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1.  A Heroin Addiction Severity-Associated Intronic Single Nucleotide Polymorphism Modulates Alternative Pre-mRNA Splicing of the μ Opioid Receptor Gene OPRM1 via hnRNPH Interactions 
The Journal of Neuroscience  2014;34(33):11048-11066.
Single nucleotide polymorphisms (SNPs) in the OPRM1 gene have been associated with vulnerability to opioid dependence. The current study identifies an association of an intronic SNP (rs9479757) with the severity of heroin addiction among Han-Chinese male heroin addicts. Individual SNP analysis and haplotype-based analysis with additional SNPs in the OPRM1 locus showed that mild heroin addiction was associated with the AG genotype, whereas severe heroin addiction was associated with the GG genotype. In vitro studies such as electrophoretic mobility shift assay, minigene, siRNA, and antisense morpholino oligonucleotide studies have identified heterogeneous nuclear ribonucleoprotein H (hnRNPH) as the major binding partner for the G-containing SNP site. The G-to-A transition weakens hnRNPH binding and facilitates exon 2 skipping, leading to altered expressions of OPRM1 splice-variant mRNAs and hMOR-1 proteins. Similar changes in splicing and hMOR-1 proteins were observed in human postmortem prefrontal cortex with the AG genotype of this SNP when compared with the GG genotype. Interestingly, the altered splicing led to an increase in hMOR-1 protein levels despite decreased hMOR-1 mRNA levels, which is likely contributed by a concurrent increase in single transmembrane domain variants that have a chaperone-like function on MOR-1 protein stability. Our studies delineate the role of this SNP as a modifier of OPRM1 alternative splicing via hnRNPH interactions, and suggest a functional link between an SNP-containing splicing modifier and the severity of heroin addiction.
doi:10.1523/JNEUROSCI.3986-13.2014
PMCID: PMC4131016  PMID: 25122903
addiction; heroin; hnRNPH; opioid receptor; SNP; splicing
2.  The 6q22.33 Locus and Breast Cancer Susceptibility 
Recently, we identified a novel breast cancer (BC) susceptibility locus at 6q22.33 following a genome-wide association study (GWAS) in the Ashkenazi Jewish (AJ) genetic isolate. To replicate these findings, we performed case-control association analysis on 6q22.33 (rs2180341) in additional 487 AJ BC cases and in an independent non-Jewish (non-AJ), predominantly European-American (EU-Am), populations of 1,466 BC cases and 1,467 controls. We have confirmed the 6q22.33 association with BC risk in the replication cohorts (per-allele OR=1.18, 95%CI 1.04–1.33, p=0.0083) with the strongest effect in the aggregate meta-analysis of 3,039 BC cases and 2,616 AJ and non-AJ controls (per-allele OR=1.24, 95%CI 1.13–1.36, P=3.85×10−7).
We have also shown that the association was slightly stronger with ER positive tumors (per-allele OR=1.35, 95%CI 1.20–1.51, p=2.2×10−5) compared to ER negative tumors (per-allele OR=1.19, 95%CI 0.97–1.47, p=0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in BC susceptibility. Due to stronger association of 6q22.33 with ER-positive BC we examined the effect of candidate genes on ER response elements (ERE). Upon transfection of overexpressed RNF146 in the MCF-7 BC cell line, we observed diminished expression of an ERE reporter construct. This study confirms the association of 6q22.33 with BC, with slightly stronger effect in ER positive tumors. Further functional studies of candidate genes are in progress and a large replication analysis is being completed as part of an international consortium.
doi:10.1158/1055-9965.EPI-09-0151
PMCID: PMC4286363  PMID: 19690183
Ashkenazi Jews; Breast Cancer; Genome-wide association studies; SNPs; estrogen receptor
3.  GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV) Seropositive Women with or at Risk for HIV Infection 
PLoS ONE  2014;9(12):e114467.
Background
GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US.
Results
438 hepatitis C virus (HCV) seropositive women, including 306 HIV-infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co-infected. Among HIV-infected women, the only significant difference between GBV-negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes.
Conclusions
Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype.
doi:10.1371/journal.pone.0114467
PMCID: PMC4262414  PMID: 25493916
4.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
5.  Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma 
PLoS ONE  2014;9(7):e101685.
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
doi:10.1371/journal.pone.0101685
PMCID: PMC4092067  PMID: 25010664
6.  Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS) 
PLoS ONE  2014;9(6):e99109.
Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10−6). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.
doi:10.1371/journal.pone.0099109
PMCID: PMC4053382  PMID: 24918582
7.  The Home Environment and Family Asthma Management Among Ethnically Diverse Urban Youth with Asthma 
While the pediatric psychology literature underscores the importance of illness related aspects of the home environment for optimal family asthma management, little is known about the contribution of more global aspects of the home environment (e.g., family routines/schedule, quality of stimulation provided to child) to asthma management in ethnic minority and urban families. The goals of this study were to: 1) explore ethnic/racial group differences in global and specific dimensions of home environment quality among Latino, non-Latino white (NLW), and African American urban children with asthma; and 2) examine associations between the quality and quantity of support and stimulation within the home environment, as measured by the HOME Inventory, and family asthma management in this sample. Urban, low-income children (N=131) between the ages of 6 and 13 with asthma and a primary caregiver participated in a multi-modal assessment including an in home observation and semi structured interviews to assess aspects of home environment quality and family asthma management practices. While controlling for poverty, no ethnic group differences were found in the global home environment; however, there were significant differences in specific dimensions (e.g. Family Participation in Developmentally Stimulating Experiences, and Aspects of the Physical Environment) of home environment quality. Across the whole sample, home environment quality predicted family asthma management. When examining this association for specific ethnic groups, this finding did not hold for the Latino subsample. The results highlight the need to consider ethnic group differences in non-illness specific aspects of the home environment when addressing families’ asthma management strategies.
doi:10.1037/a0032462
PMCID: PMC3746827  PMID: 23795627
8.  Underdiagnosed and Undertreated Allergic Rhinitis in Urban School-Aged Children with Asthma 
Allergic rhinitis (AR) is a risk factor for the development of asthma, and if poorly controlled, it may exacerbate asthma. We sought to describe AR symptoms and treatment in a larger study about asthma, sleep, and school performance. We examined the proportion (1) who met criteria for AR in an urban sample of school children with persistent asthma symptoms, (2) whose caregivers stated that they were not told of their child's allergies, (3) who had AR but were not treated or were undertreated for the disease, as well as (4) caregivers and healthcare providers' perceptions of the child's allergy status compared with study assessment, and (5) associations between self-report of asthma and AR control over a 4-week monitoring period. One hundred sixty-six children with persistent asthma participated in a clinical evaluation of asthma and rhinitis, including allergy testing. Self-report of asthma control and rhinitis control using the Childhood Asthma Control Test (C-ACT) and Rhinitis Control Assessment Test (RCAT) were measured 1 month after the study clinic session. Persistent rhinitis symptoms were reported by 72% of participants; 54% of rhinitis symptoms were moderate in severity, though only 33% of the sample received adequate treatment. AR was newly diagnosed for 53% during the clinic evaluation. Only 15% reported using intranasal steroids. Participants with poorly controlled AR had poorer asthma control compared with those with well-controlled AR. This sample of urban school-aged children with persistent asthma had underdiagnosed and undertreated AR. Healthcare providers and caregivers in urban settings need additional education about the role of allergies in asthma, recognition of AR symptoms, and AR's essential function in the comanagement of asthma. Barriers to linkages with allergy specialists need to be identified.
doi:10.1089/ped.2014.0344
PMCID: PMC4062104  PMID: 24963455
9.  Identification of a recurrent germline PAX5 mutation and susceptibility to pre-B cell acute lymphoblastic leukemia 
Nature genetics  2013;45(10):1226-1231.
doi:10.1038/ng.2754
PMCID: PMC3919799  PMID: 24013638
10.  Distinct Actions of Akt1 on Skeletal Architecture and Function 
PLoS ONE  2014;9(3):e93040.
Skeletal integrity is dependent on the coordinated actions of bone-forming osteoblasts and bone-resorbing osteoclasts, which recognize and respond to multiple environmental inputs. Here we have studied the roles in bone development and growth of Akt1 and Akt2, two closely related signaling proteins, by evaluating mice lacking either of these enzymes. Global deficiency of Akt1 but not Akt2 caused a reduction in whole body and femoral bone mineral density, in femoral cortical thickness and volume, and in trabecular thickness in both males and females when measured at 20-weeks of age, which was reflected in diminished femoral resistance to fracture. Haplo-deficiency of Akt1 in male mice also decreased femoral cortical and trabecular skeletal parameters, and reduced bone strength. Cell-based studies showed that genetic Akt1 deficiency diminished the rate of proliferation of osteoblast progenitors and impaired osteoclast differentiation in primary culture but that loss of Akt2 did not. Our results demonstrate differential effects of Akt1 and Akt2 on skeletal maturation and architecture through actions on both osteoblast and osteoclast precursors.
doi:10.1371/journal.pone.0093040
PMCID: PMC3963959  PMID: 24663486
12.  Genome-wide analysis of the role of copy-number variation in pancreatic cancer risk 
Although family history is a risk factor for pancreatic adenocarcinoma, much of the genetic etiology of this disease remains unknown. While genome-wide association studies have identified some common single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk, these SNPs do not explain all the heritability of this disease. We hypothesized that copy number variation (CNVs) in the genome may play a role in genetic predisposition to pancreatic adenocarcinoma. Here, we report a genome-wide analysis of CNVs in a small hospital-based, European ancestry cohort of pancreatic cancer cases and controls. Germline CNV discovery was performed using the Illumina Human CNV370 platform in 223 pancreatic cancer cases (both sporadic and familial) and 169 controls. Following stringent quality control, we asked if global CNV burden was a risk factor for pancreatic cancer. Finally, we performed in silico CNV genotyping and association testing to discover novel CNV risk loci. When we examined the global CNV burden, we found no strong evidence that CNV burden plays a role in pancreatic cancer risk either overall or specifically in individuals with a family history of the disease. Similarly, we saw no significant evidence that any particular CNV is associated with pancreatic cancer risk. Taken together, these data suggest that CNVs do not contribute substantially to the genetic etiology of pancreatic cancer, though the results are tempered by small sample size and large experimental variability inherent in array-based CNV studies.
doi:10.3389/fgene.2014.00029
PMCID: PMC3923159  PMID: 24592275
pancreatic cancer; copy number variation; cancer risk; SNP microarrays; CNVs
13.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
14.  Fire Promotes Pollinator Visitation: Implications for Ameliorating Declines of Pollination Services 
PLoS ONE  2013;8(11):e79853.
Pollinators serve critical roles for the functioning of terrestrial ecosystems, and have an estimated annual value of over $150 billion for global agriculture. Mounting evidence from agricultural systems reveals that pollinators are declining in many regions of the world, and with a lack of information on whether pollinator communities in natural systems are following similar trends, identifying factors which support pollinator visitation and services are important for ameliorating the effects of the current global pollinator crisis. We investigated how fire affects resource structure and how that variation influences floral pollinator communities by comparing burn versus control treatments in a southeastern USA old-field system. We hypothesized and found a positive relationship between fire and plant density of a native forb, Verbesina alternifolia, as well as a significant difference in floral visitation of V. alternifolia between burn and control treatments. V. alternifolia density was 44% greater and floral visitation was 54% greater in burned treatments relative to control sites. When the density of V. alternifolia was experimentally reduced in the burn sites to equivalent densities observed in control sites, floral visitation in burned sites declined to rates found in control sites. Our results indicate that plant density is a proximal mechanism by which an imposed fire regime can indirectly impact floral visitation, suggesting its usefulness as a tool for management of pollination services. Although concerns surround the negative impacts of management, indirect positive effects may provide an important direction to explore for managing future ecological and conservation issues. Studies examining the interaction among resource concentration, plant apparency, and how fire affects the evolutionary consequences of altered patterns of floral visitation are overdue.
doi:10.1371/journal.pone.0079853
PMCID: PMC3827174  PMID: 24265787
15.  Rare Coding Variants in ALPL Are Associated With Low Serum Alkaline Phosphatase and Low Bone Mineral Density 
Alkaline phosphatase (ALP) plays an essential role in the regulation of tissue mineralization, and its activity is highly heritable. Guided by genetic associations discovered in a murine model, we hypothesized a role for rare coding variants in determining serum ALP level and bone mineral density (BMD) in humans. We sequenced the coding regions of the ALP gene (ALPL) in men with low and normal serum ALP activity levels. Single-nucleotide ALPL variants, including 19 rare nonsynonymous variants (minor allele frequency <1%), were much more frequent among the low ALP group (33.8%) than the normal group (1.4%, p = 1 × 10−11). Within the low ALP group, men with a rare, nonsynonymous variant had 11.2% lower mean serum ALP (p = 3.9 × 10−4), 6.7% lower BMD (p = 0.03), and 11.1% higher serum phosphate (p = 0.002) than those without. In contrast, common nonsynonymous variants had no association with serum ALP, phosphate, or BMD. Multiple rare ALPL coding variants are present in the general population, and nonsynonymous coding variants may be responsible for heritable differences in mineralization and thus BMD.
doi:10.1002/jbmr.527
PMCID: PMC3810303  PMID: 21956185
OSTEOPOROSIS; HEREDITY; GENETICS; ALKALINE PHOSPHATASE
16.  THE INFLUENCE OF HLA CLASS I ALLELES AND THEIR POPULATION FREQUENCIES ON HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 CONTROL AMONG AFRICAN AMERICANS 
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
doi:10.1016/j.humimm.2011.01.003
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
17.  Susceptibility Loci Associated with Prostate Cancer Progression and Mortality 
Purpose
Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
Experimental Design
We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and PSA. We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we performed an independent analysis using a high resolution panel of 13 SNPs.
Results
On univariate analysis, 2 SNPs were associated (p<0.05) with biochemical recurrence; 3 SNPs were associated with clinical metastases; and 1 SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis).
Conclusions
We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.
doi:10.1158/1078-0432.CCR-10-0028
PMCID: PMC3732009  PMID: 20460480
Single nucleotide polymorphisms; Prostate cancer; Prognosis
18.  Germline BRCA mutations denote a clinicopathologic subset of prostate cancer 
Purpose
Increased prostate cancer risk has been reported for BRCA mutation carriers but BRCA-associated clinicopathologic features have not been clearly defined.
Experimental Design
We determined BRCA mutation prevalence in 832 Ashkenazi Jewish (AJ) men diagnosed with localized prostate cancer between 1988 and 2007 and 454 AJ controls, and compared clinical outcome measures among 26 BRCA mutation carriers and 806 non-carriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason Score (GS), and logistic regression models to determine associations between carrier status, prostate cancer risk, and GS. Hazard ratios for clinical endpoints were estimated using Cox proportional hazards models.
Results
BRCA2 mutations were associated with a threefold risk of prostate cancer (OR [95% CI]=3.18 [1.52-6.66]; p = 0.002), and presented with more poorly differentiated (GS ≥ 7) tumors(85% vs. 57%, p= 0.0002) compared with non-BRCA associated PC. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, PSA, GS, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence (HR [95% CI] = 2.41[1.23, 4.75] and 4.32 [1.31, 13.62], respectively) and prostate cancer -specific death (HR [95% CI] = 5.48 [2.03, 14.79] and 5.16 [1.09,24.53], respectively) than non-carriers.
Conclusions
BRCA2 mutation-carriers had an increased risk of prostate cancer and a higher histological grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have impact on tailoring clinical management of this subset of hereditary prostate cancer.
doi:10.1158/1078-0432.CCR-09-2871
PMCID: PMC3713614  PMID: 20215531
BRCA1; BRCA2; prostate cancer; clinicopathologic associations
19.  A Replication Study and Genome-wide Scan of Single Nucleotide Polymorphisms Associated with Pancreatic Cancer Risk and Overall Survival 
Purpose
To explore the effects of single nucleotide polymorphisms (SNPs) on pancreatic cancer risk and overall survival.
Experimental Design
The germline DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on overall survival (OS). Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Lastly, we performed a genome-wide association study of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively.
Results
Among seven risk SNPs analyzed, two (rs505922, rs9543325) were associated with risk (p<0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (p<0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Further, our GWAS identified a novel SNP (rs1482426, combined stage 1 and 2 p = 1.7 ×10−6, per-allele HR = 1.74, 95% CI 1.38–2.18) to be putatively associated with OS.
Conclusions
The effects of SNPs on pancreatic cancer risk and overall survival were replicated in our study, though further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer.
doi:10.1158/1078-0432.CCR-11-2856
PMCID: PMC3568955  PMID: 22665904
pancreatic cancer; susceptibility; overall survival; genome-wide association study (GWAS)
20.  A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms 
Nature genetics  2009;41(4):455-459.
Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis1–5. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis6–10, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci11. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
doi:10.1038/ng.342
PMCID: PMC3676425  PMID: 19287384
21.  Medication Adherence Among Latino and Non-Latino White Children With Asthma 
Pediatrics  2012;129(6):e1404-e1410.
OBJECTIVE:
Latino children of Caribbean descent remain at high risk for poorly controlled asthma. Controller medications improve asthma control; however, medication adherence remains suboptimal, particularly among minorities. This study assessed socioeconomic, family-based, and parent factors in medication adherence among children with asthma from Rhode Island (RI; Latino and non-Latino white [NLW]) and Puerto Rico.
METHODS:
Data collection occurred as part of a multicenter study of asthma disparities. Our sample included children (ages 7–16) prescribed objectively monitored controller medications (n = 277; 80 island Puerto Rico, 114 RI Latino, 83 RI NLW). Parents completed questionnaires regarding family background and beliefs about medications. Families participated in an interview regarding asthma management. Multilevel analyses (maximum likelihood estimates) accounting for children being nested within site and ethnic group assessed the contribution of social context, family, and parent variables to medication adherence.
RESULTS:
Medication adherence differed by ethnic group (F2, 271 = 7.46, P < .01), with NLW families demonstrating the highest levels of adherence. Multilevel models indicated that parental beliefs about medication necessity and family organization regarding medication use were significant predictors of adherence, even for families below the poverty threshold. With family factors in the model, a substantial improvement in model fit occurred (Akaike Information Criterion change of 103.45).
CONCLUSIONS:
Adherence to controller medications was lower among Latino children in our sample. Targeted interventions that capitalize on existing family resources, emphasize structure, and address parental beliefs about the importance of medications may be of benefit to families from different cultural backgrounds.
doi:10.1542/peds.2011-1391
PMCID: PMC3362901  PMID: 22566417
asthma; patient nonadherence; disparities
22.  Perceptual accuracy of upper airway compromise in children: Clinical relevance and future directions for research 
Allergy & Rhinology  2013;4(2):e54-e62.
Approximately 80% of children with asthma have coexisting allergic rhinitis. The accurate recognition and assessment of asthma and rhinitis symptoms is an integral component of guideline-based treatment for both conditions. This article describes the development and preliminary evaluation of a novel paradigm for testing the accuracy of children's assessment of their upper airway (rhinitis) symptoms. This work is guided by our previous research showing the clinical efficacy of tools to evaluate children's perceptual accuracy of asthma symptoms and linking accurate asthma symptom perception to decreased asthma morbidity (Fritz G, et al., Ethnic differences in perception of lung function: A factor in pediatric asthma disparities? Am J Respir Crit Care Med 182:12–18, 2010; Klein RB, et al., The Asthma Risk Grid: Clinical interpretation of symptom perception, Allergy Asthma Proc 251–256, 2004). The pilot study tests a paradigm that allows for the examination of the correspondence of children's assessment of their upper airway functioning with actual values of upper airway flow through the use of a portable, handheld nasal peak flowmeter. Nine children with persistent asthma were evaluated over a 4-week period. The article describes the rhinitis perceptual accuracy paradigm and reviews the results of a pilot study, showing a large proportion of inaccurate rhinitis symptoms “guesses” by the sample of children with persistent asthma. Patterns of inaccuracy, rhinitis control, and asthma morbidity are also described. Directions for future work are reviewed. The development of clinical tools to evaluate children's accuracy of rhinitis symptoms are needed, given the central role of the self-assessment of symptoms in guideline-based care. Accurate perception of the severity of rhinitis symptoms may enhance rhinitis control, lessen the burden of asthma, and prevent unnecessary emergency use among this high-risk group of children.
doi:10.2500/ar.2013.4.0060
PMCID: PMC3793113  PMID: 24124637
Allergy; asthma; children; perceptual accuracy; rhinitis; treatment; upper airway
23.  Identifying Individual, Cultural and Asthma-Related Risk and Protective Factors Associated With Resilient Asthma Outcomes in Urban Children and Families 
Journal of Pediatric Psychology  2012;37(4):424-437.
Objective The goal of this study is to identify individual, family/cultural, and illness-related protective factors that may minimize asthma morbidity in the context of multiple urban risks in a sample of inner-city children and families. Methods Participating families are from African-American (33), Latino (51) and non-Latino white (47) backgrounds. A total of 131 children with asthma (56% male), ages 6–13 years and their primary caregivers were included. Results Analyses supported the relationship between cumulative risks and asthma morbidity across children of the sample. Protective processes functioned differently by ethnic group. For example, Latino families exhibited higher levels of family connectedness, and this was associated with lower levels of functional limitation due to asthma, in the context of risks. Conclusions This study demonstrates the utility of examining multilevel protective processes that may guard against urban risks factors to decrease morbidity. Intervention programs for families from specific ethnic groups can be tailored to consider individual, family-based/cultural and illness-related supports that decrease stress and enhance aspects of asthma treatment.
doi:10.1093/jpepsy/jss002
PMCID: PMC3415979  PMID: 22408053
asthma outcomes; cultural factors; inner city; pediatric asthma; protective factors
24.  Genetic Structure and Linkage Disequilibrium in a Diverse, Representative Collection of the C4 Model Plant, Sorghum bicolor 
G3: Genes|Genomes|Genetics  2013;3(5):783-793.
To facilitate the mapping of genes in sorghum [Sorghum bicolor (L.) Moench] underlying economically important traits, we analyzed the genetic structure and linkage disequilibrium in a sorghum mini core collection of 242 landraces with 13,390 single-nucleotide polymorphims. The single-nucleotide polymorphisms were produced using a highly multiplexed genotyping-by-sequencing methodology. Genetic structure was established using principal component, Neighbor-Joining phylogenetic, and Bayesian cluster analyses. These analyses indicated that the mini-core collection was structured along both geographic origin and sorghum race classification. Examples of the former were accessions from Southern Africa, East Asia, and Yemen. Examples of the latter were caudatums with widespread geographical distribution, durras from India, and guineas from West Africa. Race bicolor, the most primitive and the least clearly defined sorghum race, clustered among other races and formed only one clear bicolor-centric cluster. Genome-wide linkage disequilibrium analyses showed linkage disequilibrium decayed, on average, within 10−30 kb, whereas the short arm of SBI-06 contained a linkage disequilibrium block of 20.33 Mb, confirming a previous report of low recombination on this chromosome arm. Four smaller but equally significant linkage disequilibrium blocks of 3.5−35.5 kb were detected on chromosomes 1, 2, 9, and 10. We examined the genes encoded within each block to provide a first look at candidates such as homologs of GS3 and FT that may indicate a selective sweep during sorghum domestication.
doi:10.1534/g3.112.004861
PMCID: PMC3656726  PMID: 23704283
sorghum; races; SNPs; FseI-assisted genotyping; linkage disequilibrium
25.  Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk 
Gaudet, Mia M. | Kuchenbaecker, Karoline B. | Vijai, Joseph | Klein, Robert J. | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Dunning, Alison M. | Lee, Andrew | Dennis, Joe | Healey, Sue | Dicks, Ed | Soucy, Penny | Sinilnikova, Olga M. | Pankratz, Vernon S. | Wang, Xianshu | Eldridge, Ronald C. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Schmutzler, Rita K. | Nathanson, Katherine L. | Piedmonte, Marion | Singer, Christian F. | Thomassen, Mads | Hansen, Thomas v. O. | Neuhausen, Susan L. | Blanco, Ignacio | Greene, Mark H. | Garber, Judith | Weitzel, Jeffrey N. | Andrulis, Irene L. | Goldgar, David E. | D'Andrea, Emma | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | van Rensburg, Elizabeth J. | Arason, Adalgeir | Rennert, Gad | van den Ouweland, Ans M. W. | van der Hout, Annemarie H. | Kets, Carolien M. | Aalfs, Cora M. | Wijnen, Juul T. | Ausems, Margreet G. E. M. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Jacobs, Chris | Adlard, Julian | Tischkowitz, Marc | Porteous, Mary E. | Damiola, Francesca | Golmard, Lisa | Barjhoux, Laure | Longy, Michel | Belotti, Muriel | Ferrer, Sandra Fert | Mazoyer, Sylvie | Spurdle, Amanda B. | Manoukian, Siranoush | Barile, Monica | Genuardi, Maurizio | Arnold, Norbert | Meindl, Alfons | Sutter, Christian | Wappenschmidt, Barbara | Domchek, Susan M. | Pfeiler, Georg | Friedman, Eitan | Jensen, Uffe Birk | Robson, Mark | Shah, Sohela | Lazaro, Conxi | Mai, Phuong L. | Benitez, Javier | Southey, Melissa C. | Schmidt, Marjanka K. | Fasching, Peter A. | Peto, Julian | Humphreys, Manjeet K. | Wang, Qin | Michailidou, Kyriaki | Sawyer, Elinor J. | Burwinkel, Barbara | Guénel, Pascal | Bojesen, Stig E. | Milne, Roger L. | Brenner, Hermann | Lochmann, Magdalena | Aittomäki, Kristiina | Dörk, Thilo | Margolin, Sara | Mannermaa, Arto | Lambrechts, Diether | Chang-Claude, Jenny | Radice, Paolo | Giles, Graham G. | Haiman, Christopher A. | Winqvist, Robert | Devillee, Peter | García-Closas, Montserrat | Schoof, Nils | Hooning, Maartje J. | Cox, Angela | Pharoah, Paul D. P. | Jakubowska, Anna | Orr, Nick | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Hall, Per | Couch, Fergus J. | Simard, Jacques | Altshuler, David | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Offit, Kenneth
PLoS Genetics  2013;9(3):e1003173.
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Author Summary
Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.
doi:10.1371/journal.pgen.1003173
PMCID: PMC3609647  PMID: 23544012

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