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

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

SNPs selected from 4 published GWAS in individuals of European ancestry (EU) for replication in our multiethnic sample^§.

§<p>For HDL-C, p-values ranged from 7.7×10⁻⁴ to 0.02 for 4 SNPs (in <i>italics</i>) but were ≤5×10⁻⁸ for other SNPs as well as for other lipid traits included in the table. When available, replication results in African Africans (AA) are also shown (* = discordant finding with opposite direction of association). Primarily implicated genes, associated alleles, and increased lipid levels are shown in <b>bold</b> (decreased levels in unbold). Alleles (on forward or reverse strands) reflect those stated in the original papers.</p

Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival