Citations

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

Abstract The plasma cell malignancy Multiple Myeloma (MM) is a rare but deadly form of cancer with 5 year survival rates of ∼30%. The disease exacts an especially heavy burden on African American (AA) patients. In fact, African Americans are twice a likely to be diagnosed with and die from MM as compared to Caucasian Americans. Although socio-economic factors likely influence this disparity, the role of biology has not been ruled out. We have profiled ∼250 MM tumors for somatic copy number alterations using array-based Comparative Genomic Hybridization (aCGH) and Gene Expression Profiling as part of the Multiple Myeloma Genomics Initiative. To determine if somatic alterations may play a role in the disparity in incidence and/or severity of MM in AA, we compared the frequency of specific chromosomal aberrations in genes and genomic regions previously found to be involved in progression and poor outcome in MM among a cohort of one hundred ninety-six (196) patients including 16 African Americans and 180 Caucasians. The frequency of occurrence (expressed as a percentage) was determined for each of the following aberrations: 1p deletion, homozygous deletion of p18, chromosome 13 deletion, and chromosome 13 monosomy. No significant difference was detected in the frequency of chromosome 13 deletion and chromosome 13 monosomy between the two groups. However, significant differences were observed for chromosome 1p alterations. Homozygous deletion at the p18 locus at 1p occurred in 12.5% (2/16) of tumors from AA patients and 2.8% (5/180) of CA patient tumors (p = 0.045). We further stratified tumors by hyperdiploid or non-hyperdiploid status using a-CGH profiles to determine ploidy status. Most significantly, p18 homozygous deletion was found in 25% (2/8) of AA patients with non-hyperdiploid tumors and in only 1.2% (1/83) of CA patients with non-hyperdiploid tumors (p=3.2 × 10-4). A nominally significant difference among non-hyperdiploid patients was also present for overall 1p deletion, which was observed in 2/8 (25%) of AA non-hyperdiploid tumors and 33/83 (40%) of CA with non-hyperdiploid tumors (p=0.05). No differences were observed for 1p deletion or p18 homozygous deletion among hyperdiploid tumors between AA and CA patients. These results suggest that deletions at 1p are more common among African American MM patients. Furthermore, homozygous deletion encompassing the p18 locus is more significantly common among AA MM patients, especially AA patients with non-hyperdiploid tumors. As 1p deletion and p18 homozygous deletion have been linked to poor outcome, our results suggest that the increased frequency of these alterations in tumors from AA patients may in part explain the disparity in unfavorable outcomes seen among AA MM patients Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4822.

Abstract There is increasing evidence that neighboring stromal cells are not uninvolved bystanders in the pathway to cancer. We hypothesized that SNPs in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to ovarian cancer susceptibility. We therefore used a two-stage approach to comprehensively evaluate common single nucleotide polymorphisms (SNPs) in the Ovarian Cancer Association Consortium (OCAC) for 173 genes involved in stromal-epithelial interactions. Cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1536 SNPs using an Illumina GoldenGate™ BeadArray array. Logistic regression was used to estimate odds ratios (ORs) and adjust for potential confounders. Based on Positive Predictive Value estimates, three SNPs - PODXL rs1013368, ITGA6 rs13027811 and MMP3 rs522616 - were selected for replication using TaqMan genotyping in 3,734 serous invasive cases and 10,067 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele <0.05 in the test set, and which fitted into an iPLEX design, were selected for replication by a subset of five OCAC studies (n=1771 serous invasive cases; n=4022 controls). The associations observed in the test set for the PODXL, ITGA6 and MMP3 SNPs were completely attenuated in the replication set (adj. Pper-allele ≥0.5). However, TERT rs7726159 showed evidence of a log additive association with ovarian cancer risk in the replication study (Pper-allele =0.03). Combined analysis of the test and replication sets for this SNP showed a significant association with risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04 - 1.24) p = 0.003]. A stronger association was observed for serous invasive cases when data for all ethnicities were included [adj. ORper-allele 1.18 (1.09 - 1.28) p = 2.46 × 10−5]. Stratification by histological subtype and malignant potential showed that TERT rs7726159 was also associated with risk of serous borderline tumors, but not with any other subtypes. Although TERT variants have not been previously reported to be associated with ovarian cancer, multiple genome-wide association studies have reported associations with this locus and risk of glioma, basal cell carcinoma, and several cancer types that are known to originate in the epithelium, including lung, bladder, prostate and cervical cancer. Further analysis of this locus is necessary to definitively identify the causal SNP(s). Our study adds to the growing evidence that, as well as 8q24, the TERT locus at 5p15.33, is a general cancer susceptibility locus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4727.

Abstract Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Although rare, MM is a deadly form of cancer with a 5 year survival rate of only 37%. African Americans (AA) are twice as likely to be diagnosed with and die from MM as compared to European Americans (EA). Socioeconomic factors may contribute to this disparity, however, biological factors may also be an influence. We have identified somatic copy number alterations in MM as a part of the Multiple Myeloma Genomics Initiative by profiling 250 MM tumors using array-based comparative genomic hybridization (aCGH). Using this cohort, we identified 16 African American and 180 European American patients using a MMRC database that indicated the racial demographics of each patient. To determine if somatic alterations may play a role in the disparity in incidence and/or severity of MM in AA, we compared the frequency of specific chromosomal aberrations in genes and genomic regions found to be involved in progression and poor outcome. The number of events of occurring was calculated and a univariate analysis was conducted using the Fisher's exact test. P-values were used to determine statistical significance. Results revealed significant differences for chromosome 1 p alterations. Specifically, homozygous deletion at the p18 locus at 1 p occurred in 12.5% (2/16) of tumors from AA patients and 2.8% (5/180) of EA patient tumors (p = 0.045). Further stratification of tumors by hyperdiploid or non-hyperdiploid status revealed significant differences in p18 homozygous deletion. Homozygous deletion of p18 was found in 25% (2/8) of AA patients and only 1.2% (1/83) of EA patients with non-hyperdiploid tumors (p=3.2 × 10-4). A nominally significant difference among non-hyperdiploid patients was also present for overall 1 p deletion, which was observed in 2/8 (25%) of AA non-hyperdiploid tumors and 33/83 (40%) of EA with non-hyperdiploid tumors (p=0.05). No differences were observed for 1 p deletion or p18 homozygous deletion among hyperdiploid tumors between AA and EA patients. We then combined our AA dataset with an independent dataset of 8 AA MM patients generated at the Mayo Clinic, Scottsdale AZ and repeated the analysis. Interestingly, very little or no aberrations were found in the dataset from the Mayo Clinic, however, differences of p18 homozygous deletion and 16q deletion among AA and EA remained statistically significant. To determine the correlation between hemizygous and biallelic loss of p18 and poor prognosis we used the 70 gene signature (Shaughnessy, et al., 2007) as a surrogate to identify patients with poor prognosis within the Multiple Myeloma Genomics Initiative dataset. Genomic identification of significant targets in cancer (GISTIC) was used (Beroukhim et al., 2007) to identify regions of aberrant copy number that were over-represented among samples. A relationship between poor prognosis and biallelic loss was found to be statistically significant (p = 0002) while samples with hemizygous loss showed no relationship (p = 0.57). Although the size of the current AA cohort is small, these results suggest that homozygous deletions at the p18 locus may be more common among African American MM patients with non-hyperdiploid tumors which may help to explain the disparity in AA patients with MM. Array CGH is currently being conducted on an additional 40 tumors from AA MM patients for a more robust analysis. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B64.