PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-4 (4)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts 
Atherosclerosis  2011;217(2):447-451.
Background
Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the Human CVD bead chip to explore the contribution of other candidate genes determining Lp(a) levels.
Methods
48,032 single nucleotide polymorphisms (SNPs) from the Illumina Human CVD bead chip were genotyped in 5,059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p< 10−4 outside the LPA locus were selected for replication in a total of an additional 9,463 participants of five European based studies (EAS, EPIC-Norfolk, NPHSII, PROCARDIS, and SAPHIR)
Results
In Whitehall II, apart from the LPA locus (where p values for several SNPs were < 10−30) there was significant association at four loci GALNT2, FABP1, PPARGC1A and TNFRSFF11A. However, a meta-analysis of the six studies did not confirm any of these findings.
Conclusion
Results from this meta analysis of 14,522 participants revealed no candidate genes from the Human CVD bead chip outside the LPA locus to have an effect on Lp(a) levels. Further studies with genome-wide and denser SNP coverage are required to confirm or refute this finding.
doi:10.1016/j.atherosclerosis.2011.04.015
PMCID: PMC3972487  PMID: 21592478
Lipoprotein(a); LPA; Illumina Human CVD bead chip; genetic association
2.  Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls 
PLoS Pathogens  2013;9(7):e1003515.
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
Author Summary
Comparing the frequency differences between common DNA variants in disease-affected cases and in unaffected controls has been successful in uncovering the genetic component of multiple diseases. This approach is most effective when large samples of cases and controls are available. Here we combine information from multiple studies of HIV infected patients, including more than 6,300 HIV+ individuals, with data from 7,200 general population samples of European ancestry to test nearly 8 million common DNA variants for an impact on HIV acquisition. With this large sample we did not observe any single common genetic variant that significantly associated with HIV acquisition. We further tested 22 variants previously identified by smaller studies as influencing HIV acquisition. With the exception of a deletion polymorphism in the CCR5 gene (CCR5Δ32) we found no convincing evidence to support these previous associations. Taken together these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
doi:10.1371/journal.ppat.1003515
PMCID: PMC3723635  PMID: 23935489
3.  A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol 
Surakka, Ida | Isaacs, Aaron | Karssen, Lennart C. | Laurila, Pirkka-Pekka P. | Middelberg, Rita P. S. | Tikkanen, Emmi | Ried, Janina S. | Lamina, Claudia | Mangino, Massimo | Igl, Wilmar | Hottenga, Jouke-Jan | Lagou, Vasiliki | van der Harst, Pim | Mateo Leach, Irene | Esko, Tõnu | Kutalik, Zoltán | Wainwright, Nicholas W. | Struchalin, Maksim V. | Sarin, Antti-Pekka | Kangas, Antti J. | Viikari, Jorma S. | Perola, Markus | Rantanen, Taina | Petersen, Ann-Kristin | Soininen, Pasi | Johansson, Åsa | Soranzo, Nicole | Heath, Andrew C. | Papamarkou, Theodore | Prokopenko, Inga | Tönjes, Anke | Kronenberg, Florian | Döring, Angela | Rivadeneira, Fernando | Montgomery, Grant W. | Whitfield, John B. | Kähönen, Mika | Lehtimäki, Terho | Freimer, Nelson B. | Willemsen, Gonneke | de Geus, Eco J. C. | Palotie, Aarno | Sandhu, Manj S. | Waterworth, Dawn M. | Metspalu, Andres | Stumvoll, Michael | Uitterlinden, André G. | Jula, Antti | Navis, Gerjan | Wijmenga, Cisca | Wolffenbuttel, Bruce H. R. | Taskinen, Marja-Riitta | Ala-Korpela, Mika | Kaprio, Jaakko | Kyvik, Kirsten O. | Boomsma, Dorret I. | Pedersen, Nancy L. | Gyllensten, Ulf | Wilson, James F. | Rudan, Igor | Campbell, Harry | Pramstaller, Peter P. | Spector, Tim D. | Witteman, Jacqueline C. M. | Eriksson, Johan G. | Salomaa, Veikko | Oostra, Ben A. | Raitakari, Olli T. | Wichmann, H.-Erich | Gieger, Christian | Järvelin, Marjo-Riitta | Martin, Nicholas G. | Hofman, Albert | McCarthy, Mark I. | Peltonen, Leena | van Duijn, Cornelia M. | Aulchenko, Yurii S. | Ripatti, Samuli
PLoS Genetics  2011;7(10):e1002333.
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Author Summary
Circulating serum lipids contribute greatly to the global health by affecting the risk for cardiovascular diseases. Serum lipid levels are partly inherited, and already 95 loci affecting high- and low-density lipoprotein cholesterol, total cholesterol, and triglycerides have been found. Serum lipids are also known to be affected by multiple epidemiological risk factors like body composition, lifestyle, and sex. It has been hypothesized that there are loci modifying the effects between risk factors and serum lipids, but to date only candidate gene studies for interactions have been reported. We conducted a genome-wide screen with meta-analysis approach to identify loci having interactions with epidemiological risk factors on serum lipids with over 30,000 population-based samples. When combining results from our initial datasets and 8 additional replication cohorts (maximum N = 17,102), we found a genome-wide significant locus in chromosome 4p15 with a joint P-value of 4.79×10−9 modifying the effect of waist-to-hip ratio on total cholesterol. In the area surrounding this genetic variant, there were two genes having association between the genotypes and the gene expression in adipose tissue, and we also found enrichment of association in genes belonging to lipid metabolism related functions.
doi:10.1371/journal.pgen.1002333
PMCID: PMC3197672  PMID: 22028671
4.  Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease 
Schunkert, Heribert | König, Inke R. | Kathiresan, Sekar | Reilly, Muredach P. | Assimes, Themistocles L. | Holm, Hilma | Preuss, Michael | Stewart, Alexandre F. R. | Barbalic, Maja | Gieger, Christian | Absher, Devin | Aherrahrou, Zouhair | Allayee, Hooman | Altshuler, David | Anand, Sonia S. | Andersen, Karl | Anderson, Jeffrey L. | Ardissino, Diego | Ball, Stephen G. | Balmforth, Anthony J. | Barnes, Timothy A. | Becker, Diane M. | Becker, Lewis C. | Berger, Klaus | Bis, Joshua C. | Boekholdt, S. Matthijs | Boerwinkle, Eric | Braund, Peter S. | Brown, Morris J. | Burnett, Mary Susan | Buysschaert, Ian | Carlquist, Cardiogenics, John F. | Chen, Li | Cichon, Sven | Codd, Veryan | Davies, Robert W. | Dedoussis, George | Dehghan, Abbas | Demissie, Serkalem | Devaney, Joseph M. | Do, Ron | Doering, Angela | Eifert, Sandra | El Mokhtari, Nour Eddine | Ellis, Stephen G. | Elosua, Roberto | Engert, James C. | Epstein, Stephen E. | Faire, Ulf de | Fischer, Marcus | Folsom, Aaron R. | Freyer, Jennifer | Gigante, Bruna | Girelli, Domenico | Gretarsdottir, Solveig | Gudnason, Vilmundur | Gulcher, Jeffrey R. | Halperin, Eran | Hammond, Naomi | Hazen, Stanley L. | Hofman, Albert | Horne, Benjamin D. | Illig, Thomas | Iribarren, Carlos | Jones, Gregory T. | Jukema, J.Wouter | Kaiser, Michael A. | Kaplan, Lee M. | Kastelein, John J.P. | Khaw, Kay-Tee | Knowles, Joshua W. | Kolovou, Genovefa | Kong, Augustine | Laaksonen, Reijo | Lambrechts, Diether | Leander, Karin | Lettre, Guillaume | Li, Mingyao | Lieb, Wolfgang | Linsel-Nitschke, Patrick | Loley, Christina | Lotery, Andrew J. | Mannucci, Pier M. | Maouche, Seraya | Martinelli, Nicola | McKeown, Pascal P. | Meisinger, Christa | Meitinger, Thomas | Melander, Olle | Merlini, Pier Angelica | Mooser, Vincent | Morgan, Thomas | Mühleisen, Thomas W. | Muhlestein, Joseph B. | Münzel, Thomas | Musunuru, Kiran | Nahrstaedt, Janja | Nelson, Christopher P. | Nöthen, Markus M. | Olivieri, Oliviero | Patel, Riyaz S. | Patterson, Chris C. | Peters, Annette | Peyvandi, Flora | Qu, Liming | Quyyumi, Arshed A. | Rader, Daniel J. | Rallidis, Loukianos S. | Rice, Catherine | Rosendaal, Frits R. | Rubin, Diana | Salomaa, Veikko | Sampietro, M. Lourdes | Sandhu, Manj S. | Schadt, Eric | Schäfer, Arne | Schillert, Arne | Schreiber, Stefan | Schrezenmeir, Jürgen | Schwartz, Stephen M. | Siscovick, David S. | Sivananthan, Mohan | Sivapalaratnam, Suthesh | Smith, Albert | Smith, Tamara B. | Snoep, Jaapjan D. | Soranzo, Nicole | Spertus, John A. | Stark, Klaus | Stirrups, Kathy | Stoll, Monika | Tang, W. H. Wilson | Tennstedt, Stephanie | Thorgeirsson, Gudmundur | Thorleifsson, Gudmar | Tomaszewski, Maciej | Uitterlinden, Andre G. | van Rij, Andre M. | Voight, Benjamin F. | Wareham, Nick J. | Wells, George A. | Wichmann, H.-Erich | Wild, Philipp S. | Willenborg, Christina | Witteman, Jaqueline C. M. | Wright, Benjamin J. | Ye, Shu | Zeller, Tanja | Ziegler, Andreas | Cambien, Francois | Goodall, Alison H. | Cupples, L. Adrienne | Quertermous, Thomas | März, Winfried | Hengstenberg, Christian | Blankenberg, Stefan | Ouwehand, Willem H. | Hall, Alistair S. | Deloukas, Panos | Thompson, John R. | Stefansson, Kari | Roberts, Robert | Thorsteinsdottir, Unnur | O’Donnell, Christopher J. | McPherson, Ruth | Erdmann, Jeanette | Samani, Nilesh J.
Nature genetics  2011;43(4):333-338.
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
doi:10.1038/ng.784
PMCID: PMC3119261  PMID: 21378990

Results 1-4 (4)