Browsing by Author "Aslibekyan, Stella"
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Publication An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids(Frontiers Media, 2019) Geng, Xin; Irvin, Marguerite R; Hidalgo, Bertha; Aslibekyan, Stella; Srinivasasainagendra, Vinodh; An, Ping; Frazier-Wood, Alexis C; Tiwari, Hemant K; Dave, Tushar; Ryan, Kathleen; Ordovas, Jose M; Straka, Robert J; Feitosa, Mary F; Hopkins, Paul N; Borecki, Ingrid; Province, Michael A; Mitchell, Braxton D; Arnett, Donna K; Zhi, Degui; National Institutes of Health (Estados Unidos); NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); United States Department of Agriculture; United States Department of Agriculture. National Institute of Food and AgricultureBackground: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.Publication Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization(Nature Publishing Group, 2016) Smith, Caren E.; Coltell, Oscar; Sorli, Jose V.; Estruch, Ramon; Angel Martinez-Gonzalez, Miguel; Salas-Salvado, Jordi; Fito, Montserrat; Aros, Fernando; Dashti, Hassan S.; Lai, Chao Q.; Miro, Leticia; Serra-Majem, Lluis; Gomez-Gracia, Enrique; Fiol, Miquel; Ros, Emilio; Aslibekyan, Stella; Hidalgo, Bertha; Neuhouser, Marian L.; Di, Chongzhi; Tucker, Katherine L.; Arnett, Donna K; Ordovas, Jose M; Corella, Dolores; National Institutes of Health (Estados Unidos); NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); United States Department of Agriculture. Agricultural Research Service; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Jaume I University (España); Generalitat Valenciana (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n <= 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction: 0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.Publication Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study(Wiley, 2015) Ma, Yiyi; Smith, Caren E.; Lai, Chao-Qiang; Irvin, Marguerite R.; Parnell, Laurence D.; Lee, Yu-Chi; Pham, Lucia; Aslibekyan, Stella; Claas, Steven A.; Tsai, Michael Y.; Borecki, Ingrid B.; Kabagambe, Edmond K.; Berciano, Silvia; Ordovas, Jose M; Absher, Devin M; Arnett, Donna K; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos); United States Department of AgricultureAlthough apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (>50\%) and were located in the promoter region, Group 2 exhibited hypomethylation (<50\%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (>50\%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r=-0.66, P=0.004). APOE methylation was significantly associated with age (minimum P=2.06E-08) and plasma total cholesterol (minimum P=3.53E-03). Finally, APOE methylation patterns differed across APOE epsilon variants (minimum P=3.51E-05) and the promoter variant rs405509 (minimum P=0.01), which further showed a significant interaction with age (P=0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.Publication Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)(2017-06) Aslibekyan, Stella; Irvin, Marguerite R; Hidalgo, Bertha A; Perry, Rodney T; Jeyarajah, Elias J; Garcia, Erwin; Shalaurova, Irina; Hopkins, Paul N; Province, Michael A; Tiwari, Hemant K; Ordovas, Jose M; Absher, Devin M; Arnett, Donna K; National Institutes of Health (Estados Unidos); American Heart AssociationBACKGROUND: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. METHODS AND RESULTS: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. CONCLUSIONS: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans.Publication Genomics of post-prandial lipidomic phenotypes in the Genetics of Lipid lowering Drugs and Diet Network (GOLDN) study(Public Library of Science (PLOS), 2014) Irvin, Marguerite R; Zhi, Degui; Aslibekyan, Stella; Claas, Steven A; Absher, Devin M; Ordovas, Jose M; Tiwari, Hemant K; Watkins, Steve; Arnett, Donna K; National Institutes of Health (Estados Unidos)BACKGROUND: Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response. METHODS AND RESULTS: We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)). SORBS1 has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, PRIC285, a co-activator of PPARa). CONCLUSIONS: Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.Publication Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.(American Society of Human Genetics, 2022-01-06) Hindy, George; Dornbos, Peter; Chaffin, Mark D; Liu, Dajiang J; Wang, Minxian; Selvaraj, Margaret Sunitha; Zhang, David; Park, Joseph; Aguilar-Salinas, Carlos A; Antonacci-Fulton, Lucinda; Ardissino, Diego; Arnett, Donna K; Aslibekyan, Stella; Atzmon, Gil; Ballantyne, Christie M; Barajas-Olmos, Francisco; Barzilai, Nir; Becker, Lewis C; Bielak, Lawrence F; Bis, Joshua C; Blangero, John; Boerwinkle, Eric; Bonnycastle, Lori L; Bottinger, Erwin; Bowden, Donald W; Bown, Matthew J; Brody, Jennifer A; Broome, Jai G; Burtt, Noël P; Cade, Brian E; Centeno-Cruz, Federico; Chan, Edmund; Chang, Yi-Cheng; Chen, Yii-Der I; Cheng, Ching-Yu; Choi, Won Jung; Chowdhury, Rajiv; Contreras-Cubas, Cecilia; Córdova, Emilio J; Correa, Adolfo; Cupples, L Adrienne; Curran, Joanne E; Danesh, John; de Vries, Paul S; DeFronzo, Ralph A; Doddapaneni, Harsha; Duggirala, Ravindranath; Dutcher, Susan K; Ellinor, Patrick T; Emery, Leslie S; Florez, Jose C; Fornage, Myriam; Freedman, Barry I; Fuster, Valentin; Garay-Sevilla, Ma Eugenia; García-Ortiz, Humberto; Germer, Soren; Gibbs, Richard A; Gieger, Christian; Glaser, Benjamin; Gonzalez, Clicerio; Gonzalez-Villalpando, Maria Elena; Graff, Mariaelisa; Graham, Sarah E; Grarup, Niels; Groop, Leif C; Guo, Xiuqing; Gupta, Namrata; Han, Sohee; Hanis, Craig L; Hansen, Torben; He, Jiang; Heard-Costa, Nancy L; Hung, Yi-Jen; Hwang, Mi Yeong; Irvin, Marguerite R; Islas-Andrade, Sergio; Jarvik, Gail P; Kang, Hyun Min; Kardia, Sharon L R; Kelly, Tanika; Kenny, Eimear E; Khan, Alyna T; Kim, Bong-Jo; Kim, Ryan W; Kim, Young Jin; Koistinen, Heikki A; Kooperberg, Charles; Kuusisto, Johanna; Kwak, Soo Heon; Laakso, Markku; Lange, Leslie A; Lee, Jiwon; Lee, Juyoung; Lee, Seonwook; Lehman, Donna M; Lemaitre, Rozenn N; Linneberg, Allan; Liu, Jianjun; Loos, Ruth J F; Lubitz, Steven A; Lyssenko, Valeriya; Ma, Ronald C W; Martin, Lisa Warsinger; Martínez-Hernández, Angélica; Mathias, Rasika A; McGarvey, Stephen T; McPherson, Ruth; Meigs, James B; Meitinger, Thomas; Melander, Olle; Mendoza-Caamal, Elvia; Metcalf, Ginger A; Mi, Xuenan; Mohlke, Karen L; Montasser, May E; Moon, Jee-Young; Moreno-Macías, Hortensia; Morrison, Alanna C; Muzny, Donna M; Nelson, Sarah C; Nilsson, Peter M; O'Connell, Jeffrey R; Orho-Melander, Marju; Orozco, Lorena; Palmer, Colin N A; Palmer, Nicholette D; Park, Cheol Joo; Park, Kyong Soo; Pedersen, Oluf; Peralta, Juan M; Peyser, Patricia A; Post, Wendy S; Preuss, Michael; Psaty, Bruce M; Qi, Qibin; Rao, D C; Redline, Susan; Reiner, Alexander P; Revilla-Monsalve, Cristina; Rich, Stephen S; Samani, Nilesh; Schunkert, Heribert; Schurmann, Claudia; Seo, Daekwan; Seo, Jeong-Sun; Sim, Xueling; Sladek, Rob; Small, Kerrin S; So, Wing Yee; Stilp, Adrienne M; Tai, E Shyong; Tam, Claudia H T; Taylor, Kent D; Teo, Yik Ying; Thameem, Farook; Tomlinson, Brian; Tsai, Michael Y; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Tusié-Luna, Teresa; Udler, Miriam S; van Dam, Rob M; Vasan, Ramachandran S; Viaud Martinez, Karine A; Wang, Fei Fei; Wang, Xuzhi; Watkins, Hugh; Weeks, Daniel E; Wilson, James G; Witte, Daniel R; Wong, Tien-Yin; Yanek, Lisa R; Kathiresan, Sekar; Rader, Daniel J; Rotter, Jerome I; Boehnke, Michael; McCarthy, Mark I; Willer, Cristen J; Natarajan, Pradeep; Flannick, Jason A; Khera, Amit V; Peloso, Gina M; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos)Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.