies to establish the optimal technique for reconstructive cleft surgery.

Vitamin D (25-OHD) deficiency may increase the prevalence of medication-related osteonecrosis of the jaw.

INTRODUCTION: Osteonecrosis of the jaw (ONJ) is a severe complication of antiresorptive medication (AM) in the treatment of bone-affecting cancer-related conditions and osteoporosis. Aim of this study was to reveal whether patients treated with AM and show Medication Related OsteoNecrosis of the Jaw (MRONJ) are vitamin D deficient or not. MATERIALS AND METHODS: A 2 year retrospective study evaluated hospital records of 63 patients who received AM. Patients were divided into two groups. One group (n = 45) consisted of patients who presented a stage 2 ONJ (eb+ = exposed bone). Second group patients (n = 18) (eb- = no exposed bone) presented for extraction of teeth. Serum levels of vitamin D (25-OHD) were analysed. P values ≤ 0.05 in t-test were regarded as statistically significant. RESULTS: Serum levels of 25-OHD were significantly higher in the eb(-) group (29.5 ng/ml), than in the eb(+) group (20.49 ng/ml). Blood levels of calcium were also significantly higher in eb(-) group (2.25 mmol/L; 0.11 SD) than in eb(+) group (2.175 mmol/L; 0.16 SD). CONCLUSION: Prevalence of MRONJ in AM treated patients seems to be increased by low serum 25-OHD. A measurable tendency in the role of 25-OHD for the development of MRONJ was recorded and leads to the recommendation for a sufficient vitamin D substitution in patients treated with AM.

Eagle Syndrome: a Follow-Up Examination of Four Patients After Surgical Treatment Via Cervical Approach.

OBJECTIVE: Eagle syndrome is a rare pain syndrome caused by an elongated styloid apophysis or an ossified styloid ligament. It is characterized by a complex range of symptoms in head and neck region. The most effective treatment is surgical shortening of the styloid apophysis. The authors report of a follow-up examination of 4 patients after surgical treatment via cervical approach. METHODS: Retrospectively reviewed hospital records of 5 patients (4 females and 1 male), aged from 26 to 59 years old (mean age = 45.5 years) who underwent surgical shortening of the styloid process via cervical approach. Further, a paper-based survey of 4 patients was conducted, including a clinical questionnaire and 4 visual analogue scales, consisting of questions regarding postoperative pain. RESULTS: Period of follow-up ranged from 16 to 79 months (mean 53.75 months). All patients were asymptomatic at follow-up. None of the patients reported a visible scar or hypoesthesia in the affected area. The patients demonstrated low mean visual analogue scales for each item (facial pain: 0.6 ±â€Š1.2, foreign body sensation: 0.725 ±â€Š1.45, pain of throat and neck 1.35 ±â€Š1.58 and limitation of dietary habits: 0.75 ±â€Š1.5). None of the patients reported a resurgence of pain in the head and neck region so far. CONCLUSIONS: Surgical treatment via cervical approach appears to be an effective and safe option with low morbidity and mortality in the treatment of symptomatic Eagle syndrome of adults.

The current state of facial prosthetics ­ A multicenter analysis.

Even though modern surgical techniques are dominating reconstructive facial procedures, the capability to use facial epitheses for reconstruction is still an important skill for the maxillofacial surgeon. We present an international multicenter analysis to clarify which techniques are used to fixate facial prostheses. We contacted all maxillofacial departments in Germany, Austria, Switzerland and Norway which were registered with the German society for oral and maxillofacial surgery (DGMKG). These centers were asked via electronical mail to provide information on the type of epithesis fixation systems currently in use. The return rate from 58 departments was 43.1% (n = 25). Overall, implant fixation was the preferred fixation system (92%). Plates were the second most common fixation technique (32%). No centers reported the standard use of non-invasive fixation techniques for permanent epithesis fixation. The main retention systems in use were magnets (24/25), other retention systems are used much less often. The current preferred fixation technique for facial epitheses consists of implant-based, magnet-fixated epitheses. For nasal prostheses, a plate-based, magnet-fixated system is often used.

Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin-1, a component of the bone morphogenetic protein 4 pathway.

BACKGROUND: The genes Gremlin-1 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL/P etiology. METHODS: The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case-control sample (n = 96, respectively). For rare variants observed in cases, segregation analyses were performed. RESULTS: In NOG, four rare sequence variants (minor allele frequency < 1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated. CONCLUSION: Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements.

Maximum voluntary bite force in patients with alloplastic total TMJ replacement--a prospective study.

Alloplastic temporomandibular total joint replacement (TJR) for end-stage disease, congenital disorders and following ablative oncological surgery has been shown to reduce pain and improve function. The purpose was to assess the maximum voluntary bite force and maximum interincisal opening (MIO) in patients undergoing alloplastic total temporomandibular joint replacement (TJR). Seventeen patients with different diagnoses resulting in condylar hypomobility (8 patients; 15 joints) and condylar instability (9 patients; 12 joints) had undergone alloplastic TMJ reconstruction. Maximum voluntary bite force and MIO were measured at pre-operatively (T0), 2 (T1), 6 (T2) and 12 (T3) months. For ordinal data comparison at different time-points, the Wilcoxon signed-ranks test was used. There was a significant improvement in maximum voluntary bite force for both, patients with condylar hypomobility (P = 0.003) and condylar instability (P = 0.007). Analysis of MIO revealed a significant improvement at T3 (P = 0.002). Alloplastic TJR would appear to increase maximum voluntary bite force and MIO. Biomechanical integrity of the stomatognathic system and the ability of the patient to triturate food could be improved by alloplastic temporomandibular joint (TMJ) replacement.

Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P. METHODS: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level. RESULTS: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees. CONCLUSION: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012.

Pressure pain threshold and oral health-related quality of life implications of patients with alloplastic temporomandibular joint replacement--a prospective study.

PURPOSE: Alloplastic total temporomandibular joint replacement (TJR) for end-stage disease, congenital disorders, and after ablative surgery has been shown improve function and to decrease pain. The purpose of this study was to evaluate the pain pressure threshold (PPT) and oral health-related quality of life (OHRQoL) in patients undergoing alloplastic TJR. MATERIALS AND METHODS: Subjects requiring TJR from May 2007 through February 2011 were enrolled in the study. The PPT and OHRQoL were measured preoperatively and 2, 6, and 12 months postoperatively. The primary predictor variable was postoperative time (preoperatively and 2, 6, and 12 months postoperatively). The primary outcome variables were the PPT and OHRQoL. RESULTS: Seventeen subjects requiring TJR were enrolled in and completed the required 12-month follow-up. There was no difference in the PPT at any time point. There was a significant improvement in the OHRQoL domain of psychological discomfort (P = .04) at 12 months. Facial pain intensity, temporomandibular joint pain, mandibular function, and diet were also significantly improved at 12 months (P = .001). CONCLUSION: Alloplastic TJR appears to decrease pain, improve function and diet, and decrease psychological discomfort.

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).

Mandibular kinematics in patients with alloplastic total temporomandibular joint replacement--a prospective study.

PURPOSE: The purpose was to analyze the mandibular patterns (condylar range of motion during opening; incisal range of motion during opening, lateral excursion, and protrusion; velocity during opening and closing; mandibular rotation angle during opening and closing) in patients with alloplastic total joint replacement (TJR). MATERIALS AND METHODS: Seventeen patients with different diagnoses resulting in condylar hypomobility (8 patients, 15 joints) and condylar instability (9 patients, 12 joints) had undergone alloplastic TJR. Data were recorded preoperatively and 2, 6, and at least 12 months postoperatively. For ordinal data comparison at different time points, the Wilcoxon signed-ranks test was used. RESULTS: Analysis of the kinematic data at least 12 months postoperatively showed in patients with condylar hypomobility a statistically significant increase in all measured data except the incisal range of motion lateral excursion. In patients with condylar instability, the results showed a statistically significant decrease for incisal range of motion protrusion and laterotrusion. A slight increase in condylar range of motion, incisal range of motion linear distance, and velocity during opening and closing was found. CONCLUSIONS: Even after successful alloplastic TJR, a complete restoration of normal joint function is not achievable. Nevertheless, the kinematic data indicate that alloplastic TJR results in an improved function in patients with joint hypomobility and in a decrease of abnormal hypermobility in patients with condylar instability.

SUMO1 as a candidate gene for non-syndromic cleft lip with or without cleft palate: no evidence for the involvement of common or rare variants in Central European patients.

OBJECTIVE: Studies in mice and humans have suggested that SUMO1, which codes for the small ubiquitin-related modifier 1 (SUMO1), is a promising candidate gene for non-syndromic cleft lip with or without cleft palate (NSCL/P). To investigate the possible involvement of this gene in NSCL/P patients from Central Europe, we performed: (i) a case control association study, and (ii) a resequencing study. METHODS: Genotyping and the subsequent single marker and haplotype association analyses were performed for 413 NSCL/P patients and 412 controls. A total of 17 tagging single-nucleotide polymorphisms (SNPs) were used. In the resequencing study, the complete coding region and splice sites were sequenced in 65 index patients from multiply affected families. RESULTS: One of the 17 tested SNPs (rs16838917) had a borderline significant P-value of 0.0416 in the single-marker association analysis. However, this result did not withstand correction for multiple testing (P(corr)=0.707). No association was observed for any haplotypic marker combination. Sequencing failed to identify any novel rare sequence variants. CONCLUSIONS: The results of the present study do not support the hypothesis that common or rare variants in SUMO1 play a significant role in the development of NSCL/P in Central-European patients. However, smaller effects of common variants or the presence of rare high penetrance mutations in other non-investigated familial cases cannot be excluded. Further analysis of SUMO1 in independent samples from Central European and other populations is therefore warranted.

Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate.

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 x 10(-8), relative risk in homozygotes = 1.84, 95% CI 1.34-2.53) and 10q25.3 (rs7078160, combined P = 1.92 x 10(-8), relative risk in homozygotes = 2.17, 95% CI 1.32-3.56).

Genome-wide linkage scan of nonsyndromic orofacial clefting in 91 families of central European origin.

Orofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome-wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome-wide linkage analyses, we searched for sex-specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21-q26 and 1p31-p21, with the chromosome 1 locus showing a male-specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC-associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex-specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO.

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24.

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 x 10(-24). The odds ratio was 2.57 (95% CI = 2.02-3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88-9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.