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Featured researches published by Serkalem Demissie.


Nature Genetics | 2009

Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan; Cristen J. Willer; Gina M. Peloso; Serkalem Demissie; Kiran Musunuru; Eric E. Schadt; Lee M. Kaplan; Derrick Bennett; Yun Li; Toshiko Tanaka; Benjamin F. Voight; Lori L. Bonnycastle; Anne U. Jackson; Gabriel Crawford; Aarti Surti; Candace Guiducci; Noël P. Burtt; Sarah Parish; Robert Clarke; Diana Zelenika; Kari Kubalanza; Mario A. Morken; Laura J. Scott; Heather M. Stringham; Pilar Galan; Amy J. Swift; Johanna Kuusisto; Richard N. Bergman; Jouko Sundvall; Markku Laakso

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10−8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10−15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.


Nature Genetics | 2009

Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies

Fernando Rivadeneira; Unnur Styrkarsdottir; Karol Estrada; Bjarni V. Halldórsson; Yi-Hsiang Hsu; J. Brent Richards; M. Carola Zillikens; Fotini K. Kavvoura; Najaf Amin; Yurii S. Aulchenko; L. Adrienne Cupples; Panagiotis Deloukas; Serkalem Demissie; Elin Grundberg; Albert Hofman; Augustine Kong; David Karasik; Joyce B. J. van Meurs; Ben A. Oostra; Tomi Pastinen; Huibert A. P. Pols; Gunnar Sigurdsson; Nicole Soranzo; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Frances M. K. Williams; Scott G. Wilson; Yanhua Zhou; Stuart H. Ralston; Cornelia M. van Duijn

Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 × 10−8), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.


Aging Cell | 2006

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study.

Serkalem Demissie; Daniel Levy; Emelia J. Benjamin; L. A. Cupples; Jeffrey P. Gardner; Alan Herbert; Masayuki Kimura; Martin G. Larson; James B. Meigs; John F. Keaney; Abraham Aviv

Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging‐related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40–89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = –0.41, P < 0.0001) and age‐adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) (r =–0.16, P = 0.007) and urinary 8‐epi‐PGF2α (r = –0.16, P = 0.005) – an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age‐adjusted TRF length (hypertensives = 5.93 ± 0.042 kb, normotensives = 6.07 ± 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2004

High-Density Lipoprotein Subpopulation Profile and Coronary Heart Disease Prevalence in Male Participants of the Framingham Offspring Study

Bela F. Asztalos; L. Adrienne Cupples; Serkalem Demissie; Katalin V. Horvath; Caitlin E. Cox; Marcelo Costa Batista; Ernst J. Schaefer

Objective—High-density lipoprotein (HDL) is a heterogeneous lipoprotein class and there is no consensus on the value of HDL subspecies in coronary heart disease (CHD) risk assessment. We tested the hypothesis whether specific HDL subpopulations are significantly associated with CHD-prevalence. Methods and Results—ApoA-I concentrations (mg/dL) in HDL subpopulations were quantitatively determined by native 2d gel electrophoresis, immunoblotting, and image analysis in male participants in the Framingham Offspring Study (FOS). CHD cases (n=169) had higher pre&bgr;-1 and &agr;-3 particle and lower &agr;-1, pre&agr;-3, and pre&agr;-1 particle levels than either all (n=1277) or HDL cholesterol-matched (n=358) controls. &agr;-1 and pre&agr;-3 levels had an inverse association, whereas &agr;-3 and pre&agr;-1 particle levels had a positive association with CHD prevalence after adjusting the data for established CHD risk factors. Standardized logit coefficients indicated that &agr;-1 HDL was most significantly associated with CHD prevalence. Moreover, each mg/dL increase in &agr;-1 particle level decreased odds of CHD by 26% (P<0.0001), whereas each mg/dL increase in HDL cholesterol decreased odds of CHD by 2% in a model including all established CHD risk factors. Conclusions—Specific HDL subpopulations were positively correlated, whereas others were inversely correlated with CHD prevalence in male subject in the FOS, indicating that the various HDL particles might have different roles in the cause of CHD.


Journal of Clinical Oncology | 2001

Adjuvant Tamoxifen: Predictors of Use, Side Effects, and Discontinuation in Older Women

Serkalem Demissie; Rebecca A. Silliman; Timothy L. Lash

PURPOSE To identify predictors of adjuvant tamoxifen use, side effects, and discontinuation in older women. PATIENTS AND METHODS We followed a cohort of 303 women > or = 55 years of age diagnosed with stage I or stage II breast cancer for nearly 3 years. Data were collected from womens surgical records and from computer-assisted telephone interviews at 5, 21, and 33 months after primary tumor therapy. RESULTS Two hundred ninety-two (96%) of 303 patients in the study provided information about tamoxifen use. Tamoxifen use was reported by 189 patients (65%); 26 (15%) discontinued use during the follow-up period. Patients who were 65 to 74 years of age (relative to those 55 to 64 years of age), had stage II disease, were estrogen receptor-positive, saw a greater number of breast cancer physicians, and had better perceptions of their abilities to discuss treatment options with physicians had greater odds of tamoxifen use. Those who had better physical function, had received standard primary tumor therapy, and had obtained helpful breast cancer information from books or magazines had lesser odds of tamoxifen use. Patients > or = 75 years of age (relative to those 55 to 64 years of age) and patients with better emotional health had significantly lesser odds of reporting side effects. Patients who were estrogen receptor-positive were less likely to stop taking tamoxifen; patients who experienced side effects were more likely to stop taking tamoxifen. CONCLUSION Deviations from a prescribed course of adjuvant tamoxifen occur relatively frequently. The clinical consequences of this deviation need to be identified.


BMC Medical Genetics | 2007

A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

Sekar Kathiresan; Alisa K. Manning; Serkalem Demissie; Ralph B. D'Agostino; Aarti Surti; Candace Guiducci; Lauren Gianniny; Noeel P. Burtt; Olle Melander; Marju Orho-Melander; Donna K. Arnett; Gina M. Peloso; Jose M. Ordovas; L. Adrienne Cupples

BackgroundBlood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.MethodsIn 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).ResultsLong-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.ConclusionUsing a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.


Arteriosclerosis, Thrombosis, and Vascular Biology | 2005

Value of High-Density Lipoprotein (HDL) Subpopulations in Predicting Recurrent Cardiovascular Events in the Veterans Affairs HDL Intervention Trial

Bela F. Asztalos; Dorothea Collins; L. Adrienne Cupples; Serkalem Demissie; Katalin V. Horvath; Hanna E. Bloomfield; Sander J. Robins; Ernst J. Schaefer

Objective—To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). Methods and Results—Apolipoprotein A-I (apoA-I)–containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (α-1, α-2, pre–α-1, and pre–α-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre–β-1 and α-3) levels than subjects without such events. Multivariate analyses indicated that α-1 and α-2 particle levels were significant negative risk factors, whereas α-3 level was a significant positive risk factor for new CVD events. Pre–β-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that α-1 was the most significant risk factor for recurrent CVD events among HDL particles. Conclusions—An altered HDL subpopulation profile marked with low α-1 and α-2 levels and a high α-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, α-1 and α-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.


BMC Medical Genetics | 2007

Genome-Wide Association with Bone Mass and Geometry in the Framingham Heart Study

Douglas P. Kiel; Serkalem Demissie; Josée Dupuis; Kathryn L. Lunetta; Joanne M. Murabito; David Karasik

BackgroundOsteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.MethodsWe used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates ≥80%, HWE p ≥ 0.001, and MAF ≥10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.ResultsHeritability estimates for all bone phenotypes were 30–66%. LOD scores ≥3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679–58,934,236 bp) and 22 (35,890,398–48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 × 10-6 and 2.5 × 10-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.ConclusionThe FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.


Circulation | 2002

Dietary Fat Intake Determines the Effect of a Common Polymorphism in the Hepatic Lipase Gene Promoter on High-Density Lipoprotein Metabolism Evidence of a Strong Dose Effect in This Gene-Nutrient Interaction in the Framingham Study

Jose M. Ordovas; Dolores Corella; Serkalem Demissie; L. Adrienne Cupples; Patrick Couture; Oscar Coltell; Peter W.F. Wilson; Ernst J. Schaefer; Katherine L. Tucker

Background—Gene-nutrient interactions affecting high-density lipoprotein cholesterol (HDL-C) concentrations may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Hepatic lipase (HL) is a key determinant of HDL metabolism. Four polymorphisms in linkage disequilibrium have been identified in the HL gene (LIPC), defining what is known as the −514T allele. This allele has been associated with decreased HL activity and increased HDL-C concentrations. However, the effect is variable among populations. Methods and Results—We have examined interaction effects between the −514(C/T) LIPC polymorphism, dietary fat, and HDL-related measures in 1020 men and 1110 women participating in the Framingham Study. We found a consistent and highly significant gene-nutrient interaction showing a strong dose-response effect. Thus, the T allele was associated with significantly greater HDL-C concentrations only in subjects consuming <30% of energy from fat (P <0.001). When total fat intake was ≥30% of energy, mean HDL-C concentrations were lowest among those with the TT genotype, and no differences were observed between CC and CT individuals. We found similar gene-nutrient interactions when the outcome variables were HDL2-C (P <0.001), large HDL subfraction (P <0.001), or HDL size (P =0.001). These interactions were seen for saturated and monounsaturated fat intakes (highly correlated with animal fat in this population), but not for polyunsaturated fat. Conclusions—Dietary fat intake modifies the effect of the −514(C/T) polymorphism on HDL-C concentrations and subclasses. Specifically, in the Framingham Study, TT subjects may have an impaired adaptation to higher animal fat diets that could result in higher cardiovascular risk.


BMC Medical Genetics | 2007

The Framingham Heart Study 100K SNP Genome-Wide Association Study Resource: Overview of 17 Phenotype Working Group Reports

L. Adrienne Cupples; Heather T Arruda; Emelia J. Benjamin; Ralph B. D'Agostino; Serkalem Demissie; Anita L. DeStefano; Josée Dupuis; Kathleen Falls; Caroline S. Fox; Daniel J. Gottlieb; Diddahally R. Govindaraju; Chao-Yu Guo; Nancy L. Heard-Costa; Shih-Jen Hwang; Sekar Kathiresan; Douglas P. Kiel; Jason M. Laramie; Martin G. Larson; Daniel Levy; Chunyu Liu; Kathryn L. Lunetta; Matthew D Mailman; Alisa K. Manning; James B. Meigs; Joanne M. Murabito; Christopher Newton-Cheh; George T. O'Connor; Christopher J. O'Donnell; Mona Pandey; Sudha Seshadri

BackgroundThe Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.MethodsAdult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests.ResultsThe participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 ± 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency ≥ 10%, genotype call rate ≥ 80%, Hardy-Weinberg equilibrium p-value ≥ 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.ConclusionWe have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.

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Douglas P. Kiel

Beth Israel Deaconess Medical Center

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Katherine L. Tucker

University of Massachusetts Lowell

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Fernando Rivadeneira

Erasmus University Rotterdam

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Joshua C. Bis

University of Washington

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