Sequence variants influencing the regulation of serum IgG subclass levels.

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Genome-Wide Association Study of Accessory Atrioventricular Pathways.

Importance: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. Objective: To investigate the genetics of APs and affiliated arrhythmias. Design, Setting, and Participants: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. Exposures: Sequence variants. Main Outcomes and Measures: Genome-wide significant association of sequence variants with APs. Results: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. Conclusions and Relevance: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Long-term survival of 57 premolars consecutively transplanted to premolar sites.

INTRODUCTION: The objective of this study was to report the long-term outcome of autotransplantation of premolars to other premolar recipient sites. METHODS: The sample was limited to adolescents seeking orthodontic treatment, and all had 1 or 2 premolars transplanted to a recipient site in which a premolar was congenitally missing. The transplantations were performed between 1980 and 2008, comprising 29 premolars in 22 males and 28 premolars in 22 females. Systematic clinical and radiographic follow-up varied from 1 year to 36.8 years, with a mean observation time of 18.9 years and a median of 19.2 years. Of the 57 transplanted teeth, 52 were subjected to orthodontic forces. RESULTS: A total of 9 of 57 teeth (15.8%) were lost during the observation period, and 8 of 9 lost teeth had been functional for at least 9 years posttransplantation. Of the 48 surviving transplants, 6 did not meet the criteria for success, giving an overall success rate of 73.7%. Complications were diagnosed within 5 years from the transplantation in 4 of 57 teeth (7.0%) and later in 11 of 57 (19.3%). The Kaplan-Meier survival curve shows that the complication-free proportion of transplants decreased at a constant rate over the observation time. The average survival time, taking censoring into account during follow-up of 36.8 years, was estimated as 28.5 years. The complications in the 15 teeth were classified into 4 categories: periapical lesions (6 teeth), inflammatory resorption (5 teeth), abrupt fracture (2 teeth), and ankylosis (2 teeth). CONCLUSIONS: Overall, premolar transplants in all stages of root formation have high success and survival rates. Transplants with complications may survive temporarily and preserve critical arch space and alveolar bone. Transplants with normal healing may have latent weaknesses that can eventually affect long-term survival.

Clinical and patient-level predictors of procedure and tooth survival after direct pulp capping.

BACKGROUND: Historical reports of unpredictable outcomes associated with vital pulpal therapies, particularly direct pulp capping (DPC), have contributed to clinicians' skepticism of the procedure. Contemporary reports highlight more predictable outcomes of vital pulpal therapies, inclusive of DPC. There is a dearth of reported patient-centered outcomes of these procedures. METHODS: Insurance claims were used in an observational, retrospective cohort study to evaluate outcomes of DPC performed on permanent teeth. Statistical analyses included Kaplan-Meier survival estimates and Cox proportional hazards regression. Log-rank tests were used to evaluate unadjusted differences in survival. Cox proportional hazard regression was used to evaluate the adjusted hazard of adverse event occurrence. RESULTS: The analytic cohort included 4,136 teeth from 3,716 patients. DPC procedures were identified in public-payer (85.5%) and private-payer (13.4%) insurance claims databases. After DPC, procedure survival rate was 83% and tooth survival rate was 93% during a mean follow-up time of 52 months. Molar tooth type, same-day permanent restoration placement, and amalgam restoration type were significant positive predictors of procedure (DPC) survival. Age was not a statistically significant predictor of procedure survival after controlling for tooth type, gender, time to restoration, and restoration type. Nonmolar tooth type and younger age were significant positive predictors of tooth survival after DPC. Failures were most likely to occur within the first year. CONCLUSIONS: DPC has favorable patient-centered outcomes and contributes to long-term tooth survival. PRACTICAL IMPLICATIONS: The favorable patient-centered outcomes of DPC bolster calls to consider cost-effectiveness and access to care for endodontic procedures.

Efficacy of Different Irrigation Needles and Ultrasonic Activation on Calcium Hydroxide Removal: A Micro-CT Study Using 3D-Printed Endodontic Models.

INTRODUCTION: The aim of this study was to evaluate the efficacy of different irrigation needles and passive ultrasonic activation in removing Ca(OH)2 from an endodontic model that duplicated a root canal configuration of a human natural tooth. METHODS: An extracted human maxillary premolar was subjected to root canal preparation and scanned with microcomputed tomography. A 3-dimensional reconstruction model of the natural tooth was printed to endodontic models using a polyjet printer. The root canals of the models were filled with Ca(OH)2 paste and divided into 2 groups based on the irrigation protocol: conventional syringe-needle irrigation (conventional group) and passive ultrasonic irrigation (PUI) group. Each group was subdivided into 3 groups (n = 10) according to the type of needle: half-cut, side-vented, and TruNatomy irrigation needle. Microcomputed tomographyimaging was used to assess the percentage of reduction of Ca(OH)2. Data were analyzed using two-way analysis of variance test (α = .05). RESULTS: The side-vented and TruNatomy irrigation needles showed significantly higher percentage reductions than the half-cut needle (P < .05) in the conventional irrigation group. The PUI group showed significantly higher percentage reductions of Ca(OH)2 than the conventional group regardless of the type of needle (P < .05). However, no significant difference was found among the needles in the PUI group. CONCLUSIONS: The type of irrigation needle and the use of PUI influenced the removal efficacy of Ca(OH)2. PUI enhanced the removal of Ca(OH)2 regardless of the type of irrigation needle.

Access to Care Considerations for the Endodontic Treatment of Immature Permanent Teeth: A National Survey of Pediatric Dentists and Endodontists.

INTRODUCTION: This study aimed to investigate access to care and financial considerations associated with the endodontic treatment of immature permanent teeth. METHODS: Surveys were distributed to endodontists (n = 2,457) and pediatric dentists (n = 3,974) in the United States. Data were analyzed using X2 analysis and logistic regression. The level of significance was set to 0.05. RESULTS: The response rate was 13% (n = 840). Respondent specialist groups were similar by age and years since specialty residency completion, but significantly different with regard to primary practice setting (eg private practice, Federally Qualified Health Center, hospital), (P = .001). The majority (91%) of respondents reported participation with dental insurance. Pediatric dentists (69%) were significantly more likely than endodontists (17%) to participate with public-payer dental insurance (P < .001). The majority of respondents (82%) indicated that patients reported economic factors (time or money) as a barrier to accessing endodontic treatment. Pediatric dentists were significantly more likely to consider economic factors when planning for treatment (P < .001). Pediatric dentists were more likely than endodontists to have the opinion that endodontic procedures for treatment of necrotic immature permanent teeth should cost less than root canal therapy (apexification, P < .001; regenerative endodontic procedures, P = .002). Pediatric dentists (33%) reported encountering barriers when attempting to refer their patients to an endodontist. Inability to find an endodontist that participates with dental insurance was the most frequently cited barrier. CONCLUSIONS: Limited clinician participation with dental insurance and gaps in insurance coverage for endodontic procedures appear to contribute to access to care barriers for pediatric patients.

Effects of Side Flattening on Torsional and Cyclic Fracture Resistance of Nickel-Titanium File.

INTRODUCTION: The purpose of this study was to evaluate the effect of side flattening of cutting flutes on the cyclic resistance and torsional resistance of nickel-titanium files. METHODS: Both novel flattened Platinum V.EU (PL) and standard nonflattened CC Premium V.EU (CC) rotaries were tested. For cyclic fatigue tests, all the files were rotated in an artificial root canal with a curvature of 45° and a radius of 6.06 mm at 300 rpm (n = 15 in each group). The number of cycles to failure (NCF) was calculated. For torsional tests, the files were rotated at 2 rpm clockwise until fracture occurred. The maximum torque value at fracture was measured and the toughness and distortion angle were computed. Subsequently, 5 fragments were randomly selected in each experiment, the cross-section and longitudinal direction of the fragments were photographed using a scanning electron microscope. An unpaired t-test was performed at a significance level of 95%. RESULTS: There was a statistically significant difference in NCF between CC and PL (P < .05). CC showed higher NCF than PL. There was no statistically significant difference between CC and PL with regards to the parameters related to torsional resistance (distortion angle, ultimate strength, and toughness) (P > .05). CONCLUSION: Within the limitations of this study, side flattening of the file did not improve cyclic resistance or torsional resistance of the files. As side flattening may reduce a file's cyclic resistance, such files should be used with caution in clinical practice.

A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.

Variants at the Interleukin 1 Gene Locus and Pericarditis.

Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.