Frederick S. Albright

Evidence for a heritable predisposition to death due to influenza.

Animal model studies and human epidemiological studies have shown that some infectious diseases develop primarily in individuals with an inherited predisposition. A heritable contribution to the development of severe influenza virus infection (i.e., that which results in death) has not previously been hypothesized or tested. Evidence for a heritable contribution to death due to influenza was examined using a resource consisting of a genealogy of the Utah population linked to death certificates in Utah over a period of 100 years. The relative risks of death due to influenza were estimated for the relatives of 4,855 individuals who died of influenza. Both close and distant relatives of individuals who died of influenza were shown to have a significantly increased risk of dying of influenza, consistent with a combination of shared exposure and genetic effects. These data provide strong support for a heritable contribution to predisposition to death due to influenza.

Evidence for an inherited predisposition contributing to the risk for rotator cuff disease.

BACKGROUND A genetic predisposition has been suggested to contribute to the risk for development of rotator cuff disease on the basis of observed family clusters of close relatives. We used a population-based resource combining genealogical data for Utah with clinical diagnosis data from a large Utah hospital to test the hypothesis of excess familial clustering for rotator cuff disease. METHODS The Utah Population Database contains combined health and genealogical data on over two million Utah residents. Current Procedural Terminology, Fourth Revision, codes (29827, 23412, 23410, and 23420) and International Classification of Diseases, Ninth Revision, codes (726.1, 727.61, and 840.4) entered in patient records were used to identify patients with rotator cuff disease. We tested the hypothesis of excess familial clustering using two well-established methods (the Genealogical Index of Familiality test and the estimation of relative risks in relatives) in the overall study group (3091 patients) and a subgroup of the study group diagnosed before the age of forty years (652 patients). RESULTS The Genealogical Index of Familiality test in patients diagnosed before the age of forty years showed significant excess relatedness for individuals with rotator cuff disease in close and distant relationships (as distant as third cousins) (p = 0.001). The relative risk of rotator cuff disease in the relatives of patients diagnosed before the age of forty years was significantly elevated for second degree (relative risk = 3.66, p = 0.0076) and third degree (relative risk = 1.81, p = 0.0479) relatives. CONCLUSIONS We analyzed a set of patients with diagnosed rotator cuff disease and a known genealogy to describe the familial clustering of affected individuals. The observations of significant excess relatedness of patients and the significantly elevated risks to both close and distant relatives of patients strongly support a heritable predisposition to rotator cuff disease.

A comprehensive survey of cancer risks in extended families

Purpose:Cancer is familial; yet known cancer predisposition genes, as well as recognized environmental factors, explain only a small percentage of familial cancer clusters. This population-based description of cancer clustering describes patterns of cancer coaggregation suggestive of a genetic predisposition.Methods:Using a computerized genealogy of Utah families linked to a statewide cancer registry, we estimated the relative risks for 36 different cancer sites in first-, second-, and third-degree relatives of cancer cases, for each cancer site individually, and between cancer sites. We estimated the sex- and birth-year-specific rates for cancer using 1 million individuals in the resource. We applied these rates to groups of cases or relatives and compared the observed and expected numbers of cancers to estimate relative risks.Results:Many cancer sites show significantly elevated relative risks among distant relatives for cancer of the same site, strongly supporting a heritable contribution. Multiple combinations of cancer sites were observed among first-, second-, and third-degree relatives, suggesting the existence of heritable syndromes involving more than one cancer site.Conclusion:This complete description of coaggregation of cancer by site in a well-defined population provides a set of observations supporting heritable cancer predispositions and may support the existence of genetic factors for many different cancers.Genet Med 2012:14(1):107–114

Significant evidence for a heritable contribution to cancer predisposition: a review of cancer familiality by site

Background/AimsSound and rigorous well-established, and newly extended, methods for genetic epidemiological analysis were used to analyze population evidence for genetic contributions to risk for numerous common cancer sites in Utah. The Utah Population Database (UPDB) has provided important illumination of the familial contribution to cancer risk by cancer site.MethodsWith over 15 years of new cancer data since the previous comprehensive familial cancer analysis, we tested for excess familial clustering using an expanded Genealogical Index of Familiality (dGIF) methodology that provides for a more informative, but conservative test for the existence of a genetic contribution to familial relatedness in cancer.ResultsSome new cancer sites have been analyzed for the first time, having achieved sufficiently large sample size with additions to the UPDB. This new analysis has identified 6 cancer sites with significant evidence for a heritable contribution to risk, including lip, chronic lymphocytic leukemia, thyroid, lung, prostate, and melanoma.ConclusionsBoth environmentally and genetically-based familial clustering have clinical significance, and these results support increased surveillance for cancer of the same sites among close relatives of affected individuals for many more cancers than are typically considered.

Evidence for a heritable predisposition to Chronic Fatigue Syndrome

BackgroundChronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system.MethodsWe present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases.ResultsWe observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p <0.001) and distant relationships (p = 0.010). We also observed significant excess CFS relative risk among first (2.70, 95% CI: 1.56-4.66), second (2.34, 95% CI: 1.31-4.19), and third degree relatives (1.93, 95% CI: 1.21-3.07).ConclusionsThese analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.

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

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.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer.

Identification of specific Y chromosomes associated with increased prostate cancer risk.

Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists.

Population-Based Relative Risks For Specific Family History Constellations Of Breast Cancer - Towards Individualized Risk Estimation

Purpose Using a large resource linking genealogy with decades of cancer data, RRs were estimated for breast cancer (BC) based on specific family history extending to first cousins. Methods RRs for BC were estimated in 640,366 females with breast cancer family histories that included number of first-(FDR), second-(SDR), and third-degree relatives (TDR), maternal and paternal relatives, and age at earliest diagnosis. Results RRs for first-degree relatives of BC cases ranged from 1.61 (=1 FDR affected, CI: 1.56, 1.67) to 5.00 (≥4 FDRs affected, CI: 3.35, 7.18). RRs for second degree relatives of probands with 0 affected FDRs ranged from 1.08 (≥1 SDR affected, CI: 1.04, 1.12) to 1.71 (≥4 SDRs affected, CI: 1.26, 2.27) and for second degree relatives of probands with exactly 1 FDR from 1.54 (0 SDRs affected, CI:1.47, 1.61) to 4.78 (≥ 5 SDRs; CI 2.47, 8.35). RRs for third-degree relatives with no closer relatives affected were significantly elevated for probands with >=5 affected TDRs RR=1.32, CI: 1.11, 1.57). Conclusions The majority of females analyzed had a family history of BC. Any number of affected FDRs or SDRs significantly increased risk for BC, and more than 4 TDRs, even with no affected FDRs or SDRs significantly increased risk. Risk prediction derived from specific and extended family history allows identification of females at highest risk even when they do not have a conventionally defined “high risk” family; these risks could be a powerful, efficient tool to individualize cancer prevention and screening.

Abstract 39: Association of single nucleotide polymorphisms (SNPs) in STS and SULT2B1 and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC)

Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in aHSPC, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 795 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 60 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to onset of castration resistance prostate cancer (CRPC) in 118 Caucasian men with aHSPC, i.e. those progressing after definitive treatment, undergoing treatment with ADT. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Three SNPs in STS (steroid sulfatase gene), and three SNPs in SULT2B1 (sulfotransferase 2B1 gene) were significantly associated with time to CRPC on ADT while controlling for Gleason Score (p Conclusions: SNPs in STS and SULT2B1 significantly associated with time to CRPC on ADT in aHSPC, and may serve as predictive markers to ADT in this setting. Data are being validated in a larger cohort. Citation Format: Neeraj Agarwal, Tyler Buckley, James Farnham, Shiven B. Patel, Archana Agarwal, Srinivas Tantravahi, Craig Teerlink, Frederick S. Albright, Robert A. Stephenson, Anitha Alex, Lisa Cannon-Albright. Association of single nucleotide polymorphisms (SNPs) in STS and SULT2B1 and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 39.