Search

Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC).Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance.Results: A nicotine dependence–associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05–1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04–1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03–1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53).Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC.Impact: These findings may help to identify genetic regions associated with IMPC risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2568–78. ©2014 AACR.

Supplementary Table 1. Summary of Study Design and Case/Control Definitions for participating studies. Supplementary Table 2. Distribution of the incident index and second cancer site among incident multiple primary cancer cases, stratified by study and cancer latency. Supplemental Table 3. Detailed distribution of incident index and second cancer site among incident multiple primary cancer cases for WHI study. Supplemental Table 4. Detailed distribution of incident index and second cancer site among incident multiple primary cancer cases for MEC study. Supplemental Table 5. Frequency and cancer site of IMPC cases with 3 or more cancers. Supplementary Table 6. Meta-analysis of the non-significant associations (p{greater than or equal to}0.05) between 178 risk variants for other cancers and incident multiple primary cancer risk. Supplementary Table 7. Ten SNPsa associated with other cancers and multiple primary cancer risk by race/ethnicityb

We assessed whether biological age, measured by the epigenetic clock GrimAge, mediates the association of objective and subjective neighborhood disadvantage with incident HF among Black persons.Participants were 1448 self-reported Black adults (mean age (standard deviation, SD) = 64.3 (5.5)) dually enrolled in two community-based cohorts in Jackson, Mississippi, the ARIC and JHS cohorts, who were free of HF as of January 1, 2000. Incident HF events leading to hospitalization through December 31, 2017, were classified using ICD-9 discharge codes of HF. Multilevel age- and sex-adjusted Cox causal mediation models were used to examine whether biological age (at the person and neighborhood level) mediated the effects of objective (the National Area Deprivation Index, ADI) and subjective (perceived neighborhood problems) neighborhood disadvantage on incident HF.A total of 334 incident hospitalized HF events occurred over a median follow-up of 18.0 years. The total effect of the ADI and perceived neighborhood problems (SD units) on HF was hazard ration (HR) = 1.26 and 95% confidence interval (CI) 0.98-1.56 and HR = 1.26 and 95% CI 1.10-1.41, respectively. GrimAge mediated a majority of the effect of perceived neighborhood problems on HF (person-level indirect effect HR = 1.07; 95% CI 1.02-1.12 and neighborhood-level indirect effect HR = 1.18; 95% CI 1.03-1.34), with the combined indirect effect explaining 94.8% of the relationship. The combined indirect effect of ADI on incident HF was comparable but not statistically significant.Subjective neighborhood disadvantage may confer an increased risk of HF among Black populations.

Author(s): Justice, Anne E; Young, Kristin; Gogarten, Stephanie M; Sofer, Tamar; Graff, Misa; Love, Shelly Ann M; Wang, Yujie; Klimentidis, Yann C; Cruz, Miguel; Guo, Xiuqing; Hartwig, Fernando; Petty, Lauren; Yao, Jie; Allison, Matthew A; Below, Jennifer E; Buchanan, Thomas A; Chen, Yii-Der Ida; Goodarzi, Mark O; Hanis, Craig; Highland, Heather M; Hsueh, Willa A; Ipp, Eli; Parra, Esteban; Palmas, Walter; Raffel, Leslie J; Rotter, Jerome I; Tan, Jingyi; Taylor, Kent D; Valladares, Adan; Xiang, Anny H; Sanchez-Johnsen, Lisa; Isasi, Carmen R; North, Kari E | Abstract: Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC), and hip circumference (HIP) adjusted for body mass index (adjBMI), using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL; and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban, and Dominican) background residing in the US. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for WHRadjBMI, 22 for WCadjBMI, and 28 for HIPadjBMI that reached suggestive significance (P l 1x10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed 4 novel loci (P l 0.05 and consistent direction of effect, and P l 5x10-8 after meta-analysis), including 2 for WHRadjBMI (rs13301996, rs79478137); 1 for WCadjBMI (rs3168072); and 1 for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI; 10 for WCadjBMI; 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity-susceptibility that may be ancestry-specific.

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Women’s Health Initiative cohort over median 16 years, including 85 participants with ≥3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.

Faster rates of age-related cognitive decline might result in early onset of cognitive impairment and dementia. The relationship between ethanol intake and cognitive decline, although studied extensively, remains poorly understood. Previous studies used single measurements of ethanol, and few were conducted in diverse populations. We assessed the association of 9-year trajectories of ethanol intake (1987–1998) with 15-year rate of decline in cognitive performance from mid- to late life (1996–2013) among 2,169 Black and 8,707 White participants of the US Atherosclerosis Risk in Communities study using multivariable linear regression models. We hypothesized that stable, low to moderate drinking would be associated with lesser 15-year cognitive decline, and stable, heavy drinking with greater 15-year cognitive decline. Stable, low to moderate drinking (for Blacks, adjusted mean difference (MD) = 0.03 (95% confidence interval (CI): −0.13, 0.19); for Whites, adjusted MD = 0.02 (95% CI: −0.05, 0.08)) and stable, heavy drinking (for Blacks, adjusted MD = 0.08 (95% CI: −0.34, 0.50); for Whites, adjusted MD = −0.03 (95% CI: −0.18, 0.11)) in midlife compared with stable never-drinking were not associated with 15-year decline in general cognitive function from mid- to late life. No association was observed for the stable former and “mostly” drinking trajectories with 15-year cognitive decline. Stable low, low to moderate, and stable heavy drinking in midlife are not associated with lesser and greater cognitive decline, respectively, from mid- to late life among Black and White adults.

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, and especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aim to: 1) identify novel loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC), and hip circumference (HIP), all adjusted for body mass index (adjBMI), using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); 2) determine if differences in genetic associations differ by background group within HCHS/SOL; 3) determine whether previously reported association regions generalize to HCHS/SOL. Our analyses included 7,472 women and 5,200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban, and Dominican) background residing in the US, with genome-wide array data imputed to the 1000 genomes Phase I multiethnic reference panel. We analyzed associations stratified by sex in addition to sexes combined using linear mixed-model regression. We identified 16 variants for WHRadjBMI, 22 for WCadjBMI, and 28 for HIPadjBMI that reached suggestive significance (P−6). Many of the loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in nine cohort studies (N=34,161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (ancestry-specific P−8 after meta-analysis with HCHS/SOL), including rs13301996 in the sexes-combined analysis, and rs79478137 for women-only for WHRadjBMI; rs28692724 in women-only for HIPadjBMI; and rs3168072 in the sexes combined analysis for WCadjBMI. Also, a total of eight previously reported WHRadjBMI association regions, 12 for HIPadjBMI, and 10 for WCadjBMI generalized to HCHS/SOL. Our study findings highlight the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity-susceptibility that may be ancestry-specific.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs when there is expansion of leukocyte clones in the blood due to mutations in hematopoietic stem cells. CHIP is associated with a high risk of hematologic malignancy and increased risk of cardiovascular disease (CVD). Although the environmental risk factors for CHIP remain poorly understood, radon is a ubiquitous mutagen and may deliver non-negligible doses of α-radiation to bone marrow that trigger CHIP development. Methods: We conducted a cross-sectional study of 10,495 postmenopausal women without hematologic malignancy from the Women’s Health Initiative clinical trials and observational study (mean age: 69 years; 82% white; 9% African American; 4% Hispanic/Latina; 3% Asian). Using blood from the 1993-1998 screening visit or a subsequent annual visit, and whole genome sequence data from the Trans-Omics for Precision Medicine project, we identified CHIP using the GATK Mu TECT2 somatic variant caller, a pre-specified list of leukemogenic driver mutations in 74 genes, and a threshold variant allele fraction > 0.02. We linked geocoded participant addresses at the time of blood draw to county-level, indoor, screening radon concentrations that were predicted by the Environmental Protection Agency (EPA) in 1993 using data on indoor radon, geology, aerial radioactivity, soil parameters, and foundation types. Radon exposure was classified as follows: Zone 3 (< 2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (> 4 pCi/L), the level at which EPA recommends remediation. We estimated the radon-related risk of CHIP as an odds ratio (OR, 95% CI) using logistic regression with and without adjustment for study design, participant sampling, age, race/ethnicity, smoking, and other sociodemographic / behavioral covariates. Results: We identified CHIP in 887 (8.5% of) participants. 3106 (29.6%), 3982 (37.9%), and 3407 (32.5%) had Zone 3, 2, and 1 radon exposures. The corresponding percentage of participants with CHIP across zones was 7.6%, 8.6%, and 9.1%. Relative to participants in Zone 3, those in Zones 2 and 1 had a higher adjusted risk of CHIP: OR (95% CI) = 1.13 (0.95, 1.35) and 1.24 (1.03, 1.48). Conclusion: Risk of CHIP was positively associated with indoor radon concentrations in this cross-sectional study of post-menopausal women. Longitudinal study of temporally integrated, in-home radon exposures, incident CHIP, and CVD would help confirm this novel radon-CHIP association and place it in context.

Background: Although the etiology of clonal hematopoiesis of indeterminate potential (CHIP) remains unclear, CHIP-defining somatic mutations within hematopoietic stem cells appear to expand peripheral blood leukocyte populations, promote inflammation, and thereby increase cardiovascular disease (CVD) risk. Moreover, high noise exposures have been linked to chromosomal aberrations in bone marrow and DNA repair in peripheral blood leukocytes. We therefore examined the potential of aircraft noise exposure as a novel risk factor for CHIP. Methods: We leveraged cross-sectional data on 10,050 postmenopausal women without prior hematologic malignancy in a Women’s Health Initiative (WHI) ancillary study of 5,309 women with stroke and/or venous thromboembolic disease and 4,741 controls. We ascertained CHIP using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing data, the GATK Mu TECT2 somatic variant caller, a pre-specified list of leukemogenic driver mutations in 74 genes, and a threshold variant allele frequency of > 0.02. In cooperation with the Federal Aviation Administration, we generated day-night-level (DNL) noise contours around 90 major U.S. airports using the Aviation Environmental Design Tool noise modelling software. The DNL imposes a penalty for nighttime noise exposure and is the primary means for assessing and regulating noise exposure in the U.S. We estimated geocoded participant address-specific, annual average DNL aircraft noise exposures in decibels (dB) from the contours on the day of blood draw and categorized individuals as exposed or non-exposed (DNL ≥ or < 45dB). We estimated the noise-related risk of CHIP as an odds ratio, 95% confidence interval (OR, 95% CI) using logistic regression before and after adjustment for age, race / ethnicity, case-control status, smoking, alcohol use, body mass index, physical activity, hearing loss, education, and neighborhood socioeconomic status. Results: Among this population of postmenopausal women (Mean age: 68.7 years; White: 82.1%; African American: 12.3%), 19.4% were exposed to aircraft noise, and 8.4% had CHIP. The age-adjusted CHIP proportion was higher among whites (8.1%) than African Americans (7.3%) and other racial/ethnic groups (6.4%). CHIP was also more common among women aged ≥ 70 years (11.5%) than those aged 60-69 years (7.5%) or 50-59 years (3.8%). Compared to non-exposed women, those exposed to aircraft noise were not at increased risk of CHIP: OR unadjusted (95% CI) = 0.95 (0.80, 1.14) and OR adjusted (95% CI) = 0.97 (0.81, 1.16). Results were insensitive to dichotomization of noise exposure at 55 dB and further exclusion of women with hearing loss. Conclusion: Our study found no evidence of an association between aircraft noise and CHIP suggesting that aircraft noise may not be a factor contributing to CHIP-defining somatic mutations linked to CVD.

Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence–associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05–1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04–1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03–1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2568–78. ©2014 AACR.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

The prevalence of obesity has been increasing globally, resulting in increased rates of type 2 diabetes, cardiovascular disease, and certain cancers (1). Risk factors for obesity include a sedentary lifestyle, overconsumption of energy, and genetic susceptibility (2, 3). Recent genome-wide association studies have identified several common genetic variants associated with body mass index (BMI; weight (kg)/height (m)2), a measure of adiposity (4, 5). However, the mechanisms underlying these associations have yet to be characterized. Given that macronutrient consumption plays a key role in obesity (6), understanding the biological links between inherited genetic variation and components of energy intake may suggest strategies for reducing the increasing prevalence of obesity (7). To date, at least 32 independent loci have been found to be associated with BMI (8). Many of the genes involved, such as the brain-derived neurotrophic factor gene (BDNF), the melanocortin 4 receptor gene (MC4R), and the fat mass and obesity-associated gene (FTO), are expressed in the central nervous system (9–11), suggesting that they may act through the neurological control of various aspects of energy balance. Indeed, studies have found that obesity risk variants in intron 1 of the FTO gene are associated with greater energy consumption (12–17) or frequency of energy consumption (18) and a reduction in satiety (19–21) and intake control (12, 22, 23). In a recent study of approximately 2,100 adults of mostly European descent (77%), McCaffery et al. (18) found that FTO rs1421085 was associated with percentage of calories derived from fat. Additionally, this and another study found that obesity risk variants in the potassium channel tetramerization domain-containing 15 gene (KCTD15) and BDNF were associated with macronutrient intake (24) or increased meat and dairy intake (18). However, many of these previous studies were conducted in populations of primarily European descent. To further understand the relationship between obesity single-nucleotide polymorphisms (SNPs) and energy consumption, we investigated, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study (25), the relationship between 6 obesity risk variants and intake of macronutrients (carbohydrate, protein, ethanol, and fat and its subtypes) among type 2 diabetes-free adults from 5 racial/ethnic groups.

Summary Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.

Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (βmeta = -0.2796 (standard error, 0.0709); P = 8 × 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.

Background: Genome-wide association studies have identified hundreds of susceptibility loci for various cancer sites including prostate cancer. Several of the risk loci have demonstrated pleiotropic effects with multiple cancers, suggesting shared biological pathways in carcinogenesis. In the present study, we systematically investigated the effects of other cancer-associated variants on prostate cancer risk. Methods: We examined 196 genetic risk variants identified for 18 cancer and cancer-related traits in a total of 28,135 prostate cancer cases and 37,218 controls. This large meta-analysis of multiethnic samples was assembled from three consortia: Population Architecture using Genetics and Epidemiology (PAGE), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) and Breast and Prostate Cancer Cohort Consortium (BPC3). Study- and ethnic-specific logistic regressions results were combined through fixed-effect meta-analysis to evaluate the association between each variant and prostate cancer risk, applying a Bonferroni-corrected significance threshold of 2.6×10-4. We also assessed the cumulative effect of other cancer risk variants on prostate cancer susceptibility via risk score analysis. Results: Three variants, RTEL rs6010620, TERT rs2853676 and HLA rs6457327, demonstrated statistically significant associations with prostate cancer risk after correcting for multiple comparisons. Originally reported as a follicular lymphoma risk variant, rs6457327 was associated with prostate cancer at the genome-wide significant level (meta-analysis OR=0.93, 95% CI: 0.91-0.96; p=4.5×10-8). The cumulative genetic risk score for risk variants of other cancers demonstrated a significant effect on prostate cancer risk (p=0.021). Conclusions: This systematic pleiotropy analysis identified HLA as a novel susceptibility locus for prostate cancer in a large multiethnic population. The genetic variant with pleiotropic effects on both follicular lymphoma and prostate cancer provides evidence for shared etiologic mechanisms between prostate cancer and other cancer sites. Citation Format: Ying Han, Shelly-Ann Love, William S. Bush, Daniele Campa, Anne M. Butler, Logan Dumitrescu, Konstantinos Tsilidis, Iona Cheng, Lynne R. Wilkens, Jay H. Fowke, Jose Luis Ambite, Steve Buyske, S. Lani Park, The PRACTICAL Consortium, The BPC3 Consortium, Christopher A. Haiman, Loic Le Marchand, Lucia A. Hindorff, Federico Canzian, Fredrick R. Schumacher. Pleiotropy analysis identifies a novel prostate cancer variant at 6p21.33: The PAGE, PRACTICAL, and BPC3 Consortia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5064. doi:10.1158/1538-7445.AM2014-5064

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Genome-wide association studies of cancer have succeeded in identifying over 100 susceptibility loci, including some, such as those found at chromosome 8q24 and CPTM1L-TERT that influence the risk of several malignancies. As part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, we evaluated whether established risk variants for 18 different cancer sites, excluding the lung, impact the risk of lung cancer. A total of 152 risk variants for these 18 malignancies were selected from genome-wide association studies of cancer published through May, 2009. These SNPs were genotyped in lung cancer case-control studies of the Atherosclerosis Risk in Communities (ARIC; cases/controls=297/3088), Epidemiologic Architecture for Genes Linked to Environment (EAGLE; cases/controls=432/1567), Multiethnic Cohort (MEC; cases/controls=461/9029), and the Women's Health Initiative (WHI; cases/controls=1600/5848). The total study population was comprised of 2,790 lung cancer cases and 19,532 controls of African, American Indian, Asian, European, Latino, and Pacific Islander ancestry. For each study site, unconditional logistic regression was performed to evaluate the association between SNPs and lung cancer risk, adjusting for age, sex, race/ethnicity, and smoking status. A fixed-effect meta-analysis was performed and heterogeneity across study sites was tested. Seventeen of the 152 SNPs were associated with lung cancer risk (nominal P

Background Heart failure is sometimes incorrectly listed as the underlying cause of death (UCD) on death certificates, thus compromising the accuracy and comparability of mortality statistics. Statistical redistribution of the UCD has been used to examine the effect of misclassification of the UCD attributed to heart failure, but sex- and race-specific redistribution of deaths on coronary heart disease (CHD) mortality in the United States has not been examined. Methods We used coarsened exact matching to infer the UCD of vital records with heart failure as the UCD from 1999 to 2010 for decedents 55 years old and older from states encompassing regions under surveillance by the Atherosclerosis Risk in Communities (ARIC) Study (Maryland, Minnesota, Mississippi, and North Carolina). Records with heart failure as the UCD were matched on decedent characteristics (five-year age groups, sex, race, education, year of death, and state) to records with heart failure listed among the multiple causes of death. Each heart failure death was then redistributed to plausible UCDs proportional to the frequency among matched records. Results After redistribution the proportion of deaths increased for CHD, chronic obstructive pulmonary disease, diabetes, hypertensive heart disease, and cardiomyopathy, P

Background Nearly half of adults in the United States who are diagnosed with hypertension use blood-pressure-lowering medications. Yet there is a large interindividual variability in the response to these medications. Two complementary gene–environment interaction methods have been published and incorporated into publicly available software packages to examine interaction effects, including whether genetic variants modify the association between medication use and blood pressure. The first approach uses a gene–environment interaction term to measure the change in outcome when both the genetic marker and medication are present (the “interaction model”). The second approach tests for effect-size differences between strata of an environmental exposure (the “med-diff” approach). However, no studies have quantitatively compared how these methods perform with respect to 1 or 2 degree of freedom (DF) tests or in family-based data sets. We evaluated these 2 approaches using simulated genotype–medication response interactions at 3 single nucleotide polymorphisms (SNPs) across a range of minor allele frequencies (MAFs 0.1–5.4 %) using the Genetic Analysis Workshop 19 family sample. Results The estimated interaction effect sizes were on average larger in the interaction model approach compared to the med-diff approach. The true positive proportion was higher for the med-diff approach for SNPs less than 1 % MAF, but higher for the interaction model when common variants were evaluated (MAF >5 %). The interaction model produced lower false-positive proportions than expected (5 %) across a range of MAFs for both the 1DF and 2DF tests. In contrast, the med-diff approach produced higher but stable false-positive proportions around 5 % across MAFs for both tests. Conclusions Although the 1DF tests both performed similarly for common variants, the interaction model estimated true interaction effects with less bias and higher true positive proportions than the med-diff approach. However, if rare variation (MAF

Background There is great interindividual variation in systolic blood pressure (SBP) as a result of the influences of several factors, including sex, ancestry, smoking status, medication use, and, especially, age. The majority of genetic studies have examined SBP measured cross-sectionally; however, SBP changes over time, and not necessarily in a linear fashion. Therefore, this study conducted a genome-wide association (GWA) study of SBP change trajectories using data available through the Genetic Analysis Workshop 19 (GAW19) of 959 individuals from 20 extended Mexican American families from the San Antonio Family Studies with up to 4 measures of SBP. We performed structural equation modeling (SEM) while taking into account potential genetic effects to identify how, if at all, to include covariates in estimating the SBP change trajectories using a mixture model based latent class growth modeling (LCGM) approach for use in the GWA analyses. Results The semiparametric LCGM approach identified 5 trajectory classes that captured SBP changes across age. Each LCGM identified trajectory group was ranked based on the average number of cumulative years as hypertensive. Using a pairwise comparison of these classes the heritability estimates range from 12 to 94 % (SE = 17 to 40 %). Conclusion These identified trajectories are significantly heritable, and we identified a total of 8 promising loci that influence one’s trajectory in SBP change across age. Our results demonstrate the potential utility of capitalizing on extant genetic data and longitudinal SBP assessments available through GAW19 to explore novel analytical methods with promising results.