Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans.

Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A (THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 × 10-9). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk haplotype. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.

Implementation of pharmacogenomics into inpatient general medicine.

Pharmacogenomics is a crucial piece of personalized medicine. Preemptive pharmacogenomic testing is only used sparsely in the inpatient setting and there are few models to date for fostering the adoption of pharmacogenomic treatment in the inpatient setting. We created a multi-institutional project in Chicago to enable the translation of pharmacogenomics into inpatient practice. We are reporting our implementation process and barriers we encountered with solutions. This study, 'Implementation of Point-of-Care Pharmacogenomic Decision Support Accounting for Minority Disparities', sought to implement pharmacogenomics into inpatient practice at three sites: The University of Chicago, Northwestern Memorial Hospital, and the University of Illinois at Chicago. This study involved enrolling African American adult patients for preemptive genotyping across a panel of actionable germline variants predicting drug response or toxicity risk. We report our approach to implementation and the barriers we encountered engaging hospitalists and general medical providers in the inpatient pharmacogenomic intervention. Our strategies included: a streamlined delivery system for pharmacogenomic information, attendance at hospital medicine section meetings, use of physician and pharmacist champions, focus on hospitalists' care and optimizing system function to fit their workflow, hand-offs, and dealing with hospitalists turnover. Our work provides insights into strategies for the initial engagement of inpatient general medicine providers that we hope will benefit other institutions seeking to implement pharmacogenomics in the inpatient setting.

The Role of Global and Local Ancestry on Clopidogrel Response in African Americans.

Pharmacogenomics has long lacked dedicated studies in African Americans, resulting in a lack of indepth data in this populations. The ACCOuNT consortium has collected a cohort of 167 African American patients on steady state clopidogrel with the goal of discovering population specific variation that may contribute to the response of this anti-platelet agent. Here we analyze the role of both global and local ancestry on the clinical phenotypes of P2Y12 reaction units (PRU) and high on-treatment platelet reactivity (HTPR) in this cohort. We found that local ancestry at the TSS of three genes, IRS-1, ABCB1 and KDR were nominally associated with PRU, and local ancestry-adjusted SNP association identified variants in ITGA2 associated to increased PRU. These finding help to explain the variability in drug response seen in African Americans, especially as few studies on genes outside of CYP2C19 has been conducted in this population.

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

OBJECTIVE: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. METHODS: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. RESULTS: GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. CONCLUSIONS: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Apixaban Concentrations in Routine Clinical Care of Older Adults With Nonvalvular Atrial Fibrillation.

BACKGROUND: Direct-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing. OBJECTIVES: To determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations. METHODS: A cross-sectional study of medically stable older adults with NVAF (≥75 years or ≥70 years if Black) receiving apixaban. Peak (2-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling. RESULTS: The median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 Black, and 6 Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men (P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men (P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance. CONCLUSIONS: Older women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.

Applicability of Pharmacogenomically Guided Medication Treatment during Hospitalization of At-Risk Minority Patients.

Known disparities exist in the availability of pharmacogenomic information for minority populations, amplifying uncertainty around clinical utility for these groups. We conducted a multi-site inpatient pharmacogenomic implementation program among self-identified African-Americans (AA; n = 135) with numerous rehospitalizations (n = 341) from 2017 to 2020 (NIH-funded ACCOuNT project/clinicaltrials.gov#NCT03225820). We evaluated the point-of-care availability of patient pharmacogenomic results to healthcare providers via an electronic clinical decision support tool. Among newly added medications during hospitalizations and at discharge, we examined the most frequently utilized medications with associated pharmacogenomic results. The population was predominantly female (61%) with a mean age of 53 years (range 19-86). On average, six medications were newly prescribed during each individual hospital admission. For 48% of all hospitalizations, clinical pharmacogenomic information was applicable to at least one newly prescribed medication. Most results indicated genomic favorability, although nearly 29% of newly prescribed medications indicated increased genomic caution (increase in toxicity risk/suboptimal response). More than one of every five medications prescribed to AA patients at hospital discharge were associated with cautionary pharmacogenomic results (most commonly pantoprazole/suboptimal antacid effect). Notably, high-risk pharmacogenomic results (genomic contraindication) were exceedingly rare. We conclude that the applicability of pharmacogenomic information during hospitalizations for vulnerable populations at-risk for experiencing health disparities is substantial and warrants continued prospective investigation.

Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, ßCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), ßCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); PMETA  = 3.62 × 10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

Why African Americans say "No": A Study of Pharmacogenomic Research Participation.

Objective: To identify reasons for nonparticipation by African Americans in cardiovascular pharmacogenomic research. Design: Prospective, open-ended, qualitative survey. Setting: Research staff approached patients eligible for the Discovery Project of The African American Cardiovascular pharmacogenomics CONsorTium in the inpatient or outpatient setting at four different institutions during September and October 2018. Participants: Potential Discovery Project participants self-identified as African American, aged >18 years, were on one of five cardiovascular drugs of interest, and declined enrollment in the Discovery Project. Main Outcome Measures: Reasons for nonparticipation. Methods: After declining participation in the Discovery Project, patients were asked, "What are your reasons for not participating?" We analyzed their responses using a directed content analytic approach. Ultimately, responses were coded into one of nine categories and analyzed using descriptive statistics. Results: Of the 194 people approached for the Discovery Project during an eight-week period, 82 declined participation and provided information for this study. The most common reason for refusal was concern about the amount of blood drawn (19.5%). The next most common reasons for refusal to participate included concerns about genetic testing (14.6%) and mistrust of research (12.2%). Across study sites, significantly more patients enrolled in the inpatient than outpatient setting (P<.001). Significantly more women and younger individuals declined participation due to concerns about genetic testing and too little compensation (P<.05). Conclusions: Collection of blood samples and concerns about genetic testing are obstacles for the recruitment of African Americans to pharmacogenomics studies. Efforts to overcome these barriers to participation are needed to improve representation of minorities in pharmacogenomic research. Enrolling participants from inpatient populations may be a solution to bolster recruitment efforts.

A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).

Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 single nucleotide polymorphisms (SNPs) in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an area under the curve (AUC) integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting PFS with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs.

The ACCOuNT Consortium: A Model for the Discovery, Translation, and Implementation of Precision Medicine in African Americans.

The majority of pharmacogenomic (PGx) studies have been conducted on European ancestry populations, thereby excluding minority populations and impeding the discovery and translation of African American-specific genetic variation into precision medicine. Without accounting for variants found in African Americans, clinical recommendations based solely on genetic biomarkers found in European populations could result in misclassification of drug response in African American patients. To address these challenges, we formed the Transdisciplinary Collaborative Center (TCC), African American Cardiovascular Pharmacogenetic Consortium (ACCOuNT), to discover novel genetic variants in African Americans related to clinically actionable cardiovascular phenotypes and to incorporate African American-specific sequence variations into clinical recommendations at the point of care. The TCC consists of two research projects focused on discovery and translation of genetic findings and four cores that support the projects. In addition, the largest repository of PGx information on African Americans is being established as well as lasting infrastructure that can be utilized to spur continued research in this understudied population.

Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734-44. ©2018 AACR.

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non-Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance).

Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.

Usefulness of dermoscopy in the diagnosis and monitoring treatment of demodicidosis.

Demodicidosis is a common infestation and should be considered in the differential diagnosis of recurrent or recalcitrant perioral dermatitis or rosacea-like eruptions of the face. We report on a 34-year-old male, who presented with facial erythema and desquamation accompanied by a pruritic sensation. Dermoscopic examination revealed Demodex tails and Demodex follicular openings, both specific features of this entity. Microscopically, standardized skin surface biopsy test was pathogenic and the patient had positive response to anti-demodectic drugs. To our knowledge, a few reports of the dermatoscopic features of demodicidosis have been published in the literature. Dermoscopy offers a potential new option for a real-time validation of Demodex infestation and a useful tool for monitoring treatment.

Proposal for management and dermoscopy follow-up of nevi in patients affected by oculocutaneous albinism type Ia.

Albino patients are at great risk for developing cutaneous neoplasms, including melanomas. In this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type Ia (OCA-Ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. We propose managing these patients with dermoscopy, using the comparative approach, digital follow up (DFU), and reflectance confocal microscopy as a complementary tool for difficult cases.

Validation of an Extensive CYP2D6 Assay Panel Based on Invader and TaqMan Copy Number Assays.

BACKGROUND: CYP2D6 is involved in the oxidative metabolism of approximately 20% of all clinically used medications. Genotyping cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), is a challenge because of the high complexity of the locus. METHODS: Twenty-nine CYP2D6 sequence variants were genotyped in 50 deidentified patient samples and 29 Coriell DNAs by Invader assay, and results were compared with Infiniti assay and Sanger sequencing. To determine CYP2D6 copy number, 3 TaqMan real-time hydrolysis probes were used and results were compared with long-range PCR. Discrimination of the duplicated alleles was done on 17 DNA samples with 3 copies of CYP2D6 by long-range PCR followed by Invader genotyping and single nucleotide extension for the comparison. RESULTS: Complete concordance was observed for all samples between platforms except for 2 samples due to the lack of the *45 allele in the Infiniti panel. Reproducibility with the Invader assay and TaqMan copy number was 100%. Analytical sensitivity using DNA with 2 copies was determined to be 10 ng DNA for the Invader assay and 1 ng/µL DNA for the TaqMan assay, respectively. Complete concordance and reproducibility were observed for duplicated allele discrimination with the exception of 1 sample, determined to be *29/*43X2 by the Invader test and *1X2/*29 by the Infiniti method, which did not test for *43. CONCLUSIONS: This validation study showed that Invader and TaqMan assay combined panel provides an attractive, valid, highly accurate, and reproducible approach for CYP2D6 genotyping for clinical implementation.

The aging mouth: differentiating normal aging from disease.

Aging is the physiologic change that occurs over time. In humans, this change occurs at different rates and are related to lifestyle, environment and genetics. It can be challenging to differentiate normal aging from disease. In the oral cavity, with increasing age the teeth demonstrate wearing of the enamel, chipping and fracture lines, and a darker color. The pulp chamber and canals are reduced in size as a result of the deposition of secondary dentin. Coronal or root caries, however, represent disease. A limited amount of periodontal attachment loss occurs in association with aging, usually manifesting as recession on the buccal surface of teeth. Severe periodontitis occurs in 10.5-12% of the population, with the peak incidence being observed at 35-40 years of age. Changes to the mucosal tissue that occur with age include reduced wound-healing capacity. However, environmental factors, such as smoking, dramatically increase the risk of mucosal pathology. Reduced salivary gland function is often seen in association with medication usage, as well as with disorders such as diabetes mellitus. Both medication use and chronic disorders are more common in older adults. Masticatory function is of particular importance for older adults. Maintenance of a nutritionally complete diet is important for avoiding sarcopenia and the frailty syndrome. Successful oral aging is associated with adequate function and comfort. A reduced, but functional, dentition of 20 teeth in occlusion has been proposed as a measure of successful oral aging. Healthy oral aging is important to healthy aging from both biological and social perspectives.

Tooth loss as a predictor of shortened longevity: exploring the hypothesis.

Many factors contribute to human tooth loss, including oral hygiene practices, trauma, smoking, health status, socio-economic status and individual preferences. Loss of teeth impairs quality-of-life measures, including the eating of most foods that require full masticatory function. A recent study of centenarians found that at age 65-74 years, those who lived to be 100 had a lower rate of edentulism than did younger members of their birth cohort at ages 65-74 years. Oral health was consistent with compression of morbidity toward the end of life. This article explores the hypothesis that factors associated with oral disease and noncommunicable diseases may increase the risk of tooth loss and lead to diminished longevity as a result of multifactorial interactions. It specifically addresses two critical questions. The first is: 'Can we conclude that the number of teeth in aging humans can affect longevity and life expectancy?' The answer is yes. The second is: 'Is tooth loss a predictor of shortened longevity?' Again, the answer is yes. Edentulism and partial edentulism are discussed as a disability, and how the philosophy/belief systems of dental providers and patients toward retaining teeth influences the outcome of tooth loss is also examined. Osteoporosis and cognitive impairment provide examples of modifying risk factors.