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Additional file 1: SupplementaryTable 1. Known risk-associated SNPs for colorectal canceravailable from Affymetrix Axiom™Biobank Plus Genotyping Array.

Background: SNP-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. Methods: We randomly selected 1,769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of 1.5 were categorized as low, average and elevated risk.Results: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, ppp-trend pConclusions: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

INTRODUCTION AND OBJECTIVE:About 38% of kidney cancer risk can be attributed to inherited factors. Several candidate kidney cancer susceptibility genes have been proposed. However, statistical evid...

Background: B7-H3 (CD276, PD-L3) is an immunomodulatory molecule highly expressed in prostate cancer and belonging to the B7 superfamily that also includes PD-L1 (B7-H1). Immunotherapies (antibodies, antibody-drug conjugates, and CAR-T cells) targeting B7-H3 are currently in clinical trials; thus elucidating the clinical, molecular and tumor immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. Methods: We developed an automated, clinical-grade immunohistochemistry assay to digitally quantify B7-H3 protein expression across two racially diverse cohorts of primary prostate cancer (including one with previously reported transcriptomic data), a set of prostatic neuroendocrine small cell carcinoma, and pre- and post-treatment tumor tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression is significantly lower in self-identified Black patients and inversely correlates with percent African ancestry by ancestry-informative markers. This association with race is independent of the significant association of B7-H3 expression with ERG/ETS and PTEN status. CD276 mRNA level, but not B7-H3 protein expression, is significantly correlated with regulatory (FOXP3+) T-cell density. Finally, androgen receptor activity (AR-A) scores are significantly correlated with CD276 mRNA expression, and neoadjuvant intensive hormonal therapy is associated with a significant decrease in B7-H3 protein expression. Conclusion: These data underscore the importance of studying racially and molecularly diverse prostate cancer cohorts in the era of immunotherapy. Our study is among the first to use genetic ancestry markers to add to emerging evidence that prostate tumors from men of African ancestry may have a distinct immune milieu associated with B7-H3 expression. Citation Format: Adrianna A. Mendes, Jiayun Lu, Harsimar B Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, Karen S. Sfanos, Janielle Maynard, Ashley E. Ross, Steven P. Balk, Mary-Ellen Taplin, Emmanuel S. Antonarakis, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan. Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-100.

African-American (AA) men are more likely to be diagnosed with and to die of prostate cancer than their European-American counterparts. Much of this disparity is due to access to care and social determinants of health; however, there is emerging evidence of molecular differences in prostate tumors arising in patients of different genetic ancestry. We investigated the copy number landscape of 290 grade and race-matched primary prostate tumors through interrogation of Infinium MethylationEPIC Array (Illumina) data derived from primary prostate tumors at radical prostatectomy. Our cohort was composed of 145 self-identified AA patients and 145 self-identified EA surgically-treated patients with accompanying genetic ancestry estimation via SNP array (GSAv3). EPIC array-derived copy number data estimated through the Conumee package on R was significantly correlated with genomic losses and gains identified by exome sequencing of a panel with 100 cancer driver genes. We also observed a significant association between genomic losses of the PTEN gene and PTEN protein loss by immunohistochemistry (P80k coding and non-coding regions from FANTOM CAT. Adjusted LIMMA models with age, Gleason Grade Group, and pre-operative PSA levels showed significant copy number differences by percent African ancestry in chromosomes 6p, 10q, 11p, 12p, and 17p. PTEN losses (as expected) and WT1 gains were more frequent in patients with lower percent African ancestry. Gene expression data from TCGA data showed that WT1 expression was significantly increased for self-identified EA patients. Multivariable Cox regression models adjusted for age, Gleason Grade Group, and pre-operative PSA levels revealed that chromosome 8q gains (including MYC, GRHL2, and FZD6) were significantly associated with biochemical recurrence and metastasis. However, when we stratified the models by self-identified race, only AA tumors showed significant associations with 8q gains and poor outcome. Further in silico and mechanistic validation will be conducted to confirm whether chromosome 8 gains may be a potential biomarker for prostate cancer outcome in AA men. Citation Format: Thiago Vidotto, Eddie Imada, Farzana Faizal, Siqun Zheng, Jianfeng Xu, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan. Copy number landscape of primary African-American and European-American prostate tumors [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-146.

The heart sound is the characteristic signal of cardiovascular health status. The objective of this project is to explore the correlation between Wavelet Transform and noise performance of heart sound and the adaptability of classifying heart sound using bispectrum estimation. Since the wavelet has multi-scale and multi-resolution characteristics, in this paper, the heart sound signal with different frequency ranges is decomposed through wavelet and displayed on different scales of the resolving wavelet result. According to distribution features of frequency of heart sound signals, the interference components in heart sound signal can be eliminated by selecting reconstruction coefficients. Comparing de-noising effects of four wavelets which are haar, db6, sym8 and coif6, the db6 wavelet has achieved an optimal denoising effect to heart sound signals. The de-noising result of contrasting different layers in the db6 wavelet shows that decomposing with five layers in db6 provide the optimal performance. In practice, the db6 wavelet also shows commendable denoising effects when applying to 51 clinical heart signals. Furthermore, through the clinic analyses of 29 normal signals from healthy people and 22 abnormal heart signals from coronary heart disease patients, this method can fairly distinguish abnormal signals from normal signals by applying bispectrum estimation to denoised signals via ARMA coefficients model.

The [-2]proPSA (p2PSA) and its derivatives, the p2PSA-to-free PSA ratio (%p2PSA), and the Prostate Health Index (PHI) have greatly improved discrimination between men with and without prostate cancer (PCa) in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen (tPSA), free PSA, and p2PSA. For each patient, the free-to-total PSA ratio (%fPSA), PSA density (PSAD), p2PSA-to-free PSA ratio (%p2PSA), and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUC) and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml −1 . Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.

The etiology of benign prostatic hyperplasia (BPH) has not been well established. The preferred medical treatment for many men with symptomatic benign prostatic hyperplasia is either an α-adrenergic receptor antagonist (α-blocker), or a 5α-reductase inhibitor. Single nucleotide polymorphism (SNP) is a powerful tool for successful implementation of individualized treatment.Eighteen SNPs associated with drug efficacy in a Chinese population were genotyped in 790 BPH cases (330 aggressive and 460 non-aggressive BPH cases) and 1008 controls. All BPH patients were treated with α-adrenergic blockers for at least 9 months. We tested the associations between tagging single nucleotide polymorphism and BPH risk/aggressiveness, clinical characteristics at baseline, including the International Prostate Symptom Score (IPSS) and total prostate volume, and changes in clinical characteristics after treatment.There were nine SNPs associated with BPH risk, clinical progression and therapeutic effect. (1) There were nine tSNPs been chosen in CYP3A4, CYP3A5 and RANBP3L genes. (2) The SNP, rs16902947 in RANBP3L at 5p13.2 (p = .01), was significantly associated with BPH. (3) We found two SNPs, rs16902947 in RANBP3L at 5p13.2 (p = .0388) and rs4646437 in CYP3A4 at 7q21.1 (p = .0325), associated with drug effect. (4) Allele "G" for rs16902947 was found to be risk alleles for BPH risk (OR= 2.357, 95%CI 1.01-1.48). The "A" allele of rs4646437 was associated with lower IPSS at baseline (β= -0.4232, p= .03255).rs16902947, rs16902947 and rs4646437 single nucleotide polymorphisms are significantly associated with the clinical characteristics of benign prostatic hyperplasia and the efficacy of benign prostatic hyperplasia treatment.

Common treatments for benign prostatic hyperplasia include 5α-reductase inhibitors and α-adrenergic receptor antagonists. However, these treatments can only partially decrease the risk of benign prostatic hyperplasia progression. SRD5A1 and SRD5A2 are 5α-reductase inhibitor targets. We investigated the association between drug efficacy and single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a Chinese population.We genotyped 11 tagging single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a total of 426 benign prostatic hyperplasia cases and 1,008 controls from Xinhua Hospital, Shanghai, People's Republic of China. Cases were treated with type II 5α-reductase inhibitors and α-adrenergic receptor antagonists. We tested the association of tagging single nucleotide polymorphisms with benign prostatic hyperplasia risk/progression, clinical characteristics at baseline, including the I-PSS (International Prostate Symptom Score) and total prostate volume, and changes in clinical characteristics after treatment.The 11 tagging single nucleotide polymorphisms were not significantly associated with benign prostatic hyperplasia risk or progression (each p0.05). In the SRD5A1 gene rs6884552 and rs3797177 were significantly associated with baseline I-PSS (p = 0.04 and 0.003, respectively). In the SRD5A2 gene rs523349 (V89L) and rs9332975 were significantly associated with baseline total prostate volume (p = 0.01 and 0.001, respectively). In SRD5A1 rs166050 was significantly associated with the posttreatment change in total prostate volume (p = 0.04). In SRD5A2 rs523349 and rs612224 were significantly associated with the posttreatment I-PSS change (p = 0.03 and 0.009, respectively).SRD5A1 and SRD5A2 single nucleotide polymorphisms are significantly associated with the clinical characteristics of benign prostatic hyperplasia and the efficacy of benign prostatic hyperplasia treatment.

BACKGROUND Benign prostatic hyperplasia (BPH) is a common disease prevalent in elderly men. However, the genetic determinants of BPH remain unclear. Because BPH and prostate cancer (PCa) share some common pathological characteristics, we investigated whether susceptibility loci for PCa contributed to BPH risk and BPH aggressiveness in Chinese men. METHODS Fourteen SNPs associated with PCa risk in a Chinese population were genotyped in 426 BPH cases (184 aggressive and 242 non-aggressive BPH cases) and 1,008 controls. The association between the SNPs and BPH risk/aggressiveness was estimated using logistic regression analysis. In addition, effects of the 14 SNPs on BPH related clinical traits, including International Prostate Symptom Score (IPSS), prostate volume, total PSA, and free PSA were evaluated using linear regression analysis. RESULTS Two SNPs, rs12621278 in ITGA6 at 2q31 (OR = 0.82, P = 0.05) and rs339331 in RFX6 at 6q22 (OR = 1.22, P = 0.04) were significantly associated with BPH. In addition, rs12621278 (OR = 0.73, P = 0.05) and rs12653946, 13 kb upstream of IRX4 at 5p15 (OR = 1.40, 0.03), were significantly associated with aggressive BPH. Moreover, the risk allele of rs12621278 (G) and rs12653946 (T) for aggressive BPH were significantly associated with elevated IPSS after treatment (P = 0.01). CONCLUSIONS This is the first systematic investigation on the contributions of PCa susceptibility loci to risk and aggressiveness of BPH. Our findings advance our understanding of the genetic basis of BPH, especially aggressive BPH. In addition, our results provide new insights into the genetic determinants shared between BPH and PCa. Prostate 73: 1182–1190, 2013. © 2013 Wiley Periodicals, Inc.

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.

Purpose: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. Experimental Design: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. Results: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. Conclusions: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.

COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case–control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI = 0.64–0.96) and 0.65 (95% CI = 0.45–0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p = 0.036, global simulated p-value = 0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer. © 2006 Wiley-Liss, Inc.

IL1-RN is an important anti-inflammatory cytokine that modulate the inflammation response by binding to IL1 receptors, and as a consequence inhibits the action of proinflammatory cytokines IL1alpha and IL1beta. In this study, we hypothesise that sequence variants in the IL1-RN gene are associated with prostate cancer risk. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 779 control subjects. We first selected 18 sequence variants covering the IL1-RN gene and genotyped these single-nucleotide polymorphisms (SNPs) in 96 control subjects. Gene-specific haplotypes of IL1-RN were constructed and four haplotype-tagging single-nucleotide polymorphisms (htSNPs) were identified (rs878972, rs315934, rs3087263 and rs315951) that could uniquely describe95% of the haplotypes. All study subjects were genotyped for the four htSNPs. No significant difference in genotype frequencies between cases and controls were observed for any of the four SNPs based on a multiplicative genetic model. Overall there was no significant difference in haplotype frequencies between cases and controls; however, the prevalence of the most common haplotype (ATGC) was significantly higher among cases (38.7%) compared to controls (33.5%) (haplotype-specific P = 0.009). Evaluation of the prostate cancer risk associated with carrying the 'ATGC' haplotype revealed that homozygous carriers were at significantly increased risk (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2-2.2), compared to noncarriers, while no significant association was found among subjects heterozygous for the haplotype (OR = 1.0, 95% CI = 0.8-1.2). Restricting analyses to advanced prostate cancer strengthened the association between the 'ATGC' haplotype and disease risk (OR for homozygous carriers vs noncarriers 1.8, 95% CI = 1.3-2.5). In conclusion, the results from this study support the hypothesis that inflammation has a role of in the development of prostate cancer, but further studies are needed to identify the causal variants in this region and to elucidate the biological mechanism for this association.

African American men have the highest incidence of prostate cancer in the world. Despite this statistic, linkage studies designed to localise prostate cancer susceptibility alleles have included primarily men of Caucasian descent. In this report, we performed a linkage analysis using 33 African American prostate cancer families from two independent research groups. In total, 126 individuals (including 89 men with prostate cancer) were genotyped using markers that map to five prostate cancer susceptibility loci, namely HPC1 at 1q24-25, PCAP at 1q42.2-43, CAPB at 1p36, HPC20 on chromosome 20, and HPCX at Xq27-28. Multipoint mode-of-inheritance-free linkage analyses were performed using the GENEHUNTER software. Some evidence of prostate cancer was detected to HPC1 using all families with a maximum NPL Z score of 1.12 near marker D1S413 (P=0.13). Increased evidence of linkage was observed in the 24 families with prostate cancer diagnosis prior to age 65 years and in the 20 families with male-to-male transmission. Some evidence of prostate cancer linkage was also detected at markers mapping to PCAP, HPC20, and HPCX. Continued collection and analysis of African American prostate cancer families will lead to an improved understanding of inherited susceptibility in this high-risk group.

CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP.

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer related mortality for men in the United States. There is strong empirical and epidemiological evidence supporting a stronger role of genetics in early-onset prostate cancer. We performed a genome-wide association scan for early-onset prostate cancer. Novel aspects of this study include the focus on early-onset disease (defined as men with prostate cancer diagnosed before age 56 years) and use of publically available control genotype data from previous genome-wide association studies. We found genome-wide significant (p

Benign prostatic hyperplasia (BPH) is a common disease prevalent in elderly men. However, the genetic determinants of BPH remain unclear. Because BPH and prostate cancer (PCa) share some common pathological characteristics, we investigated whether susceptibility loci for PCa contributed to BPH risk and BPH aggressiveness in Chinese men.Fourteen SNPs associated with PCa risk in a Chinese population were genotyped in 426 BPH cases (184 aggressive and 242 non-aggressive BPH cases) and 1,008 controls. The association between the SNPs and BPH risk/aggressiveness was estimated using logistic regression analysis. In addition, effects of the 14 SNPs on BPH related clinical traits, including International Prostate Symptom Score (IPSS), prostate volume, total PSA, and free PSA were evaluated using linear regression analysis.Two SNPs, rs12621278 in ITGA6 at 2q31 (OR = 0.82, P = 0.05) and rs339331 in RFX6 at 6q22 (OR = 1.22, P = 0.04) were significantly associated with BPH. In addition, rs12621278 (OR = 0.73, P = 0.05) and rs12653946, 13 kb upstream of IRX4 at 5p15 (OR = 1.40, 0.03), were significantly associated with aggressive BPH. Moreover, the risk allele of rs12621278 (G) and rs12653946 (T) for aggressive BPH were significantly associated with elevated IPSS after treatment (P = 0.01).This is the first systematic investigation on the contributions of PCa susceptibility loci to risk and aggressiveness of BPH. Our findings advance our understanding of the genetic basis of BPH, especially aggressive BPH. In addition, our results provide new insights into the genetic determinants shared between BPH and PCa.

Background Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene ( MSR1 ) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis. Methods Smokers (≥ 20 pack-years) who were > 40 years (n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293×_C/T), four missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G, and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, and IVS5-59_C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A_CG/GG and eight P275A_CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1). Results The MSR1 -coding SNP P275A was associated with susceptibility to COPD in smokers ( P 1 , FEV 1 /FVC, and pp forced expiratory flow (FEF) 25–75 ( P = .03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vitro ( P Conclusions The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.

Because androgens likely play a key role in prostate growth and prostate cancer development, variants of genes involved in androgen biosynthesis may be related to prostate cancer risk. The enzyme P450c17alpha, encoded by the CYP17 gene, catalyzes the conversion of progesterone and pregnenolone into precursors of potent androgens. In the 5' promoter region of the CYP17 gene, a T (A1 allele) to C substitution (A2 allele) has been hypothesized to increase CYP17 gene expression, resulting in higher levels of androgens. To investigate a possible role of CYP17 in prostate diseases, we evaluated the risk of prostate cancer and benign prostatic hyperplasia (BPH) in relation to variation in CYP17 genotype in a population-based case-control study conducted in Shanghai, China. The study included 174 prostate cancer cases, 182 BPH cases and 274 population controls. We observed no statistically significant overall associations of CYP17 genotypes with prostate cancer risk, although associations of the A1/A1 (odds ratio (OR) =1.42, 95% confidence interval (CI) 0.83-2.48) and A1/A2 (OR 1.41, 95% CI 0.91-2.17) genotypes with prostate cancer were suggested. A similar association of the A1/A1 genotype with BPH was suggested. We found no associations of CYP17 genotypes with serum sex hormone levels or other biomarkers after correction for multiple comparisons. Large population-based studies are needed to clarify whether CYP17 plays a role in prostate cancer risk and whether genotype effects vary in different racial/ethnic and other subgroups.

X-Linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by reduced peroxisomal very long chain fatty acid (VLCFA) beta-oxidation. The X - ALD gene product (ALDP) is a peroxisomal transmembrane protein with an ATP binding cassette (ABC). ALDP and three other ABC proteins (PMP70, ALDR, P70R) localize to the peroxisomal membrane. The function of this family of peroxisomal membrane proteins is unknown. We used complementation studies to begin analysis of their role in VLCFA beta-oxidation and on the peroxisomal membrane. Expression of either ALDP or PMP70 restores VLCFA beta-oxidation in X-ALD fibroblasts, indicating overlapping functions. Their expression also restores peroxisome biogenesis in cells that are deficient in the peroxisomal membrane protein Pex2p. Thus it is likely that complex protein interactions are involved in the function and biogenesis of peroxisomal membranes that may contribute to disease heterogeneity.

Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.

PPP2R2A, a gene mapped to 8p21.2, encodes α isoform of the regulatory B55 subfamily of the protein phosphatase 2 (PP2A). PP2A is one of the four major Ser/Thr phosphatases, and is implicated in the negative control of cell growth and division. Because of its known functions and its location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity were found, we hypothesized that either germline sequence variants or somatic copy number changes in PPP2R2A may increase prostate cancer (PCa) risk. To address this, we first sequenced PPP2R2A in 96 probands of hereditary prostate cancer (HPC) families recruited at John Hopkins Hospital; each family had at least three first-degree relatives affected with prostate cancer. Twenty-five germ-line variants were identified in this analysis, including 15 known SNPs and 10 new sequence variants. Most new sequence variants were rare, except 2 new sequence variants with minor allele frequency (MAF) ≥ 0.05 (−482T/C MAF=0.072 and -78C/G MAF=0.058). Thereafter, it was less likely that these sequence variants of PPP2R2A would be co-segregated with PCa. Second, to see if there are any genetic variants in PPP2R2A associated with sporadic PCa, we analyzed 10 SNPs of 15 known SNPs that span the complete PPP2R2A gene in Cancer Genetic Markers of Susceptibility (CGEMS, 737 cases and 1,105 controls) and in Cancer of the Prostate in Sweden (CAPS, 498 cases and 494 controls) from a Sweden population, as genotypes of these 10 SNPs had already been available in both studies. No consistent significant differences in the allele and genotype frequencies were observed among these sporadic PCa cases and controls. Finally, we examined the deletion status in 141 clinical PCa samples from John Hopkins using Affymetrix 6.0 SNP arrays. With the allele-specific analysis of intensities from all paired tumor and normal tissue samples, it was found that PPP2R2A was commonly (67.1%) deleted in these tumor samples including a homozygous deletion in 3 tumors (2.1%). These results suggest that somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2769. doi:10.1158/1538-7445.AM2011-2769

PREGNANCY OUTCOMES, INDEPENDENT OF PLACENTAL VASCULAR DISEASE MONIQUE CHIREAU, DAVID CROSSLIN, ELIZABETH HAUSER, ANDREW OLSHAN, SIQUN ZHENG, CAROLYN M SALAFIA, JOHN THORP, Duke University, Obstetrics and Gynecology, Durham, North Carolina, Duke University, Center for Human Genetics, Durham, North Carolina, University of North Carolina at Chapel Hill, Epidemiology, Chapel Hill, North Carolina, Wake Forest University-Baptist Medical Center, Center for Human Genomics, , North Carolina, Columbia-Presbyterian Coll. of Physicians and Surgeons, Pathology, New York, New York, University of North Carolina at Chapel Hill, Obstetrics and Gynecology, Chapel Hill, North Carolina OBJECTIVE: To determine whether single nucleotide polymorphisms (SNPs) in endothelial function genes are associated with timing of delivery and fetal growth, through the intermediate of placental vascular disease, measured by chronic inflammation (CI) or vascular pathology (VP) on placental histology. STUDY DESIGN: We performed a case-control study of the association between SNPs in endothelial function genes, VP or CI, and preterm birth (PTB) or smallfor-gestational-age (SGA) birth. Genotyping was carried out on 476 women from the Pregnancy, Infection and Nutrition Study at the University of North CarolinaChapel Hill, using MALDI-TOF. Genes studied were known to be associated with adult cardiovascular disease and included Apo A1 G75A, Apo A5 T1131C, ApoC3 C482T, endothelin-1 K198N, E-selectin A561C, ICAM-1 K469E, IL-6 G174C, MTHFR A222V, VEG-F C936T, and VEG-F C2568A. Placentas were scored by a placental pathologist. Univariate and multivariate logistic regression analyses were performed. RESULTS: 83% of women were White and 17% Black. 15.2% and 7% of births were preterm or SGA, respectively. VP was noted in 34% and CI in 17% of placentas. VP was associated with decreased risk for SGA independent of genotype. Among White women the ApoC3 SNP was associated with decreased risk for VP (p 0.04, OR 0.69, CI 0.483-0.989). In PTB models including genotype, placental histology and maternal characteristics, the EDT-1 K469E SNP was associated with decreased PTB risk (p 0.006, OR 0.54, CI 0.35-0.84), independent of VP or CI. CONCLUSION: VP is associated with decreased risk for SGA. The endothelin-1 K198Ar SNP appears to be associated with reduced risk of PTB, but not with VP or CI, suggesting that it does not act through the intermediate of placental vascular disease; our power to detect differences for CI was low given sample size. Geneenvironment interactions may modulate these associations. Future studies of associations between genotype and ethnicity need to more fully account for genetic variation.