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Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

Background: The vaginal microbiome has been associated with adverse pregnancy outcomes, but information on the impact of diet on microbiome composition is largely unexamined. Objective: To estimate the association between prenatal diet and vaginal microbiota composition overall and by race. Methods: We leveraged a racially diverse prenatal cohort of North Carolina women enrolled between 1995 and 2001 to conduct this analysis using cross‐sectional data. Women completed food frequency questionnaires about diet in the previous 3 months and foods were categorised into subgroups: fruits, vegetables, nuts/seeds, whole grains, low‐fat dairy, sweetened beverages and red meat. We additionally assessed dietary vitamin D, fibre and yogurt consumption. Stored vaginal swabs collected in mid‐pregnancy were sequenced using 16S taxonomic profiling. Women were categorised into three groups based on predominance of species: Lactobacillus iners, Lactobacillus miscellaneous and Bacterial Vaginosis (BV)‐associated bacteria. Adjusted Poisson models with robust variance estimators were run to assess the risk of being in a specific vagitype compared to the referent. Race‐stratified models (Black/White) were also run. Results: In this study of 634 women, higher consumption of dairy was associated with increased likelihood of membership in the L. crispatus group compared to the L. iners group in a dose‐dependent manner (risk ratio quartile 4 vs. 1: 2.01, 95% confidence interval 1.36, 2.95). Increased intake of fruit, vitamin D, fibre and yogurt was also associated with increased likelihood of membership in L. crispatus compared to L. iners, but only among black women. Statistical heterogeneity was only detected for fibre intake. There were no detected associations between any other food groups or risk of membership in the BV group. Conclusions: Higher consumption of low‐fat dairy was associated with increased likelihood of membership in a beneficial vagitype, potentially driven by probiotics. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene-environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn's disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls. Subjects and methods: Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs). Results: A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls. Conclusion: This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene-environment interactions in complex chronic conditions such as CD. [ABSTRACT FROM AUTHOR]

Background As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100™). Methods 105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types. Results 20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes. Conclusions There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of potential blood biomarkers. [ABSTRACT FROM AUTHOR]

Background: The Internet has successfully been used for patient-oriented survey research. Internet-based translational research may also be possible. Objective: Our aim was to study the feasibility of collecting biospecimens from CCFA Partners, an Internet-based inflammatory bowel disease (IBD) cohort. Methods: From August 20, 2013, to January 4, 2014, we randomly sampled 412 participants, plus 179 from a prior validation study, and invited them to contribute a biospecimen. Participants were randomized to type (blood, saliva), incentive (none, US $20, or US $50), and collection method for blood. The first 82 contributors were also invited to contribute stool. We used descriptive statistics and t tests for comparisons. Results: Of the 591 participants, 239 (40.4%) indicated interest and 171 (28.9%) contributed a biospecimen. Validation study participants were more likely to contribute than randomly selected participants (44% versus 23%, P<.001). The return rate for saliva was higher than blood collected by mobile phlebotomist and at doctors' offices (38%, 31%, and 17% respectively, P<.001). For saliva, incentives were associated with higher return rates (43-44% versus 26%, P=.04); 61% contributed stool. Fourteen IBD-associated single nucleotide polymorphisms were genotyped, and risk allele frequencies were comparable to other large IBD populations. Bacterial DNA was successfully extracted from stool samples and was of sufficient quality to permit quantitative polymerase chain reaction for total bacteria. Conclusions: Participants are willing to contribute and it is feasible to collect biospecimens from an Internet-based IBD cohort. Home saliva kits yielded the highest return rate, though mobile phlebotomy was also effective. All samples were sufficient for genetic testing. These data support the feasibility of developing a centralized collection of biospecimens from this cohort to facilitate IBD translational studies. [ABSTRACT FROM AUTHOR]

Background: Rapid growth in the number of US cancer survivors drives the need for ongoing research efforts to improve outcomes and experiences after cancer. In this study, we describe the University of North Carolina (UNC) Cancer Survivorship Cohort, a medical center-based cohort of adults with cancer that integrates medical record-abstracted cancer information, patient-reported outcomes, and biological specimens., Methods: Participants ages 18+ were recruited from UNC oncology clinics between April 2010 and August 2016. After enrollment, participants completed questionnaires on a range of topics including demographics, health history, healthcare access and utilization, quality of life, and symptoms. Blood samples and tumor tissue specimens were collected and processed by study staff, and cancer characteristics and other clinical data were abstracted from electronic medical records. Participants consented to recontact for future studies and linkage of their data with other data resources., Results: In total, 3,999 participants with a cancer diagnosis were enrolled in the cohort. The most common cancer types among those enrolled included breast (N = 866), uterine (N = 458), colorectal (N = 300), prostate (N = 296), and head and neck (N = 248) cancers. Blood specimens were collected for 3,027 participants (76%). Additional participants without cancer (N = 1,299) were also enrolled, and the majority (62%) provided biospecimen samples., Conclusions: We encourage a wide collaboration with investigators across institutions seeking to advance research in cancer survivorship. Procedures are in place to support proposals for use of existing or linked data and for proposals that require participant recontact or analysis of biospecimens., Impact: The UNC Cancer Survivorship Cohort is a unique resource for cancer survivorship research., (©2024 American Association for Cancer Research.)

Early childhood caries (ECC) is a biofilm-mediated disease. Social, environmental, and behavioral determinants as well as innate susceptibility are major influences on its incidence; however, from a pathogenetic standpoint, the disease is defined and driven by oral dysbiosis. In other words, the disease occurs when the natural equilibrium between the host and its oral microbiome shifts toward states that promote demineralization at the biofilm-tooth surface interface. Thus, a comprehensive understanding of dental caries as a disease requires the characterization of both the composition and the function or metabolic activity of the supragingival biofilm according to well-defined clinical statuses. However, taxonomic and functional information of the supragingival biofilm is rarely available in clinical cohorts, and its collection presents unique challenges among very young children. This paper presents a protocol and pipelines available for the conduct of supragingival biofilm microbiome studies among children in the primary dentition, that has been designed in the context of a large-scale population-based genetic epidemiologic study of ECC. The protocol is being developed for the collection of two supragingival biofilm samples from the maxillary primary dentition, enabling downstream taxonomic (e.g., metagenomics) and functional (e.g., transcriptomics and metabolomics) analyses. The protocol is being implemented in the assembly of a pediatric precision medicine cohort comprising over 6000 participants to date, contributing social, environmental, behavioral, clinical, and biological data informing ECC and other oral health outcomes.

Oral health and disease are known to be influenced by complex interactions between environmental (e.g., social and behavioral) factors and innate susceptibility. Although the exact contribution of genomics and other layers of "omics" to oral health is an area of active research, it is well established that the susceptibility to dental caries, periodontal disease, and other oral and craniofacial traits is substantially influenced by the human genome. A comprehensive understanding of these genomic factors is necessary for the realization of precision medicine in the oral health domain. To aid in this direction, the advent and increasing affordability of high-throughput genotyping has enabled the simultaneous interrogation of millions of genetic polymorphisms for association with oral and craniofacial traits. Specifically, genome-wide association studies (GWAS) of dental caries and periodontal disease have provided initial insights into novel loci and biological processes plausibly implicated in these two common, complex, biofilm-mediated diseases. This paper presents a summary of protocols, methods, tools, and pipelines for the conduct of GWAS of dental caries, periodontal disease, and related traits. The protocol begins with the consideration of different traits for both diseases and outlines procedures for genotyping, quality control, adjustment for population stratification, heritability and association analyses, annotation, reporting, and interpretation. Methods and tools available for GWAS are being constantly updated and improved; with this in mind, the presented approaches have been successfully applied in numerous GWAS and meta-analyses among tens of thousands of individuals, including dental traits such as dental caries and periodontal disease. As such, they can serve as a guide or template for future genomic investigations of these and other traits.

The purpose of the study reported here was to identify, by size, a set of microsatellite markers for use in diagnostic genetic monitoring of FVB/N mouse colonies. A large panel of microsatellite markers were chosen on the basis oftheir high degree of allelic variability. These markers were then tested for their ability to amplify well under a standard set of polymerase chain reaction analysis conditions and to present an easily identifiable band on an agarose gel. From this panel, we chose at least one marker on each chromosome that amplified well under our standard high-throughput conditions. Using this approach, we identified the allele sizes for 27 microsatellite markers in the FVB/N strain of mice. Each autosomal chromosome and the X chromosome were analyzed using at least one locus marker. We have determined a precise size for FVB/N microsatellite alleles, as opposed to a description of size in relation to that of a known allele.