Purpose: Higher socioeconomic status (SES) men are at higher risk of prostate cancer (PCa) diagnosis, an association commonly interpreted as a function of higher rates of prostate screening among ...higher SES men. However, the extent to which screening explains this association has not been well quantified. Methods: Within a Detroit area cohort of 6,692 men followed up after a benign prostate procedure, a case–control study was conducted of 494 PCa cases and controls matched on age, race, duration of follow-up, and date of initial benign finding; 2000 Census data were used in a principal component analysis to derive a single factor, labeled the neighborhood SES index (NSESI), representing zip code-level SES. Results: Among cases, higher SES was associated with a younger age at initial biopsy: −1.48 years (95 % CI, −2.32, −0.64) per unit NSESI. After adjustment for confounders and duration of follow-up, higher SES was associated with more PSA tests and DRE during follow-up; 9 % (95 % CI, 2, 16) and 8 % (95 % CI, 1, 15) more respectively, per unit NSESI. Higher SES was associated with a higher risk of PCa diagnosis during follow-up, multivariable adjusted OR = 1.26 per unit increase in NSESI (95 % CI, 1.04, 1.49). Further adjustment for screening frequency somewhat reduced the association between SES and PCa risk (OR = 1.19 per unit NSESI, 95 % CI, 0.98, 1.44). Conclusions: Differences in screening frequency only partially explained the association between higher zip code SES and PCa risk; other health care-related factors should also be considered as explanatory factors.
Despite convincing evidence that 2‐amino‐1‐methyl‐6‐phenylimidazo4,5‐bpyridine (PhIP)—a heterocyclic amine generated by cooking meats at high temperatures—is carcinogenic in animal models, it remains ...unclear whether PhIP exposure leads to increased cancer risk in humans. PhIP‐DNA adduct levels were measured in specimens from 534 prostate cancer case‐control pairs nested within a historical cohort of men with histopathologically benign prostate specimens. We estimated the overall and race‐stratified risk of subsequent prostate cancer associated with higher adduct levels. PhIP‐DNA adduct levels in benign prostate were significantly higher in Whites than African Americans (0.274 optical density units (OD) ±0.059 vs. 0.256 OD ±0.054; p<0.0001). Prostate cancer risk for men in the highest quartile of PhIP‐DNA adduct levels was modestly increased odds ratio (OR) = 1.25; 95% confidence interval (CI) = 0.76–2.07. In subset analyses, the highest risk estimates were observed in White patients diagnosed more than 4 years after cohort entry (OR = 2.74; 95% CI = 1.01–7.42) or under age 65 (OR = 2.80; 95% CI = 0.87–8.97). In Whites, cancer risk associated with high‐grade prostatic intraepithelial neoplasia combined with elevated PhIP‐DNA adduct levels (OR = 3.89; 95% CI = 1.56–9.73) was greater than risk associated with either factor alone. Overall, elevated levels of PhIP‐DNA adducts do not significantly increase prostate cancer risk. However, our data show that White men have higher PhIP‐DNA adduct levels in benign prostate tissue than African American men, and suggest that in certain subgroups of White men high PhIP‐DNA adduct levels may predispose to an increased risk for prostate cancer.
What's new?
While exposure to high levels of PhIP (2‐amino‐1‐methyl‐6‐phenylimidazo4,5‐bpyridine)—a heterocyclic amine found in cooked meat—is associated with the development of prostate malignancies in animals, it is unclear whether this same risk exists in humans. Here, risk of prostate cancer in men was found to be increased only in the presence of both glandular inflammation and elevated levels of PhIP‐DNA adducts, based on analysis of benign prostate specimens. However, certain subgroups of White males, who had higher PhIP‐DNA adduct levels than African Americans, may be at greater risk for the disease. Given the putative role of inflammation in cancer, targeted prevention strategies in men with known high PhIP exposure levels may lead to beneficial health outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
BACKGROUND
Obesity is associated with risk of aggressive prostate cancer (PCa), but not with over‐all PCa risk. However, obese men have larger prostates which may lower biopsy accuracy and cause a ...systematic bias toward the null in epidemiologic studies of over‐all risk.
METHODS
Within a cohort of 6692 men followed‐up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case‐control study was conducted of 495 prostate cancer cases and controls matched on age, race, follow‐up duration, biopsy versus TURP, and procedure date. Data on body mass index and prostate volume at the time of the initial procedure were ed from medical records.
RESULTS
Prior to consideration of differences in prostate volume, overweight (OR = 1.41; 95%CI 1.01, 1.97), and obese status (OR = 1.59; 95%CI 1.09, 2.33) at the time of the original benign biopsy or TURP were associated with PCa incidence during follow‐up. Prostate volume did not significantly moderate the association between body‐size and PCa, however it did act as an inverse confounder; adjustment for prostate volume increased the effect size for overweight by 22% (adjusted OR = 1.52; 95%CI 1.08, 2.14) and for obese status by 23% (adjusted OR = 1.77; 95%CI 1.20, 2.62). Larger prostate volume at the time of the original benign biopsy or TURP was inversely associated with PCa incidence during follow‐up (OR = 0.92 per 10 cc difference in volume; 95%CI 0.88, 0.97). In analyses that stratified case‐control pairs by tumor aggressiveness of the case, prostate volume acted as an inverse confounder in analyses of non‐aggressive PCa but not in analyses of aggressive PCa.
CONCLUSIONS
In studies of obesity and PCa, differences in prostate volume cause a bias toward the null, particularly in analyses of non‐aggressive PCa. A pervasive underestimation of the association between obesity and overall PCa risk may exist in the literature.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP ...markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Past research suggests that environmental factors may be associated with sarcoidosis risk. We conducted a case control study to test a priori hypotheses that environmental and occupational exposures ...are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-, race-, and sex-matched control subjects. Interviewers administered questionnaires containing questions regarding occupational and nonoccupational exposures that we assessed in univariable and multivariable analyses. We observed positive associations between sarcoidosis and specific occupations (e.g., agricultural employment, odds ratio OR 1.46, confidence interval CI 1.13-1.89), exposures (e.g., insecticides at work, OR 1.52, CI 1.14-2.04, and work environments with mold/mildew exposures environments with possible exposures to microbial bioaerosols, OR 1.61, CI 1.13-2.31). A history of ever smoking cigarettes was less frequent among cases than control subjects (OR 0.62, CI 0.50-0.77). In multivariable modeling, we observed elevated ORs for work in areas with musty odors (OR 1.62, CI 1.24-2.11) and with occupational exposure to insecticides (OR 1.61, CI 1.13-2.28), and a decreased OR related to ever smoking cigarettes (OR 0.65, CI 0.51-0.82). The study did not identify a single, predominant cause of sarcoidosis. We identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment, and microbial bioaerosols.
HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis ...susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio OR, 2.11; 95% confidence interval CI, 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.
Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and ...non-Löfgren's syndrome (non-LS).
A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (
= 3,843), Germany (
= 3,342), and the United States (
= 2,918), followed by an SNP lookup in the UK Biobank (UKB,
= 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex.
We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and
. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified.
Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.
Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate ...cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The etiology of many complex diseases involves both environmental exposures and inherited genetic predisposition as well as interactions between them. Gene–environment‐wide interaction studies ...(GEWIS) provide a means to identify the interactions between genetic variation and environmental exposures that underlie disease risk. However, current GEWIS methods lack the capability to adjust for the potentially complex correlations in studies with varying degrees of relationships (both known and unknown) among individuals in admixed populations. We developed novel generalized estimating equation (GEE) based methods—GEE‐adaptive and GEE‐joint—to account for phenotypic correlations due to kinship while accounting for covariates, including, measures of genome‐wide ancestry. In simulation studies of admixed individuals, both methods controlled family‐wise error rates, an advantage over the case‐only approach. They demonstrated higher power than traditional case–control methods across a wide range of underlying alternative hypotheses, especially where both marginal and interaction effects were present. We applied the proposed method to conduct a GEWIS of a known sarcoidosis risk factor (insecticide exposure) and risk of sarcoidosis in African Americans and identified two novel loci with suggestive evidence of G × E interaction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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