Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program.

BACKGROUND: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). RESULTS: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics. CONCLUSIONS: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Analysis of gut microbiota diversity in Hashimoto's thyroiditis patients.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune disease. Recent studies have found that the gut microbiota may play an important role in inducing HT, but there are no systematic studies on the changes in the gut microbiota during the development of HT. METHODS: In this study, 16S rDNA high-throughput sequencing technology in combination with the Kruskal-Wallis test, CCA/RDA analysis, Spearman correlation analysis, and other statistical methods were used to analyze the effects of age, gender, hormones, and other environmental factors on gut microbiota by comparing the differences in the microbiota at different stages of HT development. RESULTS: The results showed that there were differences in the gut microbiota composition between healthy people (HCA) and in patients with HT. Lachnoclostridium, Bilophila, and Klebsiella were enriched in the HCA group, while Akkermansia, Lachnospiraceae, Bifidobacterium, Shuttleia, and Clostriworthdia were enriched in the HT group. Environmental factors analysis revealed that the Bifidobacterium and Klebsiella were two groups of bacteria that have undergone dramatic changes in HCA and HT, and mainly affected by gender. Romboutsia and Haemophilus regulated by the hormone of free triiodothyronine (FT3) may promote the development of HT, while Faecalibacterium and Lachnospiraceae regulated by free thyroxine (FT4) may protect the host. CONCLUSIONS: Comprehensive studies have shown that gender is an important factor affecting gut microbial composition, but with the development of HT, hormones, age, and TSH begin to become dominant factors.

Longitudinal assessment of colonoscopy adverse events in the prospective Cooperative Studies Program no. 380 colorectal cancer screening and surveillance cohort.

BACKGROUND AND AIMS: Data are limited regarding colonoscopy risk during long-term, programmatic colorectal cancer screening and follow-up. We aimed to describe adverse events during follow-up in a colonoscopy screening program after the baseline examination and examine factors associated with increased risk. METHODS: Cooperative Studies Program no. 380 includes 3121 asymptomatic veterans aged 50 to 75 years who underwent screening colonoscopy between 1994 and 1997. Periprocedure adverse events requiring significant intervention were defined as major events (other events were minor) and were tracked during follow-up for at least 10 years. Multivariable odds ratios (ORs) were calculated for factors associated with risk of follow-up adverse events. RESULTS: Of 3727 follow-up examinations in 1983 participants, adverse events occurred in 105 examinations (2.8%) in 93 individuals, including 22 major and 87 minor events (examinations may have had >1 event). Incidence of major events (per 1000 examinations) remained relatively stable over time, with 6.1 events at examination 2, 4.8 at examination 3, and 7.2 at examination 4. Examinations with major events included 1 perforation, 3 GI bleeds requiring intervention, and 17 cardiopulmonary events. History of prior colonoscopic adverse events was associated with increased risk of events (major or minor) during follow-up (OR, 2.7; 95% confidence interval, 1.6-4.6). CONCLUSIONS: Long-term programmatic screening and surveillance was safe, as major events were rare during follow-up. However, serious cardiopulmonary events were the most common major events. These results highlight the need for detailed assessments of comorbid conditions during routine clinical practice, which could help inform individual decisions regarding the utility of ongoing colonoscopy follow-up.

Ten or More Cumulative Lifetime Adenomas Are Associated with Increased Risk for Advanced Neoplasia and Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice. AIMS: We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy. METHODS: We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50-75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan-Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression. RESULTS: The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%-9.62%). Age 60-69 or 70-75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0-9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41-30.84), including CRC (OR 7.00; 95% CI 2.84-17.28), but not extra-colonic malignancies. CONCLUSIONS: Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas.

[White blood segmentation based on dual path and atrous spatial pyramid pooling].

The count and recognition of white blood cells in blood smear images play an important role in the diagnosis of blood diseases including leukemia. Traditional manual test results are easily disturbed by many factors. It is necessary to develop an automatic leukocyte analysis system to provide doctors with auxiliary diagnosis, and blood leukocyte segmentation is the basis of automatic analysis. In this paper, we improved the U-Net model and proposed a segmentation algorithm of leukocyte image based on dual path and atrous spatial pyramid pooling. Firstly, the dual path network was introduced into the feature encoder to extract multi-scale leukocyte features, and the atrous spatial pyramid pooling was used to enhance the feature extraction ability of the network. Then the feature decoder composed of convolution and deconvolution was used to restore the segmented target to the original image size to realize the pixel level segmentation of blood leukocytes. Finally, qualitative and quantitative experiments were carried out on three leukocyte data sets to verify the effectiveness of the algorithm. The results showed that compared with other representative algorithms, the proposed blood leukocyte segmentation algorithm had better segmentation results, and the mIoU value could reach more than 0.97. It is hoped that the method could be conducive to the automatic auxiliary diagnosis of blood diseases in the future.

Baseline Colonoscopy Findings Associated With 10-Year Outcomes in a Screening Cohort Undergoing Colonoscopy Surveillance.

BACKGROUND & AIMS: Few studies have evaluated long-term outcomes of ongoing colonoscopic screening and surveillance in a screening population. We aimed to determine the 10-year risk for advanced neoplasia (defined as adenomas ≥10mm, adenomas with villous histology or high-grade dysplasia, or colorectal cancer [CRC]) and assessed whether baseline colonoscopy findings were associated with long-term outcomes. METHODS: We collected data from the Department of Veterans Affairs Cooperative Studies Program Study on 3121 asymptomatic veterans (50-75 years old) who underwent a screening colonoscopy from 1994 through 1997 at 13 medical centers and were then followed for 10 years or until death. We included 1915 subjects with at least 1 surveillance colonoscopy and estimated cumulative incidence of advanced neoplasia by Kaplan-Meier curves. We then fit a longitudinal joint model to estimate risk of advanced neoplasia at each subsequent examination after baseline, adjusting for multiple colonoscopies within individuals. RESULTS: Through 10 years of follow-up, there were 146 individuals among all baseline colonoscopy groups found to have at least 1 incident advanced neoplasia. The cumulative 10-year incidence of advanced neoplasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with baseline advanced adenoma (AA) (21.9%; 95% CI 15.7-28.1). The cumulative 10-year incidence of advanced neoplasia was 6.3% (95% CI 4.1%-8.5%) and 4.1% (95% CI 2.7%-5.4%) for baseline 1 to 2 small adenomas (<1cm, and without villous histology or high-grade dysplasia) and no neoplasia, respectively (log-rank P = .10). After adjusting for prior surveillance, the risk of advanced neoplasia at each subsequent examination was not significantly increased in veterans with 1 or 2 small adenomas at baseline (odds ratio 0.96; 95% CI 0.67-1.41) compared with veterans with no baseline neoplasia. CONCLUSIONS: Baseline screening colonoscopy findings associate with advanced neoplasia within 10 years. Individuals with only 1 or 2 small adenomas at baseline have a low risk of advanced neoplasia over 10 years. Alternative surveillance strategies, could be considered for these individuals.

Evaluation of the Effect of Hemolysis on Quantitative Chemiluminescent Immunoassay Results for 10 Analytes.

BACKGROUND: The aim is to evaluate the effect of hemolysis on the quantitative chemiluminescent immunoassay results of 10 analytes and to provide a basis for formulating specific sample rejection criteria and reviewing report results. METHODS: Hemolysis based on the clinical hemolysis index, hemolysis 1+, 2+, and 3+ samples and matched normal samples were collected. The quantitative chemiluminescent immunoassay results of 10 analytes from the two samples (hemolysis and normal) were determined and differences between the results obtained from samples with different degrees of hemolysis and those obtained from normal samples were evaluated. RESULTS: A total of 34 pairs of samples were collected, including 10 pairs of 1+ hemolysis samples, 10 pairs of 2+ hemolysis samples, and 14 pairs of 3+ hemolysis samples. The quantitative chemiluminescence immunoassay detection results for the 10 analytes showed that regardless of the degree of hemolysis, the differences in alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA19-9), luteinizing hormone (LH), folli-cle-stimulating hormone (FSH), and ferritin (FER) between the hemolysis and normal samples were all lower than the total allowable error (TEa) based on biological variation; there were no statistically significant differences between the samples. However, the results for insulin (INS) began to decrease significantly at a hemolytic index of 1+, folic acid (FOL) showed an increase at a hemolytic index of 2+, and there was a significant difference at a he-molytic index of 3+. CONCLUSIONS: This research identified the analytes that are susceptible to hemolysis interference in chemiluminescent immunoassays. The influence of hemolysis on hemolytic clinical laboratory tests was closely related to the assay system used; thus, laboratories should evaluate the effect of hemolysis on their own analysis systems and define assay-specific hemolysis warning indices.

Evaluation of Disease Activity of Systemic Lupus Erythematosus by D-dimer Combined with Red Blood Cell Distribution Width.

BACKGROUND: To investigate the value of D-dimer combined with red blood cell distribution width (RDW) in evaluating the disease activity of systemic lupus erythematosus (SLE). METHODS: A total of 105 SLE patients confirmed in our hospital from July 2018 to September 2020 were collected as the SLE group, and 60 healthy persons matched in age and gender during the same period were collected as the control group. According to the SLEDAI score, SLE patients were divided into SLE active group and SLE inactive group, and RDW and D-Dimer levels were detected. RESULTS: The level of RDW in the SLE active group [14.8 (13.4, 16.8)] was significantly higher than that in the SLE inactive group [13.4 (12.6, 14.37)] and control group [12.3 (12, 12.7)], with statistically significant differences (p < 0.05). The D-dimer level in the SLE active group was 1.36 (0.9, 2.25) mg/L, which was significantly higher than that in SLE inactive group [0.34 (0.22, 0.52)] mg/L and control group [0.15 (0.08, 0.19)] mg/L, with statistically significant differences (p < 0.05). Both RDW and D-dimer were positively correlated with the SLEDAI score (r = 0.393, p = 0.000), (r = 0.483, p = 0.000). The results of receiver operating characteristic curve showed that the area under the curve of RDW and D-Dimer alone was 0.875 and 0.954, respectively, while the area under the curve of RDW combined with D-Dimer was the largest, 0.984. CONCLUSIONS: The levels of RDW and D-dimer are closely related to the disease activity of SLE patients, and RDW combined with D-dimer is more valuable in assessing the disease activity of SLE patients.

High-Risk Adenomas at Screening Colonoscopy Remain Predictive of Future High-Risk Adenomas Despite an Intervening Negative Colonoscopy.

INTRODUCTION: Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS: We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS: HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION: In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

Diagnostic value of urinary microprotein concentration for patients with negative urinary protein test results and positive urinary casts on microscopic examination.

OBJECTIVE: To analyze the association between positive urinary casts on microscopic examination and urinary microprotein concentration in the case of negative urinary protein test results. This study also investigated the diagnostic value of urinary microprotein examination. SUBJECTS: A total of 949 samples that were analyzed with a UF-1000i Urine Analyzer and returned cast alarm results were categorized into two groups, a positive and negative group, according to qualitative urinary protein sulfosalicylic acid test results. Then, 54 samples with negative protein test results but positive cast results according to microscopic examination were selected as the study group; 60 normal people with healthy physical examination results were selected as the control group. Both groups underwent urinary microprotein tests, including urinary microalbumin (mAlb), α1-microglobulin (A1M), transferrin (TRU), and immunoglobulin G (IgG). T tests were used to evaluate mean differences between groups and chi-square tests were used to calculate ratio differences between groups. RESULTS: (a) Microscopic examinations of the positive and negative protein groups revealed no statistically significant difference in cast detection rate (P = .421). (b) Among the 54 samples in the study group, 37 were found to have abnormal casts, while in the remaining 17 samples, only hyaline casts were detected. (c) The detection levels of mAlb, A1M, and IgG in the study group were significantly higher than the control group (P values < .05). CONCLUSION: Urinary microprotein test should be included in the re-examination rules for routine tests for patients with negative protein results and positive casts under microscopic examination.

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.

Association of the NQO1 C609T polymorphism with Alzheimer's disease in Chinese populations: a meta-analysis.

Several molecular genetics studies have investigated the association of NQO1 C609T polymorphism with Alzheimer's disease (AD) susceptibility in Chinese populations; however, the findings are inconclusive. To investigate the association, we performed the present meta-analysis of 5 case-control studies (including 735 AD cases and 828 controls). We searched literature from PubMed, Embase, HuGNet and CNKI databases for eligible articles that evaluated the association between NQO1 C609T polymorphism and AD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association. Overall, C609T polymorphism was significantly associated with an increased AD risk (homozygote: OR = 1.87, 95% CI = 1.39-2.51, P = 0.000; heterozygote: OR = 1.93, 95% CI = 1.22-3.06, P = 0.019; dominant: OR = 1.97, 95% CI = 1.25-3.12, P = 0.004). When stratified by source of control, significant results were observed in subjects of population-based (PB), whereas no increased risk was observed among the hospital-based (HB). When stratified by APOEϵ4 carrier status, no effect of the NQO1 C609T polymorphism was seen in subjects of APOEϵ4 carriers and APOEϵ4 non-carriers. In conclusion, our results showed that NQO1 C609T polymorphism increases the risk of AD in Chinese populations. Larger studies with different ethnic populations are required to validate our findings.

Gut microbiota and its metabolic products in acute respiratory distress syndrome.

The prevalence rate of acute respiratory distress syndrome (ARDS) is estimated at approximately 10% in critically ill patients worldwide, with the mortality rate ranging from 17% to 39%. Currently, ARDS mortality is usually higher in patients with COVID-19, giving another challenge for ARDS treatment. However, the treatment efficacy for ARDS is far from satisfactory. The relationship between the gut microbiota and ARDS has been substantiated by relevant scientific studies. ARDS not only changes the distribution of gut microbiota, but also influences intestinal mucosal barrier through the alteration of gut microbiota. The modulation of gut microbiota can impact the onset and progression of ARDS by triggering dysfunctions in inflammatory response and immune cells, oxidative stress, cell apoptosis, autophagy, pyroptosis, and ferroptosis mechanisms. Meanwhile, ARDS may also influence the distribution of metabolic products of gut microbiota. In this review, we focus on the impact of ARDS on gut microbiota and how the alteration of gut microbiota further influences the immune function, cellular functions and related signaling pathways during ARDS. The roles of gut microbiota-derived metabolites in the development and occurrence of ARDS are also discussed.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Association between Interleukin-4-590C>T Polymorphism and the Susceptibility to Asthma: A Meta-Analysis of Case-Control Study.

This study was aimed to investigate the relationship between the interleukin-4-590C > T gene polymorphism and the susceptibility to asthma by meta-analysis. To explore the underlying relationship between the polymorphism of IL-4-590C > T and the susceptibility to asthma, this study systematically retrieved the literature including cohort studies and case-control studies published before June 2019 in PubMed, Embase, and Cochrane Library. Data on the odds ratio (OR) and 95% confidence interval (CI) of the literature were included in the relative studies. Subsequently, the included data were weighted by an inverse variance and then analyzed by the fixed or random effects model. Overall, 818 asthma patients and 831 healthy individuals participated in the 8 independent case-control studies in the current meta-analysis. There was no correlation between IL-4-590C > T TT genotype and the increased susceptibility to asthma (dominant model: OR = 1.31, 95% CI = 0.68-2.53). Subgroup analysis by ethnicity showed no significant results in the Asians (OR = 1.28, 95% CI = 0.24-6.80); however, IL-4-590C > T TT genotype significantly elevated the susceptibility to asthma in the Caucasians (OR = 1.43, 95%CI = 1.03-1.98). Meanwhile, subgroup analysis was performed by source of control. A statistically significant result was found in the population-based control group (OR = 1.33, 95% CI = 1.01-1.76), but not in the hospital-based control group (OR = 1.22, 95% CI = 0.27-5.46). The results demonstrated that IL-4-590C > T TT genotype could significantly enhance the susceptibility to asthma in Caucasians without increasing that in Asian populations. However, it still required a large sample of high-quality studies in multicentral hospital to further confirm its reliability.

Screening Colonoscopy Findings Are Associated With Noncolorectal Cancer Mortality.

INTRODUCTION: Controversy exists regarding the impact of various risk factors on noncolorectal cancer (CRC) mortality in healthy screening populations. We examined the impact of known CRC risk factors, including baseline colonoscopy findings, on non-CRC mortality in a screening population. METHODS: Cooperative Studies Program (CSP) #380 is comprised of 3,121 veterans aged 50-75 years who underwent screening colonoscopy from 1994 to 97 and were then followed for at least 10 years or until death. Hazard ratios (HRs) for risk factors on non-CRC mortality were estimated by multivariate Cox proportional hazards. RESULTS: Current smoking (HR 2.12, 95% confidence interval [CI] 1.78-2.52, compared with nonsmokers) and physical activity (HR 0.89, 95% CI 0.84-0.93) were the modifiable factors most associated with non-CRC mortality in CSP#380. In addition, compared with no neoplasia at baseline colonoscopy, non-CRC mortality was higher in participants with ≥3 small adenomas (HR 1.43, 95% CI 1.06-1.94), advanced adenomas (HR 1.32, 95% CI 0.99-1.75), and CRC (HR 2.95, 95% CI 0.98-8.85). Those with 1-2 small adenomas were not at increased risk for non-CRC mortality (HR 1.15, 95% CI 0.94-1.4). DISCUSSION: In a CRC screening population, known modifiable risk factors were significantly associated with 10-year non-CRC mortality. Furthermore, those who died from non-CRC causes within 10 years were more likely to have had high-risk findings at baseline colonoscopy. These results suggest that advanced colonoscopy findings may be a risk marker of poor health outcomes. Integrated efforts are needed to motivate healthy lifestyle changes during CRC screening, particularly in those with high-risk colonoscopy findings and unaddressed risk factors.

Ordered subset analysis for case-control studies.

Genetic heterogeneity, which may manifest on a population level as different frequencies of a specific disease susceptibility allele in different subsets of patients, is a common problem for candidate gene and genome-wide association studies of complex human diseases. The ordered subset analysis (OSA) was originally developed as a method to reduce genetic heterogeneity in the context of family-based linkage studies. Here, we have extended a previously proposed method (OSACC) for applying the OSA methodology to case-control datasets. We have evaluated the type I error and power of different OSACC permutation tests with an extensive simulation study. Case-control datasets were generated under two different models by which continuous clinical or environmental covariates may influence the relationship between susceptibility genotypes and disease risk. Our results demonstrate that OSACC is more powerful under some disease models than the commonly used trend test and a previously proposed joint test of main genetic and gene-environment interaction effects. An additional unique benefit of OSACC is its ability to identify a more informative subset of cases that may be subjected to more detailed molecular analysis, such as DNA sequencing of selected genomic regions to detect functional variants in linkage disequilibrium with the associated polymorphism. The OSACC-identified covariate threshold may also improve the power of an additional dataset to replicate previously reported associations that may only be detectable in a fraction of the original and replication datasets. In summary, we have demonstrated that OSACC is a useful method for improving SNP association signals in genetically heterogeneous datasets.

Myocilin mutations in black South Africans with POAG.

PURPOSE: Myocilin (MYOC) mutations are associated with primary open-angle glaucoma (POAG) in multiple populations. Here we examined the role of MYOC mutations in a black South African population with primary open-angle glaucoma (POAG). METHODS: Unrelated black South African subjects with POAG and unaffected controls were recruited from the St. John Eye Hospital (Soweto, Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa). A complete eye examination including visual field assessment was performed in all subjects. Blood samples were obtained for DNA extraction. The complete coding region of MYOC was sequenced using the PCR-based Sanger method. Identified mutations were compared to known MYOC mutations. RESULTS: One hundred-thirteen POAG cases and 131 controls were recruited for analysis. A total of 19 variants were observed. Probable glaucoma-causing mutations were observed in 4.4% of POAG cases. A previously reported glaucoma-causing mutation, Tyr453MetfsX11, was observed in three cases and one control. Two other sequence variants, Gly374Val and Lys500Arg, occurred only in cases. Other sequence variants, including 6 novel variants, occurred in at least one control. CONCLUSIONS: A small minority of black South Africans with POAG carry MYOC mutations. The Gly374Val mutation might represent a novel glaucoma-causing mutation. The Tyr453MetFSX11 mutation appears to be a glaucoma-causing mutation with incomplete penetrance.

Assessment of LD matrix measures for the analysis of biological pathway association.

Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression (Wang et al., 2008). To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis). In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r=0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.