Comorbidity and Cancer Disease Rates among Those at High-Risk for Alzheimer's Disease: A Population Database Analysis.

(1) Importance: Alzheimer's disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates. (2) Objective: To examine the rates of various comorbidities and cancers in individuals at high-risk for AD, but without a clinical diagnosis, relative to individuals from the same population with normal AD risk. (3) Design, Setting, and Participants: We conducted a study using data from the Utah Population Database (UPDB). The UPDB contains linked data from the Utah Cancer Registry, Utah death certificates, the Intermountain Health patient population, and the University of Utah Health patient population. Subjects were selected based on the availability of ancestral data, linked health information, and self-reported biometrics. (4) Results: In total, 75,877 participants who were estimated to be at high risk for AD based on family history, but who did not have an active AD diagnosis, were analyzed. A lower incidence of diabetes (RR = 0.95, 95% CI [0.92,0.97], p < 0.001), hypertension (RR = 0.97, 95% CI [0.95,0.99], p < 0.001), and heart disease (RR = 0.95, 95% CI [0.93,0.98], p < 0.001) was found. There was no difference in rates of cerebrovascular disease or other forms of dementia. Of the 15 types of cancer analyzed: breast (RR = 1.23, 95% CI [1.16, 1.30], p < 0.001); colorectal (RR = 1.30, 95% CI [1.21, 1.39], p < 0.001); kidney (RR = 1.49, 95% CI (1.29, 1.72), p < 0.001); lung (RR = 1.25, 95% CI [1.13, 1.37], p < 0.001); non-Hodgkin's Lymphoma (RR = 1.29, 95% CI [1.15, 1.44], p < 0.001); pancreas (RR = 1.34, 95% CI [1.16, 1.55], p < 0.001); stomach (RR = 1.59, 95% CI [1.36, 1.86], p < 0.001); and bladder (RR = 1.40, 95% CI [1.25, 1.56], p < 0.001), cancers were observed in significant excess among individuals at high-risk for AD after correction for multiple testing. (5) Conclusions and Relevance: Since age is the greatest risk factor for the development of AD, individuals who reach more advanced ages are at increased risk of developing AD. Consistent with this, people with fewer comorbidities earlier in life are more likely to reach an age where AD becomes a larger risk. Our findings show that individuals at high risk for AD have a decreased incidence of various other diseases. This is further supported by our finding that our high-risk group was also found to have an increased incidence of various cancers, which also increase in risk with age. There is the possibility that a more meaningful or etiological relationship exists among these various comorbidities. Further research into the etiological relationship between AD and these comorbidities may elucidate these possible interactions.

Genome-wide analysis of high-risk primary brain cancer pedigrees identifies PDXDC1 as a candidate brain cancer predisposition gene.

BACKGROUND: There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. METHODS: Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. RESULTS: Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. CONCLUSIONS: Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.

Colorectal cancer risk based on extended family history and body mass index.

Family history and body mass index (BMI) are well-known risk factors for colorectal cancer (CRC), however, their joint effects are not well described. Using linked data for genealogy, self-reported height and weight from driver's licenses, and the Utah Surveillance, Epidemiology, and End-Results cancer registry, we found that an increasing number of first-degree relatives (FDR) with CRC is associated with higher standardized incidence ratio (SIR) for overweight/obese probands but not for under/normal weight probands. For probands with two CRC-affected FDRs, the SIR = 1.91 (95% CI [0.52, 4.89]) for under/normal weight probands and SIR = 4.31 (95% CI [2.46, 7.00]) for overweight/obese probands. In the absence of CRC-affected FDRs, any number of CRC-affected SDRs did not significantly increase CRC risk for under/normal weight probands, but for overweight/obese probands with at least three CRC-affected SDRs the SIR = 2.68 (95% CI [1.29, 4.93]). In the absence of CRC-affected FDRs and SDRs, any number of CRC-affected third-degree relatives (TDRs) did not increase risk in under/normal weight probands, but significantly elevated risk for overweight/obese probands with at least two CRC-affected TDRs was observed; SIR = 1.32 (95% CI [1.04, 1.65]). For nonsyndromic CRC, maximum midlife BMI affects risk based on family history and should be taken into account for CRC risk communication when possible.

A population-based study of testicular cancer risk among children and young adults from Norway and Utah, USA.

Similar family-based cancer and genealogy data from Norway and Utah allowed comparisons of the incidence of testicular cancer (TC), and exploration of the role of Scandinavian ancestry and family history of TC in TC risk. Our study utilizes data from the Utah Population Database and Norwegian Population Registers. All males born during 1951-2015 were followed for TC until the age of 29 years. A total of 1,974,287 and 832,836 males were born in Norway and Utah, respectively, of whom 2,686 individuals were diagnosed with TC in Norway and 531 in Utah. The incidence per year of TC in Norway (10.6) was twice that observed in Utah (5.1) for males born in the last period (1980-1984). The incidence rates of TC in Utah did not differ according to the presence or absence of Scandinavian ancestry (p = 0.669). Having a brother diagnosed with TC was a strong risk factor for TC among children born in Norway and Utah, with HR = 9.87 (95% CI 5.68-17.16) and 6.02 (95% CI 4.80-7.55), respectively; with even higher HR observed among the subset of children in Utah with Scandinavian ancestry (HR = 12.30, 95% CI 6.78-22.31). A clear difference in TC incidence among individuals born in Norway and descendants of Scandinavian people born in Utah was observed. These differences in TC rates point to the possibility of environmental influence. Family history of TC is a strong risk factor for developing TC in both populations.

Increased risk for other cancers in individuals with Ewing sarcoma and their relatives.

BACKGROUND: There are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks. METHODS: Using a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives. RESULTS: Cancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives. CONCLUSIONS: This analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives.

Relative risk for Alzheimer disease based on complete family history.

OBJECTIVE: The inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates. METHODS: A population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives. RESULTS: Any affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59-1.87]; ≥2 FDRs: RR 3.98 [3.26-4.82]; ≥3 FDRs: RR 2.48 [1.07-4.89]; ≥4 FDRs: RR 14.77 [5.42-32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80-54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21-1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed. CONCLUSIONS: This population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.

Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC.

Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q.

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.

A Nonsynonymous Variant in the GOLM1 Gene in Cutaneous Malignant Melanoma.

Background: Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene. Methods: Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test. Results: A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02). Conclusion: These findings support GOLM1 as a candidate melanoma predisposition gene.

Similar survival of patients with multiple versus single primary melanomas based on Utah Surveillance, Epidemiology, and End Results data (1973-2011).

BACKGROUND: Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). OBJECTIVES: We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. METHODS: Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. RESULTS: Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P < .001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). LIMITATIONS: Breslow depth, ulceration status, and specific cause of death were not available for all patients. CONCLUSIONS: Patients with MPM had similar survival times as patients with SPM.

Correction to: Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

CORRECTION: The original version of this article [1] unfortunately contained a typographical error. The 'Alzheimer's Disease Neuroimaging Initiative' was erroneously included as 'Alzheimer's Disease Neuroimaging Initative' in the author list of the article.

Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. RESULTS: Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aß42 (p value = 0.0003) and in the Aß42/Aß40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). CONCLUSIONS: Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.

Population-based risks for cancer in patients with ALS.

OBJECTIVE: To estimate the risks for cancer (overall and site-specific) in an amyotrophic lateral sclerosis (ALS) cohort. METHODS: In this observational longitudinal study, ALS and cancer cases were identified in a computerized Utah genealogy database (Utah Population Database) linked to a statewide cancer registry and death certificates. Hazard ratios (HRs) were estimated as the ratio of observed to expected number of cancers. Site-specific rates for cancer were estimated within the Utah Population Database; sex, birth year (5-year range), and birth state (Utah or not) cohorts were used to estimate the expected number of cancers among ALS cases. To account for an overall shortened lifespan, Cox regression was used to include years at risk in estimation of cancer risks for ALS cases. RESULTS: An overall decreased hazard (hazard ratio [HR] 0.80, p = 0.014, 95% confidence interval [CI] 0.66-0.96) was found for cancer of any site in 1,081 deceased patients with ALS. A decreased hazard was found for lung cancer (HR 0.23, p = 0.002, CI 0.05-0.63). An increased hazard was found for salivary (HR 5.27, p = 0.041, 95% CI 1.09-15.40) and testicular (HR 3.82, p = 0.042, 95% CI 1.06-9.62) cancers. A nonsignificant hazard was observed for cutaneous malignant melanoma (HR 1.62, p = 0.12, 95% CI 0.88-2.71) for which increased risk has previously been reported. CONCLUSIONS: Using a unique population database, the overall risk of cancer of any site was found to be significantly reduced in cases with ALS, as was the risk of lung cancer. Significantly increased risk was observed for salivary and testicular cancers.

Inherited Variants in SULT1E1 and Response to Abiraterone Acetate by Men with Metastatic Castration Refractory Prostate Cancer.

PURPOSE: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. MATERIALS AND METHODS: We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. RESULTS: Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). CONCLUSIONS: Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

Evidence for an Environmental and Inherited Predisposition Contributing to the Risk for Global Tendinopathies or Compression Neuropathies in Patients With Rotator Cuff Tears.

BACKGROUND: Rotator cuff tearing has been found to be clinically associated with other tendinopathies and compression neuropathies; a significant excess of these phenotypes has been seen in patients with rotator cuff tears. It is unclear if the association is secondary to environmental or genetic influences. PURPOSE: To examine population-based data for comorbid association of rotator cuff tearing and tendinopathies and compression neuropathies and to determine whether the association extends to relatives of patients with rotator cuff tears, which could suggest a genetic contribution. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The Utah Population Database (UPDB) contains health and genealogical data on over 2 million Utah residents. Current Procedural Terminology, Fourth Revision, codes (CPT 4) and International Classification of Diseases, Ninth Revision, codes (ICD-9) entered in patient records were used to identify patients with rotator cuff tearing and with comorbid tendinopathies and compression neuropathies. We tested the hypothesis of excess familial clustering of these other phenotypes with rotator cuff tearing using a well-established method (estimation of relative risks) in the overall study group of rotator cuff patients (N = 1889). RESULTS: Significantly elevated risk for elbow, hand/wrist, foot/ankle, knee, and hip tendinopathies, as well as for all tendinopathies and compression neuropathies, was observed in rotator cuff tear cases themselves (P < 2.8e(-13)), in their spouses (P < .02), and in their first-degree relatives (P < 5.5e(-4)). A significant excess of elbow (P = .01), foot/ankle (P = .04), and all tendinopathies (P = 3.1e(-3)) was also observed in second-degree relatives, and a significant excess of compression neuropathies (P = .03) was observed in third-degree relatives. CONCLUSION: The current study shows strong evidence of familial clustering of rotator cuff tearing with other tendinopathies and with compression neuropathy. Observed increased risks in spouses and first-degree relatives supports shared environmental risk factors for rotator cuff tearing, most tendinopathies, and compression neuropathies. Increased risks to third-degree relatives for compression neuropathy suggest an association of these phenotypes that may have a shared genetic etiology.

Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.

BACKGROUND: The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. MATERIALS AND METHODS: A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). RESULTS: Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. CONCLUSIONS: This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing.

Evidence for pelvic organ prolapse predisposition genes on chromosomes 10 and 17.

OBJECTIVE: We conducted a genomewide linkage analysis to identify pelvic organ prolapse (POP) predisposition genes using a resource of high-risk POP pedigrees. STUDY DESIGN: Cases are defined as women who reported bothersome symptoms of POP based on standardized symptom questions (Pelvic Floor Distress Inventory, moderately or quite bothered), and/or received treatment for POP documented in medical records. Our complete pedigree resource contains 299 familial POP cases in 83 high-risk pedigrees. Genotype data were obtained from Illumina HumanHap550, 610Q, the Human1M-Duo, Human Omni1-Quad, or the Human Omni 2.5 platforms. A set of single nucleotide polymorphism markers common to all platforms was identified and markers in high linkage disequilibrium were removed. We performed a genomewide linkage analysis under general dominant and recessive models using a Markov chain, Monte Carlo linkage analysis method implemented in MCLINK (University of Utah) software. Because 70 individuals in 32 pedigrees were used in a previously published linkage analysis for a phenotype of POP requiring treatment/surgery, we also performed linkage only including the 225 newly recruited and genotyped cases in 61 pedigrees. RESULTS: Linkage analysis using our complete pedigree resource for the loosened criteria of bothersome POP showed evidence for significant genomewide linkage on chromosome 10q24-26 (recessive model, maximum heterogeneity logarithm of odds 3.4); suggestive evidence was identified on chromosomes 6 and 17, and an additional region on chromosome 10. In the subset of only the newly recruited familial POP cases, significant evidence for genomewide linkage was observed on chromosome 17q25 (recessive model, maximum heterogeneity logarithm of odds 3.3), and suggestive evidence for linkage was observed on chromosomes 10 and 11. Neither analysis duplicated the previously published linkage evidence for the POP requiring treatment/surgery phenotype observed on chromosome 9. CONCLUSION: While the etiology of this common condition is unknown, this study provides evidence that loci on chromosomes 10q and 17q may contribute to POP etiology.

Prostate cancer risk prediction based on complete prostate cancer family history.

BACKGROUND: Prostate cancer (PC) relative risks (RRs) are typically estimated based on status of close relatives or presence of any affected relatives. This study provides RR estimates using extensive and specific PC family history. METHODS: A retrospective population-based study was undertaken to estimate RRs for PC based on complete family history of PC. A total of 635,443 males, all with ancestral genealogy data, were analyzed. RRs for PC were determined based upon PC rates estimated from males with no PC family history (without PC in first, second, or third degree relatives). RRs were determined for a variety of constellations, for example, number of first through third degree relatives; named (grandfather, father, uncle, cousins, brothers); maternal, paternal relationships, and age of onset. RESULTS: In the 635,443 males analyzed, 18,105 had PC. First-degree RRs ranged from 2.46 (=1 first-degree relative affected, CI = 2.39-2.53) to 7.65 (=4 first-degree relatives affected, CI = 6.28-9.23). Second-degree RRs for probands with 0 affected first-degree relatives ranged from 1.51 (≥1 second-degree relative affected, CI = 1.47-1.56) to 3.09 (≥5 second-degree relatives affected, CI = 2.32-4.03). Third-degree RRs with 0 affected first- and 0 affected second-degree relatives ranged from 1.15 (≥1 affected third-degree relative, CI = 1.12-1.19) to 1.50 (≥5 affected third-degree relatives, CI = 1.35-1.66). RRs based on age at diagnosis were higher for earlier age at diagnoses; for example, RR = 5.54 for ≥1 first-degree relative diagnosed before age 50 years (CI = 1.12-1.19) and RR = 1.78 for >1 second-degree relative diagnosed before age 50 years, CI = 1.33, 2.33. RRs for equivalent maternal versus paternal family history were not significantly different. CONCLUSIONS: A more complete PC family history using close and distant relatives and age at diagnosis results in a wider range of estimates of individual RR that are potentially more accurate than RRs estimated from summary family history. The presence of PC in second- and even third-degree relatives contributes significantly to risk. Maternal family history is just as significant as paternal family history. PC RRs based on a proband's complete constellation of affected relatives will allow patients and care providers to make more informed screening, monitoring, and treatment decisions.