Growth Hormone Genes and Prostate Cancer Risk

Background: Growth hormone (GH) SNPs are associated with breast cancer and colon cancer. The author investigated the association of prostate cancer with genetic polymorphisms in GH SNPs in the Ancillary MrOS study. Methods: Included in the current investigation were 128 men with prostate cancer and 743 healthy men, 65 years of age or older. SNPs were tested in Growth Hormone 1 (GH1, n=4), Growth Hormone Receptors (GHR, n=15), Growth Hormone-Releasing Hormone (GHRH, n=4), Growth Hormone-Releasing Hormone Receptors (GHRHR, n=10), Ghrelin (GHRL, n=8), and Growth Hormone Secretagogue Receptor (GHSR, n=9) genes for an association with prostate cancer risk. SNPs were selected based on HapMap Phase 1 and based on functional variation. The SNPs were genotyped using Illumina Assay and were included if the minor allele frequency was 1% or greater. Logistic regression analysis was used to examine associations, adjusted for age, weight, BMI, truncal % fat, total % fat, and diabetes. Similarly, tests of trends and tests of dominant/recessive effect were performed. Results: After adjusting for potential confounding factors, two GH1 SNPs, one GHR SNP, one GHRH SNP, two GHRHR SNPs, one GHRL SNP, and one GHSR SNP showed significant associations with prostate cancer risk. Public Health Significance: If the relationships observed in this study are confirmed, it would justify the investigation of approaches that would reduce the activity of GH in those at high risk for prostate cancer. Conclusions: The results of the current study suggest that GH SNPs are associated with prostate cancer risk. This provides support for replication of these findings in other studies

Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus

<p>Abstract</p> <p>Background</p> <p>Low serum paraoxonase (PON) activity is associated with the risk of coronary artery disease, diabetes and systemic lupus erythematosus (SLE). Our prior studies have shown that the <it>PON1</it>/rs662 (p.Gln192Arg), <it>PON1</it>/rs854560 (p.Leu55Met), <it>PON3</it>/rs17884563 and <it>PON3</it>/rs740264 SNPs (single nucleotide polymorphisms) significantly affect serum PON activity. Since <it>PON1, PON2 </it>and <it>PON3 </it>share high degree of structural and functional properties, in this study, we examined the role of <it>PON2 </it>genetic variation on serum PON activity, risk of SLE and SLE-related clinical manifestations in a Caucasian case-control sample.</p> <p>Methods</p> <p><it>PON2 </it>SNPs were selected from HapMap and SeattleSNPs databases by including at least one tagSNP from each bin defined in these resources. A total of nineteen <it>PON2 </it>SNPs were successfully genotyped in 411 SLE cases and 511 healthy controls using pyrosequencing, restriction fragment length polymorphism (RFLP) or TaqMan allelic discrimination methods.</p> <p>Results</p> <p>Our pair-wise linkage disequilibrium (LD) analysis, using an <it>r</it>^{<it>2 </it>}cutoff of 0.7, identified 14 <it>PON2 </it>tagSNPs that captured all 19 <it>PON2 </it>variants in our sample, 12 of which were not in high LD with known <it>PON1 </it>and <it>PON3 </it>SNP modifiers of PON activity. Stepwise regression analysis of PON activity, including the known modifiers, identified five <it>PON2 </it>SNPs [rs6954345 (p.Ser311Cys), rs13306702, rs987539, rs11982486, and rs4729189; <it>P </it>= 0.005 to 2.1 × 10^-6] that were significantly associated with PON activity. We found no association of <it>PON2 </it>SNPs with SLE risk but modest associations were observed with lupus nephritis (rs11981433, rs17876205, rs17876183) and immunologic disorder (rs11981433) in SLE patients (<it>P </it>= 0.013 to 0.042).</p> <p>Conclusions</p> <p>Our data indicate that <it>PON2 </it>genetic variants significantly affect variation in serum PON activity and have modest effects on risk of lupus nephritis and SLE-related immunologic disorder.</p

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility

Whole Exome Sequencing Analysis of Common Rare Variants in Parkinson and ALS (P05.054)

OBJECTIVE: Using Whole Exome Sequencing (WES) we examined if known ALS genes or those involved in RNA metabolism had rare variants ( BACKGROUND: Genetic variants in three genes ( ANG (angiogenin), VPS35 and C9ORF72 ) have been implicated to increase the risk for developing ALS and PD. WES allows the entire exome to be examined at once in multiple genes. Thus whole groups and famiies of genes can be screened for rare changes in the genome. DESIGN/METHODS: 219 PD cases and 85 controls were included in the initial analysis. Rare variants (RVs, RESULTS: Two genes, FIG4 and ALS2 had significant clustering on analysis. FIG4 had significantly more functional variants in PD versus controls using both RVASSOC and SKAT (p=0.03, 0.02 respectively). ALS2 had more deleterious very rare RVs (Polyphen2) than controls (SKAT, p=0.03), with a trend in RVASSOC (p=0.08). Several specific RVs were only found in PD, and segregated in multiplex families. Interestingly, several specific RVs that were identified have been reported to lead to Spastic Paraplegia as well as ALS. CONCLUSIONS: FIG4 interacts in a complex that regulates biosynthesis of PI9(3,5)P2 signaling lipid. FIG4 null mice develop neurodegeneration. Interestingly,FIG4 compound heterozygotes with partial enzyme activity cause Charcot-Marie-Tooth 4J and have been suggested to contribute to ALS as well. Mutations in ALS2 lead to juvenile ALS. Additional data is needed to confirm if these genes have a wider role in the common forms of neurodegeneration. Supported by: NIH grant 1P50NS071674. Disclosure: Dr. Vance has received personal compensation for activities with Covance. Dr. Vance has received royalty payments from Athena Diagnostics. Dr. Nuytemans has nothing to disclose. Dr. Dressen has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Inchausti has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Mehta has nothing to disclose. Dr. Scott has nothing to disclose

A multiethnic replication study of plasma lipoprotein levels-associated SNPs identified in recent GWAS.

Genome-wide association studies (GWAS) have identified a number of loci/SNPs associated with plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels. The purpose of this study was to replicate 40 recent GWAS-identified HDL-C-related new loci in 3 epidemiological samples comprising U.S. non-Hispanic Whites (NHWs), U.S. Hispanics, and African Blacks. In each sample, the association analyses were performed with all 4 major lipid traits regardless of previously reported specific associations with selected SNPs. A total of 22 SNPs showed nominally significant association (p<0.05) with at least one lipid trait in at least one ethnic group, although not always with the same lipid traits reported as genome-wide significant in the original GWAS. The total number of significant loci was 10 for TC, 12 for LDL-C, 10 for HDL-C, and 6 for TG levels. Ten SNPs were significantly associated with more than one lipid trait in at least one ethnic group. Six SNPs were significantly associated with at least one lipid trait in more than one ethnic group, although not always with the same trait across various ethnic groups. For 25 SNPs, the associations were replicated with the same genome-wide significant lipid traits in the same direction in at least one ethnic group; at nominal significance for 13 SNPs and with a trend for association for 12 SNPs. However, the associations were not consistently present in all ethnic groups. This observation was consistent with mixed results obtained in other studies that also examined various ethnic groups

Summary of SNP associations with 4 lipid traits in our multi-ethnic study samples^§.

§<p>Significant p-values (<0.05) are shown in <b>bold</b>. ‘Log10’ transformation was used for HDL-C and TG levels in Non-Hispanic Whites (NHWs) and Hispanics, ‘natural log’ transformation for TC and TG levels in African Blacks, and ‘square root’ transformation for LDL-C and HDL-C levels in African Blacks. The genotypic effects were modeled as the additive effect of the population-specific minor allele in each ethnic group (minor alleles that differed from those in NHWs are shown in <i>italics</i>). The results were adjusted for relevant covariates in each ethnic group. ^*N.A: These SNPs were not analyzed in African Blacks among which they did not have sufficient minor allele frequency (MAF). Six SNPs showed lower genotyping call rate (<95%) in one of the 3 ethnic groups studied (MAF <u>underlined</u>) while the remaining SNPs had high call rates in all ethnic groups. <b>^‡</b>This SNP showed low rate (0.5%) of discrepancy among replicates included in genotyping.</p

SNPs significantly (<i>p</i><0.05) associated with at least one lipid trait in at least one ethnic group in our study, as well as those that showed a trend for the same direction of association (<i>p</i> between 0.05–0.20, <i>italic traits</i>) as seen for at least one genome-wide significant lipid trait in the original GWAS^§ (only relevant observations have been included in the table).

§<p>Alternate alleles evaluated as compared to GWAS alleles (in <b>bold</b>), for which opposite effects are expected, are shown in <i>italics</i>. Up-regulated lipid traits are shown in <b>bold</b> vs. down-regulated in unbold. MAF: Minor allele frequency, NHWs: Non-Hispanic Whites, HSPs: Hispanics, ABs: African Blacks, EU: Individuals of European descent included in original GWAS, AA: African American replication sample in original GWAS (* = discordant finding with opposite direction of association), na: not analyzed.</p