Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume

<div><p>Prostate enlargement leading to clinical benign prostatic hyperplasia (BPH) is associated with metabolic dysregulation and obesity. The genetic basis of this association is unclear. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV). Participants included 876 men referred for prostate biopsy and found to be prostate cancer free. PV was measured by transrectal ultrasound. Samples were genotyped using the Illumina Cardio-MetaboChip platform. Multivariable adjusted linear regression models were used to evaluate SNPs (additive coding) in relation to natural-log transformed (log) PV. We compared SNP-PV results from biopsy-negative men to 442 men with low-grade prostate cancer with similar levels of obesity and PV. Beta-coefficients from the discovery and replication samples were then aggregated with fixed effects inverse variance weighted meta-analysis. SNP rs11736129 (near the pseudo-gene <i>LOC100131429</i>) was significantly associated with log-PV (beta: 0.16, p-value 1.16x10^-8) after adjusting for multiple testing. Other noteworthy SNPs that were nominally associated (p-value < 1x10^-4) with log-PV included rs9583484 (intronic SNP in <i>COL4A2</i>), rs10146527 (intronic SNP in <i>NRXN3</i>), rs9909466 (SNP near <i>RPL32P31</i>), and rs2241606 (synonymous SNP in <i>SLC12A7</i>). We found several SNPs in metabolic loci associated with PV. Further studies are needed to confirm our results and elucidate the mechanism between these genetic loci, PV, and clinical BPH.</p></div

MetaboChip SNPs Nominally Associated with Natural-log Transformed Prostate Volume at p <1x10^-4 in Men without Prostate Cancer (PC) and Men with Low-grade PC: the Nashville Men’s Health Study.

<p>CHR = Chromosome; SNP = Single Nucleotide Polymorphism MA = Minor Allele; RA = Referent Allele; MAF = Minor Allele Frequency; Beta Coefficient from linear regression model evaluating natural log transformed prostate volume as a continuous dependent variable, while adjusting for age (continuous), body mass index (continuous), height (continuous), and 10 genetic ancestry principal components.</p><p>*SNP is on the gene; but is on the intron region</p><p>MetaboChip SNPs Nominally Associated with Natural-log Transformed Prostate Volume at p <1x10^-4 in Men without Prostate Cancer (PC) and Men with Low-grade PC: the Nashville Men’s Health Study.</p

Genetic Determinants of Prostate Volume at p<1x10^-4 from Meta-analysis Combining Results across Diagnostic Groups: the Nashville Men’s Health Study.

<p>CHR = Chromosome; SNP = Single Nucleotide Polymorphism MA = Minor Allele; RA = Referent Allele; MAF = Minor Allele Frequency; I² = amount of heterogeneity between groups not explained due to chance; Table sorted by Fixed effects P value;</p><p>*SNP is on the intron region of the gene</p><p>**SNP is on the exon region of the gene</p><p>Genetic Determinants of Prostate Volume at p<1x10^-4 from Meta-analysis Combining Results across Diagnostic Groups: the Nashville Men’s Health Study.</p

Study Characteristics of Men without Prostate Cancer (PC) and with Low-grade PC: the Nashville Men’s Health Study.

<p>*p-values from student’s t-test with unequal variances (for comparing group means), or from Mann-Whitney test (for comparing group medians), or Pearson’s chi-squared test (for categorical variables). SD = Standard deviation; IQR = Inter quartile range</p><p>Study Characteristics of Men without Prostate Cancer (PC) and with Low-grade PC: the Nashville Men’s Health Study.</p

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids

<div><p>Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10^-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10^-5) around <i>ADTRP</i> (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10^-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10^-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes <i>COL5A2</i>, and <i>TFPI</i>, an immediate downstream target of <i>ADTRP</i>. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.</p></div

Regional association plots for SNP x BMI (continuous) interaction p-values for targeted region in chromosome 6 before and after meta-analysis with European American women.

<p>Plotted p-values are for BMI x SNP interaction term in the following scenarios: a) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA; b) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA + BIOVU EA.</p

Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.

<p>Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.</p

Summary of empirically inferred local ancestry x BMI interaction analyses at top chromosome 2q31-32 SNP rs12999125: Continuous and stratified by BMI categories.

<p>Summary of empirically inferred local ancestry x BMI interaction analyses at top chromosome 2q31-32 SNP rs12999125: Continuous and stratified by BMI categories.</p

Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.

<p>Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.</p

Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.

<p>Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.</p