Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG.

BACKGROUND: In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS: In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS: Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS: These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.

Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer.

OBJECTIVE: • To determine whether the prostate-specific antigen velocity (PSAV) risk count (i.e. the number of times PSAV exceeds a specific threshold) could increase the specificity of screening for prostate cancer and potentially life-threatening tumours. PATIENTS AND METHODS: • From 1989 to 2001, we calculated two serial PSAV measurements in 18 214 prostate cancer screening-study participants, of whom 1125 (6.2%) were diagnosed with prostate cancer. • The PSAV risk count was determined as the number of PSAV measurements of >0.4 ng/mL/year (0, 1, or 2). • We used receiver operating characteristic (ROC) and reclassification analyses to examine the ability of PSAV risk count to predict screen-detected and high-grade prostate cancer. RESULTS: • The PSAV was >0.4 ng/mL/year twice (risk count 2) in 40% of prostate cancer cases compared with only 4% of those with no cancer (P < 0.001). • After adjusting for age and PSA level, a PSAV risk count of 2 was associated with an 8.2-fold increased risk of prostate cancer (95% confidence interval 7.0-9.6, P < 0.001) and 5.4-fold increased risk of Gleason score 8-10 prostate cancer on biopsy. • Compared with a model with age and PSA level, the addition of the PSAV risk count significantly improved discrimination (area under the ROC curve 0.625 vs 0.725, P= 0.031) and reclassified individuals for the risk of high-grade prostate cancer (net reclassification, P < 0.001). CONCLUSIONS: • Sustained rises in PSA indicate a significantly greater risk of prostate cancer, particularly high-grade disease. • Compared with men with a risk count of ≤1, those with two PSAV measurements of >0.4 ng/mL/year (risk count 2) had an 8-fold increased risk of prostate cancer and 5.4-fold increased risk of Gleason 8-10 disease on biopsy, adjusting for age and PSA level. • Compared to PSA alone, PSAV risk count may be useful in reducing unnecessary biopsies and the diagnosis of low-risk prostate cancer.

Prostate cancer risk alleles significantly improve disease detection and are associated with aggressive features in patients with a "normal" prostate specific antigen and digital rectal examination.

BACKGROUND: Several reports suggest that a combination of risk alleles may be associated with prostate cancer (CaP) risk and tumor features. However, their ability to detect CaP and tumor characteristics in patients with a "normal" PSA (<4 ng/ml) and non-suspicious digital rectal examination (DRE) remains to be determined. METHODS: We examined 203 men of European ancestry with clinical stage T1c CaP diagnosed at a "normal" PSA and 611 healthy volunteer controls. The genotypes for 17 different risk alleles were compared between CaP cases and controls. Additional analyses were used to compare the pathologic features between carriers and non-carriers (defined using best-fit genetic model) of these variants. RESULTS: All risk alleles were present at an increased frequency in cases with "normal" PSA values and DRE compared to controls. Amongst CaP patients, carriers of an increasing number of genetic risk factors (i.e., alleles and positive family history) were at a significantly increased risk of CaP (P-trend <0.001). Specifically, men with >10 genetic risk factors had an 11.2-fold risk (95% CI 4.3-29.2) of having the disease compared to men with ≤5 variants. There also was a higher frequency of many the variants amongst men with adverse pathologic features. CONCLUSIONS: A substantial proportion of biopsy-detectable CaP occurs in men with "normal" PSA levels and negative DRE. In this population, CaP risk alleles and family history are significantly associated with CaP risk and may help predict aggressive disease. Future studies are warranted to determine the utility of incorporating these variants into CaP screening programs.

Delay of surgery in men with low risk prostate cancer.

PURPOSE: Treatment options for patients with low risk prostate cancer include radical prostatectomy, radiation therapy, and active surveillance. Among patients treated with radical prostatectomy, prior studies have demonstrated significantly higher biochemical progression rates with surgical delays of 6 months or greater. We determined the impact of surgical delay on radical prostatectomy outcomes specifically in low risk patients. MATERIALS AND METHODS: From our radical prostatectomy database we identified men who fulfilled the D'Amico low risk criteria (clinical stage T1c/T2a, prostate specific antigen less than 10 ng/ml, and biopsy Gleason 6 or less). Pathological tumor features and biochemical progression rates were compared between men with and without surgical delay. We used Cox proportional hazards models to examine predictors of biochemical progression. RESULTS: Of 1,111 men who fulfilled the D'Amico low risk criteria, those with a surgical delay of 6 months or more were significantly older, had a higher proportion of African American men, and a lower proportion of clinical stage T2a (vs T1). A surgical delay of 6 months or more was associated with a greater risk of high grade disease at prostatectomy (p = 0.001) and biochemical progression (p = 0.04). The progression-free survival rate was significantly lower among men with a surgical delay. On multivariate analysis with prostate specific antigen and clinical stage, surgical delays of 6 months or more were significantly and independently associated with time to biochemical progression. CONCLUSIONS: In men who met the D'Amico low risk criteria, a surgical delay of 6 months or more was associated with significantly worse radical prostatectomy outcomes, including more pathology upgrading and a higher rate of biochemical progression. Low risk patients choosing to defer initial definitive therapy should be counseled regarding the possibility of worse treatment outcomes at a later date.

Can prostate specific antigen velocity thresholds decrease insignificant prostate cancer detection?

PURPOSE: A controversy of current prostate specific antigen based prostate cancer screening is the over detection of potentially insignificant prostate cancer. Because PSA kinetics were previously linked to prostate cancer specific mortality, we determined whether prostate specific antigen velocity is associated with clinically significant prostate cancer. MATERIALS AND METHODS: A total of 1,073 men underwent radical prostatectomy from 1992 to 2008 with data available on prostate specific antigen velocity and tumor volume. Insignificant cancer was defined by the Ohori criteria as organ confined, tumor volume 0.5 cc or less and no primary or secondary Gleason pattern 4 or 5. We calculated the proportion of men with pathologically insignificant prostate cancer stratified by prostate specific antigen velocity. RESULTS: Preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year was significantly associated with high grade disease (p = 0.008), positive surgical margins (p = 0.003) and seminal vesicle invasion (p = 0.007) at radical prostatectomy. Median tumor volume was also significantly higher in men with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year (3.1 vs 2.4 cc, p = 0.0001). Overall 69 men (6%) met the Ohori criteria for insignificant cancer. Patients with preoperative prostate specific antigen velocity greater than 0.4 ng/ml per year were 50% less likely to have insignificant disease (10% vs 5%, p = 0.003). CONCLUSIONS: A prostate specific antigen velocity threshold of 0.4 ng/ml per year was associated with the likelihood of insignificant prostate cancer. This suggests that prostate specific antigen velocity may be a useful adjunct in prostate cancer screening to increase specificity for identifying patients with clinically significant disease.

Preoperative prostate specific antigen doubling time is not a useful predictor of biochemical progression after radical prostatectomy.

PURPOSE: Postoperative prostate specific antigen doubling time may be used as a surrogate for prostate cancer specific mortality in patients with biochemical recurrence after radical prostatectomy. Less is known about the usefulness of preoperative prostate specific antigen doubling time for the initial prediction of prostatectomy outcomes. MATERIALS AND METHODS: Preoperative prostate specific antigen doubling time was calculated in 1,208 men from a large prostate cancer screening study who were treated with radical prostatectomy. We examined the relationship of prostate specific antigen doubling time with tumor features and biochemical progression-free survival. RESULTS: Overall prostate specific antigen doubling time was associated with nonorgan confined disease (OR 0.996, 95% CI 0.992-0.999, p = 0.013) but not with biochemical progression (HR 1.000, 95% CI 0.998-1.001, p = 0.66). Using previously published 18 and 36-month thresholds for prostate specific antigen doubling time there was no significant relationship between doubling time and specific adverse pathological features or biochemical progression. Using the concordance index prostate specific antigen doubling time did not enhance the prediction of biochemical progression beyond that achieved by a model with prostate specific antigen, clinical stage and biopsy Gleason score. CONCLUSIONS: In our series of men with newly diagnosed, clinically localized prostate cancer shorter preoperative prostate specific antigen doubling time was associated with nonorgan confined disease but not with biochemical progression after radical prostatectomy. All calculations of prostate specific antigen kinetics may not be equivalent. Caution should be exercised when using prostate specific antigen doubling time in the pretreatment setting.

Genetic prostate cancer risk assessment: common variants in 9 genomic regions are associated with cumulative risk.

PURPOSE: Five genetic variants along chromosomes 8q24 and 17q have a cumulative association with prostate cancer risk. Our research group previously reported an association between these variants and clinicopathological characteristics. More recently 4 additional prostate cancer susceptibility variants were identified on chromosomes 2p15, 10q11, 11q13 and Xp11. We performed cumulative risk assessment incorporating all 9 genetic variants and determined the relationship of the new variants to clinicopathological tumor features. MATERIALS AND METHODS: The genotype of 9 variants was determined in 687 men of European ancestry who underwent radical prostatectomy from 2002 to 2008 and in 777 healthy volunteer controls. We compared the incidence of these variants in prostate cancer cases and controls, and assessed their cumulative risk. We also determined the relationship of carrier status for the 4 new variants and clinicopathological tumor features. RESULTS: Prostate cancer cases had an increased incidence of all 9 risk variants compared to controls. A cumulative model including the 9 single nucleotide polymorphisms provided greater prostate cancer risk stratification than a model restricted to the original 5 single nucleotide polymorphisms described. Specifically men with 6 or more variants were at greater than 6-fold increased risk for prostate cancer. Although 2p15 and 11q13 carriers were more likely to have aggressive features, other clinicopathological features were similar in carriers and noncarriers. CONCLUSIONS: Genetic variants located in 9 regions have a cumulative association with prostate cancer risk. Identification of an increasing number of single nucleotide polymorphisms may provide greater understanding of their combined relationship with CaP risk and disease aggressiveness.

[-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study.

PURPOSE: Due to the limited specificity of prostate specific antigen for prostate cancer screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme prostate specific antigen called [-2]proenzyme prostate specific antigen may enhance the specificity of prostate specific antigen based screening. We examined the usefulness of this isoform in a prospective prostate cancer screening study. MATERIALS AND METHODS: From a population of 2,034 men undergoing prostate cancer screening we examined the relationship between the measurement of the [-2]isoform of proenzyme prostate specific antigen (p2PSA) and prostate cancer detection. Specifically we compared the usefulness of total prostate specific antigen, the ratio of free-to-total prostate specific antigen, the ratio of p2PSA-to-free prostate specific antigen, and a formula combining prostate specific antigen, free prostate specific antigen and p2PSA (the Beckman Coulter prostate health index or phi) to predict prostate cancer in men from the study undergoing prostate biopsy with a prostate specific antigen of 2.5 to 10 ng/ml and nonsuspicious digital rectal examination. RESULTS: Despite similar total prostate specific antigen (p = 0.88), percent free prostate specific antigen (p = 0.02) and %p2PSA (p = 0.0006) distinguished between positive and negative biopsy results. On ROC analysis %p2PSA (AUC 0.76) outperformed prostate specific antigen (AUC 0.50) and percent free prostate specific antigen (AUC 0.68) for differentiating between prostate cancer and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity as well as positive and negative predictive values. The Beckman Coulter prostate health index (AUC 0.77) had the best overall performance characteristics. CONCLUSIONS: This is the first prospective study to our knowledge to demonstrate that p2PSA provides improved discrimination between prostate cancer and benign disease in screened men with a prostate specific antigen of 2.5 to 10 ng/ml and a negative digital rectal examination.

Number of prostate cancer risk alleles may identify possibly 'insignificant' disease.

OBJECTIVE: To determine whether the cumulative effects of five prostate cancer risk alleles (three single-nucleotide polymorphisms [SNPs] on chromosome 8Q24 and two SNPs on chromosome 17a) could help to identify possibly 'insignificant' disease. MATERIALS AND METHODS: We genotyped 629 men of European ancestry who underwent radical prostatectomy at our institution between 2002 and 2007. Possibly 'insignificant' CaP was defined using the Ohori criteria (organ-confined, tumour volume <0.5 mL, Gleason pattern ≤4). Statistical analysis was used to compare patients with 'insignificant' and all other 'significant' cancer based upon genotype. Carrier status for the 5 SNPs were compared between patients with 'insignificant' disease and a separate population of 801 controls without CaP. RESULTS: Overall, 38 (6.0%) patients with CaP met the Ohori criteria for 'insignificant' disease. Men with 'significant' cancer had a greater frequency of any of the five risk alleles than either patients with 'insignificant' disease or controls. None of the individual alleles genotyped on chromosomes 8 or 17 distinguished between 'significant' and 'insignificant' CaP. However, carriers of two or more risk alleles were more likely to have 'significant' disease. CONCLUSIONS: Although no single risk allele distinguished 'insignificant' CaP, 'insignificant' disease was nearly three times as likely among carriers of ≤ one risk allele. Future studies are needed to further elucidate the cumulative relationship between CaP risk alleles and CaP aggressiveness.

Reducing blood loss in open radical retropubic prostatectomy with prophylactic periprostatic sutures.

OBJECTIVE: To determine whether the placement of small-calibre, rapidly absorbed prophylactic periprostatic sutures before the mobilization of the prostate could reduce blood loss during open retropubic radical prostatectomy (RRP). PATIENTS AND METHODS: In 2007, during open RRP, we began placing prophylactic haemostatic sutures of 4-0 and 3-0 plain catgut in the anterior portions of the distal neurovascular bundles (NVBs) and lateral to the proximal NVBs and prostate pedicles before initiating the nerve-sparing dissection and mobilizing the prostate gland. To evaluate whether this reduced intraoperative blood loss, we compared estimated blood loss (EBL), non-autologous transfusion rates, and postoperative haemoglobin (Hb) levels between 100 consecutive patients treated immediately before and 100 consecutive patients treated immediately after the adoption of the prophylactic periprostatic suture technique. RESULTS: Before the use of prophylactic haemostatic sutures, the mean intraoperative blood loss was 1285 mL, and one patient (1%) received an intraoperative non-autologous transfusion. After the adoption of prophylactic sutures, the mean EBL was 700 mL (P < 0.001), and there were no transfusions. The mean Hb concentration the morning after RRP was 10.9 g/dL before and 11.8 g/dL after the initiation of prophylactic haemostatic sutures (P < 0.001). CONCLUSION: Prophylactic periprostatic haemostatic sutures significantly reduce intraoperative blood loss during open RRP.

Is statin use associated with prostate cancer aggressiveness?

OBJECTIVE: To further examine the association between statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) and pathological features in a large group of patients undergoing radical prostatectomy (RP), as epidemiological studies have suggested that statins, in addition to their beneficial cardiovascular effects, might reduce the risk of aggressive prostate cancer. PATIENTS AND METHODS: From 2003 to 2009, 1351 men with data on preoperative statin use had RP by one surgeon. The clinical and pathological tumour features were compared between 504 users of statins and 847 who were not users. RESULTS: Statin users were significantly older and had a higher mean body mass index than non-users. The preoperative serum prostate-specific antigen levels, tumour volume and percentage of cancer in the RP specimen were significantly lower in patients taking statins. Overall, statin users had a proportionately lower rate of adverse tumour pathology features, including a significantly lower risk of positive (cancerous) surgical margins. CONCLUSION: Our results suggest that the use of statins might be associated with more favourable pathological features at RP. The long-term disease-specific outcomes and the underlying link between statins and prostate cancer require further investigation.

Characteristics of prostate cancers detected at prostate specific antigen levels less than 2.5 ng/ml.

PURPOSE: The Prostate Cancer Prevention Trial reported that 15% of men with a prostate specific antigen less than 4 ng/ml and a normal digital rectal examination have biopsy detectable prostate cancer. However, limited published data describe the tumor features of prostate cancer detected at low prostate specific antigen levels (less than 2.5 ng/ml). MATERIALS AND METHODS: A total of 1,278 men underwent radical retropubic prostatectomy by 1 surgeon between 2003 and 2008. We describe the clinicopathological features of 77 patients with a preoperative prostate specific antigen of less than 2.5 ng/ml. RESULTS: Of the men with a low prostate specific antigen (less than 2.5 ng/ml) tumor 51 (66%) had findings suspicious for prostate cancer on digital rectal examination. Indications for prostate biopsy in the remainder of men included an increased prostate specific antigen velocity, hematospermia and abnormal transrectal ultrasound findings. Prostate cancer was detected at transurethral resection of the prostate in the remaining 8% of men. Despite having a low prostate specific antigen at diagnosis 8 (10.4%) and 20 (26%) men, respectively, had biopsy and radical retropubic prostatectomy Gleason grade 7 disease or greater, while 7 (9%) and 6 (7.8%), respectively, had extracapsular tumor extension or positive surgical margins. Compared to men with a normal digital rectal examination mean tumor volume was significantly higher in those with a suspicious digital rectal examination (3.3 vs 1.7 cc, p = 0.018). CONCLUSIONS: Despite having a prostate specific antigen of less than 2.5 ng/ml at diagnosis, a considerable proportion of men had aggressive pathological features at radical retropubic prostatectomy. Digital rectal examination remains an important component of early prostate cancer detection.

Pathological outcomes associated with the 17q prostate cancer risk variants.

PURPOSE: Recent studies have identified 2 distinct genetic variants along chromosome 17, including allele T of single nucleotide polymorphism rs4430796 on 17q12 and allele G of single nucleotide polymorphism rs1859962 on 17q24, that have been linked to prostate cancer risk. Less is known about tumor pathological features in carriers of these variants. MATERIALS AND METHODS: Genotypes for regions 17q12 and 17q24 were determined in 759 white men with prostate cancer and compared to those in 790 healthy control volunteers using logistic regression. In patients with prostate cancer the Fisher exact or Kruskal-Wallis test was used as appropriate to assess the relationship(s) between clinical and pathological characteristics with 17q carrier status. RESULTS: The frequency of the 17q12 and 17q24 genetic variants was significantly higher in patients with prostate cancer compared to that in controls (OR 1.32, 1.15, respectively). Of patients with prostate cancer 83% and 77% were carriers of the 17q12 and 17q24 variants as well as 75% and 75% of controls, respectively. Carriers of 17q12 risk variants were significantly more likely to have high grade disease using an additive best fit genetic model. In addition, there were trends toward adverse pathological features associated with 17q12 independent of the best fit genetic model. CONCLUSIONS: Sequence variants along 17q12 and 17q24 were present in a significantly higher proportion of our prostate cancer cases than in our controls. Adverse pathological features, including higher Gleason grade and pathological stage, were more frequent in 17q12 carriers. Since these alleles may act in conjunction with variants on other chromosomes to influence prostate cancer risk, additional research is required to determine the cumulative associations of genetic risk variants with prognosis.

Does diabetes mellitus modify the association between 17q12 risk variant and prostate cancer aggressiveness?

OBJECTIVE: To examine further the relationship between diabetes mellitus (DM), genotype and prostate cancer aggressiveness. Specifically, we sought to evaluate for effect modification between DM, a newly discovered prostate cancer susceptibility locus on chromosome 17q12 (single nucleotide polymorphism rs4430796) and prostate cancer features. PATIENTS AND METHODS: In 593 genotyped men treated with radical prostatectomy (RP), we examined RP features stratified by DM and rs4430796 carrier status. RESULTS: Despite a significantly higher body mass index among patients with DM, individual pathological features were similar between men with and without DM. Using a dominant model, 17q12 carriers were less likely to have DM and more likely to have a RP Gleason score of >or=7. However, the presence or absence of DM did not modify the relationship between 17q12 susceptibility alleles and pathological features. CONCLUSION: Among 17q12 risk allele carriers, there was no significant relationship between DM and adverse tumour features. However, there were relatively few men with DM (7%) in our RP cohort, particularly compared with its 21% prevalence in the USA population aged >60 years. It is unclear whether this reflects selection bias, genetic protection from prostate cancer among patients with DM, or both. Despite these limitations, the present data suggest that DM alone does not appear to modify any association between 17q12 risk alleles with prostate cancer features.

Outcomes of radical prostatectomy for patients with clinical stage T1a and T1b disease.

OBJECTIVE: To compare the outcomes between patients with stage T1a/b with those of patients with T1c cancer of the prostate treated with radical retropubic prostatectomy (RRP), as the appropriate management of clinical stage T1a/b prostate cancer is subject to debate; although many patients are managed expectantly, some have adverse pathological features suggesting that more active treatment might be beneficial. PATIENTS AND METHODS: From 1983 to 2003, 3478 men had RRP by one surgeon. From this group, we retrospectively identified 29 men with clinical stage T1a and 83 with clinical stage T1b disease. Using statistical analysis we compared the treatment outcomes of these patients with those of 1774 men with clinical stage T1c disease. RESULTS: Men with T1a/b disease had a significantly lower preoperative prostate-specific antigen (PSA) level, a greater proportion with organ-confined disease, and a lower mean/median prostatectomy Gleason score than those with T1c disease. Also, men with T1a/b disease were less likely to be potent before surgery, although the frequency of recovery of potency was similar among all groups. On multivariate analysis with age, year of surgery, PSA level and Gleason score, there was no statistical difference in the rates of biochemical recurrence and the 10-year overall survival rates. However, patients with T1b disease had a significantly lower cancer-specific survival. CONCLUSIONS: T1a and T1b prostate cancer can be associated with aggressive pathological features and have a similar rate of progression as clinical stage T1c disease. That notwithstanding, most patients in the study were cured with RRP and had favourable long-term functional outcomes.

Prostate specific antigen assay standardization bias could affect clinical decision making.

PURPOSE: Although prostate specific antigen is widely used to detect and manage prostate cancer, many patients and physicians are unaware of which prostate specific antigen assay is being used. Most commercial prostate specific antigen assays are standardized to the WHO 90:10 standard or aligned with the original Hybritech assay with potentially disparate results. MATERIALS AND METHODS: A total of 1,916 men participated in a prostate cancer screening study in 2007. On the day of collection prostate specific antigen was tested from the same serum sample using the Access (Hybritech standard) and ADVIA Centaur (WHO 90:10 prostate specific antigen standard) assays. We examined the differences between the 2 assays and the effect that this might have on clinical decisions. RESULTS: Median prostate specific antigen was 0.9 and 1.05 ng/ml for the Centaur and Access assays, respectively, representing a 17% difference. Mean prostate specific antigen was 3.45 and 4.79 ng/ml, respectively, representing a 38% difference. Using a prostate specific antigen threshold of 2.5 ng/ml 5% of men would have been recommended to undergo biopsy using the Access but not the Centaur assay. Furthermore, prostate specific antigen differed by greater than 0.4 ng/ml in 26%, greater than 0.75 ng/ml in 14.5% and greater than 2 ng/ml in 4.5% of men in the same sample simply by using the different assays. CONCLUSIONS: In our prospective screening population median prostate specific antigen was 17% lower using WHO vs Hybritech based assay standardization. As such, if these assays were instead used on a serial basis in the same patient, this could lead to false acceleration or false deceleration in prostate specific antigen velocity. Thus, the assay may influence the likelihood of prostate biopsy and, thereby, prostate cancer detection.

An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP).

A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.

Linkage for BMI at 3q27 region confirmed in an African-American population.

Significant and suggestive linkage for BMI on 3q27 has been reported by several groups, including our own study in African Americans. To further establish the linkage evidence on 3q27, we recruited an independent African-American sample comprising 545 individuals in 128 families. We genotyped 15 short tandem-repeat markers evenly spaced in the 112 cM region around the peak on 3q27 identified in our earlier study. Multipoint linkage analysis by GENEHUNTER2 gave the maximum logarithm of odds (LOD) score 2.4 at map position 188 cM in this sample. When we combined the two samples, linkage evidence was increased to a maximum LOD score (MLS) of 4.3 (point-wise P = 4.34 x 10(-6)) at 188 cM, with a 7 cM 1-LOD-drop interval around the peak. The multiple replications of linkage evidence in the region on 3q27 strongly confirm its potential importance as a candidate region in the search for obesity-related genes.

A genome-wide scan for obesity in African-Americans.

A genome-wide scan using 387 short tandem repeat markers was conducted for obesity among 618 black individuals from 202 families residing in a suburb of Chicago. Evidence for linkage was evaluated with BMI and percent body fat (PBF) using a variance component analysis approach. Suggestive evidence for linkage was found for BMI on chromosome 5 (logarithm of odds [LOD] score = 1.9) and PBF on chromosome 6 (LOD score = 2.7). One additional region on chromosome 3 was linked to these phenotypes at a lower level of significance (LOD score = 1.8 and 0.95 for BMI and PBF, respectively); the linked marker on this chromosome lies in the same region implicated as harboring obesity genes in a previous study of a white population. The replication of linkage evidence using different ethnic groups reinforces the potential significance of this latter candidate region.

Genetic effects on blood pressure localized to chromosomes 6 and 7.

OBJECTIVE: To identify quantitative trait loci (QTL) contributing to the variation in blood pressure in a west African population. METHODS: We conducted a multi-stage genome scan in a population sample from rural Nigeria. A 10 centimorgan genome-wide screen for log-transformed systolic blood pressure (SBP) and diastolic blood pressure (DBP) was first performed based on 1054 individuals from 188 families. In the second phase we performed a similar analysis in an independent sample of 621 individuals from 101 families. In a third follow-up fine mapping phase we genotyped 25 additional markers in the three regions identified in the first two phases. RESULTS: Genome-wide significant linkage evidence was found for SBP on chromosome 7p (lod = 4.73, genome wide P < or = 0.01, point-wise P = 1.53 x 10) in the combined sample. Suggestive linkage evidence was also detected on 6q (lod = 2.9, point-wise P = 0.00013) and 7q (lod = 2.6, point-wise P = 0.00027) for SBP, and 7q (lod = 1.6, point-wise P = 0.003) for DBP. CONCLUSIONS: This study has identified several regions that may harbor genetic variants affecting the variation in blood pressure. Further association mapping under the linkage peaks will be required to refine the linkage evidence that has emerged from our analysis.