Biomedical subjects

Scott J Hebbring

Publications and source records attributed to Scott J Hebbring.

10 recordsLinked to original sources

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed2006

Human SULT1A1 gene: copy number differences and functional implications.

SULT1A1, which catalyzes the sulfate conjugation of a wide variety of natural and synthetic compounds, is genetically polymorphic. Biochemical and pharmacogenetic studies have demonstrated that individual variation in the level of enzyme activity is inherited. Common single-nucleotide polymorphisms (SNPs) located in the open reading frame and in the 5'-flanking region (5'-FR) may account for a portion of this individual variation. In this study, we demonstrate the presence of SULT1A1 gene deletions and duplications, representing an additional source of variability in the metabolic activity of this enzyme. A quantitative multiplex PCR assay was used to measure the extent of copy number differences and the frequency of these events in different populations. An analysis of DNA from 362 Caucasian-American and 99 African-American showed the presence of 1 to approximately 5 copies of SULT1A1 in individual samples: 5% of Caucasian subjects contained a single copy of the gene and 26% had three or more copies, while 63% of African-American subjects had three or more copies. Analysis of the genomic region surrounding the SULT1A1 gene in three separate cases with a deletion demonstrated that the entire SULT1A1 gene was affected. Reporter assays, constructed for each of the various 5'-FR SNP haplotypes, suggest that these may also play a role in SULT1A1 activity. However, the variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability were considered (P < 0.0001). Overall, these observations have obvious implications for the effectiveness of SULT1A1 as a drug and hormone metabolizing enzyme and its potential role as a risk factor for disease.

Adult↗

PubMed2006

Polymorphisms in genes involved in sex hormone metabolism may increase risk of benign prostatic hyperplasia.

BACKGROUND: This study investigates associations between polymorphisms in genes involved in sex hormone metabolism and measures of benign prostatic hyperplasia (BPH). METHODS: Community-dwelling Caucasian men (n=510, median age 60 years in 2000) from the Olmsted County, MN, participated in a longitudinal study of BPH. From 1990 through 2000, urologic measures of BPH were assessed biennially from lower urinary tract symptom severity, peak flow rates, prostate volume, serum prostate specific antigen (PSA) level, acute urinary retention, and treatment for BPH. Men were genotyped for polymorphisms in genes involved in sex hormone metabolism. RESULTS: With the wildtype genotype as reference, men with HSD3B1 (c.1100 A/C) heterozygous genotype (hazard ratio (HR)=0.7, 95% confidence intervals (CI)=0.6, 0.9) were at decreased risk of an enlarged prostate and men with CYP19 (TTTA)(n) genotype homozygous for >or=175 TTTA repeats (HR=1.5, 95% CI=1.1, 2.1), and CYP19 (c.1531 C/T) homozygous T variant (HR=1.6, 95% CI=1.1, 2.2) were at increased risk of an enlarged prostate. The homozygous A variant of the PSA gene (g.-252 G/A), was associated with treatment for BPH (HR=2.3, 95% CI=1.2, 4.4). In multivariate analyses, the homozygous variant genotypes of AKR1C3 (c.15 G/A and c.90 G/A) were associated with a decreased risk of an enlarged prostate (HR=0.56, 95% CI=0.35, 0.90 and HR=0.57, 95% CI=0.33, 0.98). CONCLUSIONS: Polymorphisms in HSD3B1, CYP19, AKR1C3 genes may be associated with an enlarged prostate in older men. These data provide insights into genes that should be examined further for their potential role in the pathogenesis of BPH.

3-Hydroxysteroid Dehydrogenases↗

PubMed2006

Growth factor, cytokine, and vitamin D receptor polymorphisms and risk of benign prostatic hyperplasia in a community-based cohort of men.

OBJECTIVES: To investigate the associations between benign prostatic hyperplasia (BPH) and polymorphisms in genes that encode growth factors, cytokines, and vitamin D and their receptors. METHODS: A total of 510 white men (median age 60 years) randomly selected from the Olmsted County, Minnesota community participated in a study of BPH from 1990 to 2000. Biennial measurements were made to assess the International Prostate Symptom Score, peak urinary flow rate, and prostate volume. Genotyping of genes that encode transforming growth factor, interleukin-10, tumor necrosis factor, and vitamin D receptor, among others, was performed. RESULTS: The CC genotype of the transforming growth factor-beta 1 gene was inversely associated with treatment for BPH (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.15 to 0.98). The presence of at least one allele with 17 or more CA repeats of the epidermal growth factor receptor gene was positively associated with an International Prostate Symptom Score greater than 7 (HR 1.32, 95% CI 1.01 to 1.73). The AA genotype of tumor necrosis factor-alpha was inversely associated with peak urinary flow rate (HR 0.33, 95% CI 0.12 to 0.90). For the vitamin D receptor gene, positive associations were found between prostate volume and the CC genotype of the T_C (Taq 1) polymorphism (HR 1.39, 95% CI 1.0 to 1.92) and the AA genotype of the G_A (Bsm 1) polymorphism (HR 1.36, 95% CI 1.06 to 1.74). CONCLUSIONS: These findings suggest that transforming growth factor-beta 1, tumor necrosis factor-alpha, epidermal growth factor receptor, and vitamin D receptor polymorphisms may be involved in the pathogenesis of BPH.

Adult↗

PubMed2006

Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer.

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples.

Aged↗

PubMed2005

Nonparametric tests of association of multiple genes with human disease.

The genetic basis of many common human diseases is expected to be highly heterogeneous, with multiple causative loci and multiple alleles at some of the causative loci. Analyzing the association of disease with one genetic marker at a time can have weak power, because of relatively small genetic effects and the need to correct for multiple testing. Testing the simultaneous effects of multiple markers by multivariate statistics might improve power, but they too will not be very powerful when there are many markers, because of the many degrees of freedom. To overcome some of the limitations of current statistical methods for case-control studies of candidate genes, we develop a new class of nonparametric statistics that can simultaneously test the association of multiple markers with disease, with only a single degree of freedom. Our approach, which is based on U-statistics, first measures a score over all markers for pairs of subjects and then compares the averages of these scores between cases and controls. Genetic scoring for a pair of subjects is measured by a "kernel" function, which we allow to be fairly general. However, we provide guidelines on how to choose a kernel for different types of genetic effects. Our global statistic has the advantage of having only one degree of freedom and achieves its greatest power advantage when the contrasts of average genotype scores between cases and controls are in the same direction across multiple markers. Simulations illustrate that our proposed methods have the anticipated type I-error rate and that they can be more powerful than standard methods. Application of our methods to a study of candidate genes for prostate cancer illustrates their potential merits, and offers guidelines for interpretation.

Case-Control Studies↗

PubMed2005

Polymorphisms in the 5alpha reductase type 2 gene and urologic measures of BPH.

BACKGROUND: The objective of the study was to examine associations between SRD5A2 polymorphisms and measures of benign prostatic hyperplasia (BPH). METHODS: Participants were 510 Caucasian men (median age 60 years), randomly selected from the Olmsted County, MN community to participate in a longitudinal study of BPH. From 1990 through 2000, biennial measurements of lower urinary tract symptom severity (assessed from the American Urological Association Symptom Index, AUASI), peak urinary flow rates (Qmax), and prostate volume were made. Genotyping of SRD5A2 V89L, A49T, and TA repeat polymorphisms were performed. RESULTS: Compared with the VV genotype, the LL genotype was associated with an enlarged prostate (Hazard ratio (HR)=1.62, 95% confidence interval (CI)=1.06, 2.43) but not with AUASI, Qmax, or PSA. The A49T and TA repeat polymorphisms were not associated with BPH. When the LL/VL, AT/TT, and TA0/TA0 genotypes were considered high risk, the number of high risk genotypes increased with increasing prostate volume (32.3, 30.7, 34.1, and 38.7, respectively, P for trend=0.04). CONCLUSIONS: These findings do not demonstrate consistent associations between SRD5A2 genotypes and BPH. However, they suggest that the associations of V89L polymorphisms and prostate volume should be investigated further.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2004

Androgen receptor gene polymorphisms and increased risk of urologic measures of benign prostatic hyperplasia.

The association between androgen receptor gene polymorphisms and benign prostatic hyperplasia was investigated among 510 men randomly selected from Olmsted County, Minnesota. From 1990 through 2000, lower urinary tract symptom severity was assessed by the American Urological Association Symptom Index (AUASI), and peak urinary flow rate, prostate volume, and serum prostate-specific antigen level were measured. Androgen receptor CAG and GGN genotyping was performed. A CAG repeat length of <21 was associated with an enlarged prostate (hazard ratio (HR) = 1.4, 95% confidence interval (CI): 1.0, 1.9) and a serum prostate-specific antigen level >1.4 ng/ml (HR = 1.5, 95% CI: 1.1, 2.0). A GGN repeat length of <16 was associated with an AUASI >7 (HR = 1.6, 95% CI: 1.1, 2.3) and a serum prostate-specific antigen level >1.4 ng/ml (HR = 1.5, 95% CI: 1.0, 2.3). Having <21 CAG repeats and <16 GGN repeats compared with having neither was associated with an enlarged prostate (HR = 2.5, 95% CI: 1.5, 4.2), a serum prostate-specific antigen level >1.4 ng/ml (HR = 2.8, 95% CI: 1.6, 4.7), a peak flow rate <12 ml/second (HR = 1.9, 95% CI: 1.1, 3.4), and an AUASI >7 (HR = 1.6, 95% CI: 1.0, 2.7). Androgen receptor gene polymorphisms may have a potential role in the pathogenesis of benign prostatic hyperplasia.

Antigens, Neoplasm↗

PubMed2004

Gluthatione-S-transferase P1 polymorphism I105V in familial and sporadic prostate cancer.

Several reports suggest that the glutathione-S-transferase (GST) family of enzymes is involved in a variety of cancers, due to their carcinogen-detoxification properties. A polymorphism in codon 105 of the pi variant (GSTP1 I105V), which affects the enzymatic activity of the enzyme, has been linked to the incidence of cancers from different organs. However, the published data in prostate cancer (PCa) is controversial. Some studies report an association with the GSTP1 I105V polymorphism and sporadic PCa, whereas other studies report no association. Recently, one study showed a positive correlation between the GSTP1 I105V polymorphism and familial PCa in a Japanese population. In the present study, we assessed the correlation of the GSTP1 I105V polymorphism with familial and sporadic PCa in an American population. We analyzed DNA samples from 438 patients with familial PCa, 499 patients with sporadic PCa, and 510 controls. We found no significant association between the GSTP1 I105V polymorphism and familial or sporadic PCa when compared to the control group [odds ratio (OR) =1.0 (0.74-1.37); P=0.58]. Moreover, no association was found after stratification for age of diagnosis, Gleason grade, or lymph node involvement [OR =0.84 (0.65-1.09), P=0.37]. These data indicate that there is no associated risk for sporadic or familial PCa in American families containing the GSTP1 I105V polymorphism.

Adult↗

PubMed2004

Allelic imbalance of 8p indicates poor survival in gastric cancer.

Gastric cancer is a common tumor worldwide and a tremendous health burden. However, the underlying mechanisms of tumorigenesis in this cancer's development are primarily undefined. Allelic imbalance (AI) of 8p has been reported in many cancers, yet, the target(s) of alteration and the importance of allelic imbalance on this chromosomal arm in gastric carcinoma development remained to be characterized. Our findings confirmed a high rate of AI on 8p in gastric cancers. Moreover, we demonstrated that AI on 8p, either overall or at marker D8S560, was associated with poorer survival in patients with gastric cancer. Finally, gastric cancers with a high rate of microsatellite instability were significantly associated with noncardia tumors and with female gender.

Adult↗