Boerwinkle E

References (24)

Title : Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity - Turcot_2018_Nat.Genet_50_26
Author(s) : Turcot V , Lu Y , Highland HM , Schurmann C , Justice AE , Fine RS , Bradfield JP , Esko T , Giri A , Graff M , Guo X , Hendricks AE , Karaderi T , Lempradl A , Locke AE , Mahajan A , Marouli E , Sivapalaratnam S , Young KL , Alfred T , Feitosa MF , Masca NGD , Manning AK , Medina-Gomez C , Mudgal P , Ng MCY , Reiner AP , Vedantam S , Willems SM , Winkler TW , Abecasis G , Aben KK , Alam DS , Alharthi SE , Allison M , Amouyel P , Asselbergs FW , Auer PL , Balkau B , Bang LE , Barroso I , Bastarache L , Benn M , Bergmann S , Bielak LF , Bluher M , Boehnke M , Boeing H , Boerwinkle E , Boger CA , Bork-Jensen J , Bots ML , Bottinger EP , Bowden DW , Brandslund I , Breen G , Brilliant MH , Broer L , Brumat M , Burt AA , Butterworth AS , Campbell PT , Cappellani S , Carey DJ , Catamo E , Caulfield MJ , Chambers JC , Chasman DI , Chen YI , Chowdhury R , Christensen C , Chu AY , Cocca M , Collins FS , Cook JP , Corley J , Corominas Galbany J , Cox AJ , Crosslin DS , Cuellar-Partida G , D'Eustacchio A , Danesh J , Davies G , Bakker PIW , Groot MCH , Mutsert R , Deary IJ , Dedoussis G , Demerath EW , Heijer M , Hollander AI , Ruijter HM , Dennis JG , Denny JC , Angelantonio E , Drenos F , Du M , Dube MP , Dunning AM , Easton DF , Edwards TL , Ellinghaus D , Ellinor PT , Elliott P , Evangelou E , Farmaki AE , Farooqi IS , Faul JD , Fauser S , Feng S , Ferrannini E , Ferrieres J , Florez JC , Ford I , Fornage M , Franco OH , Franke A , Franks PW , Friedrich N , Frikke-Schmidt R , Galesloot TE , Gan W , Gandin I , Gasparini P , Gibson J , Giedraitis V , Gjesing AP , Gordon-Larsen P , Gorski M , Grabe HJ , Grant SFA , Grarup N , Griffiths HL , Grove ML , Gudnason V , Gustafsson S , Haessler J , Hakonarson H , Hammerschlag AR , Hansen T , Harris KM , Harris TB , Hattersley AT , Have CT , Hayward C , He L , Heard-Costa NL , Heath AC , Heid IM , Helgeland O , Hernesniemi J , Hewitt AW , Holmen OL , Hovingh GK , Howson JMM , Hu Y , Huang PL , Huffman JE , Ikram MA , Ingelsson E , Jackson AU , Jansson JH , Jarvik GP , Jensen GB , Jia Y , Johansson S , Jorgensen ME , Jorgensen T , Jukema JW , Kahali B , Kahn RS , Kahonen M , Kamstrup PR , Kanoni S , Kaprio J , Karaleftheri M , Kardia SLR , Karpe F , Kathiresan S , Kee F , Kiemeney LA , Kim E , Kitajima H , Komulainen P , Kooner JS , Kooperberg C , Korhonen T , Kovacs P , Kuivaniemi H , Kutalik Z , Kuulasmaa K , Kuusisto J , Laakso M , Lakka TA , Lamparter D , Lange EM , Lange LA , Langenberg C , Larson EB , Lee NR , Lehtimaki T , Lewis CE , Li H , Li J , Li-Gao R , Lin H , Lin KH , Lin LA , Lin X , Lind L , Lindstrom J , Linneberg A , Liu CT , Liu DJ , Liu Y , Lo KS , Lophatananon A , Lotery AJ , Loukola A , Luan J , Lubitz SA , Lyytikainen LP , Mannisto S , Marenne G , Mazul AL , McCarthy MI , McKean-Cowdin R , Medland SE , Meidtner K , Milani L , Mistry V , Mitchell P , Mohlke KL , Moilanen L , Moitry M , Montgomery GW , Mook-Kanamori DO , Moore C , Mori TA , Morris AD , Morris AP , Muller-Nurasyid M , Munroe PB , Nalls MA , Narisu N , Nelson CP , Neville M , Nielsen SF , Nikus K , Njolstad PR , Nordestgaard BG , Nyholt DR , O'Connel JR , O'Donoghue ML , Olde Loohuis LM , Ophoff RA , Owen KR , Packard CJ , Padmanabhan S , Palmer CNA , Palmer ND , Pasterkamp G , Patel AP , Pattie A , Pedersen O , Peissig PL , Peloso GM , Pennell CE , Perola M , Perry JA , Perry JRB , Pers TH , Person TN , Peters A , Petersen ERB , Peyser PA , Pirie A , Polasek O , Polderman TJ , Puolijoki H , Raitakari OT , Rasheed A , Rauramaa R , Reilly DF , Renstrom F , Rheinberger M , Ridker PM , Rioux JD , Rivas MA , Roberts DJ , Robertson NR , Robino A , Rolandsson O , Rudan I , Ruth KS , Saleheen D , Salomaa V , Samani NJ , Sapkota Y , Sattar N , Schoen RE , Schreiner PJ , Schulze MB , Scott RA , Segura-Lepe MP , Shah SH , Sheu WH , Sim X , Slater AJ , Small KS , Smith AV , Southam L , Spector TD , Speliotes EK , Starr JM , Stefansson K , Steinthorsdottir V , Stirrups KE , Strauch K , Stringham HM , Stumvoll M , Sun L , Surendran P , Swift AJ , Tada H , Tansey KE , Tardif JC , Taylor KD , Teumer A , Thompson DJ , Thorleifsson G , Thorsteinsdottir U , Thuesen BH , Tonjes A , Tromp G , Trompet S , Tsafantakis E , Tuomilehto J , Tybjaerg-Hansen A , Tyrer JP , Uher R , Uitterlinden AG , Uusitupa M , Laan SW , Duijn CM , Leeuwen N , van Setten J , Vanhala M , Varbo A , Varga TV , Varma R , Velez Edwards DR , Vermeulen SH , Veronesi G , Vestergaard H , Vitart V , Vogt TF , Volker U , Vuckovic D , Wagenknecht LE , Walker M , Wallentin L , Wang F , Wang CA , Wang S , Wang Y , Ware EB , Wareham NJ , Warren HR , Waterworth DM , Wessel J , White HD , Willer CJ , Wilson JG , Witte DR , Wood AR , Wu Y , Yaghootkar H , Yao J , Yao P , Yerges-Armstrong LM , Young R , Zeggini E , Zhan X , Zhang W , Zhao JH , Zhao W , Zhou W , Zondervan KT , Rotter JI , Pospisilik JA , Rivadeneira F , Borecki IB , Deloukas P , Frayling TM , Lettre G , North KE , Lindgren CM , Hirschhorn JN , Loos RJF
Ref : Nat Genet , 50 :26 , 2018
Abstract : Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
ESTHER : Turcot_2018_Nat.Genet_50_26
PubMedSearch : Turcot_2018_Nat.Genet_50_26
PubMedID: 29273807

Title : Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles - Gregson_2017_Eur.J.Prev.Cardiol_24_492
Author(s) : Gregson JM , Freitag DF , Surendran P , Stitziel NO , Chowdhury R , Burgess S , Kaptoge S , Gao P , Staley JR , Willeit P , Nielsen SF , Caslake M , Trompet S , Polfus LM , Kuulasmaa K , Kontto J , Perola M , Blankenberg S , Veronesi G , Gianfagna F , Mannisto S , Kimura A , Lin H , Reilly DF , Gorski M , Mijatovic V , Munroe PB , Ehret GB , Thompson A , Uria-Nickelsen M , Malarstig A , Dehghan A , Vogt TF , Sasaoka T , Takeuchi F , Kato N , Yamada Y , Kee F , Muller-Nurasyid M , Ferrieres J , Arveiler D , Amouyel P , Salomaa V , Boerwinkle E , Thompson SG , Ford I , Wouter Jukema J , Sattar N , Packard CJ , Shafi Majumder AA , Alam DS , Deloukas P , Schunkert H , Samani NJ , Kathiresan S , Nordestgaard BG , Saleheen D , Howson JM , Di Angelantonio E , Butterworth AS , Danesh J
Ref : Eur J Prev Cardiol , 24 :492 , 2017
Abstract : Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA(2). We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results Lp-PLA(2) activity was decreased by 64% ( p = 2.4 x 10(-25)) with carriage of any of the four loss-of-function variants, by 45% ( p < 10(-300)) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 x 10(-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% ( p < 10(-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.
ESTHER : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedSearch : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedID: 27940953
Gene_locus related to this paper: human-PLA2G7

Title : Distinct loci in the CHRNA5\/CHRNA3\/CHRNB4 gene cluster are associated with onset of regular smoking - Stephens_2013_Genet.Epidemiol_37_846
Author(s) : Stephens SH , Hartz SM , Hoft NR , Saccone NL , Corley RC , Hewitt JK , Hopfer CJ , Breslau N , Coon H , Chen X , Ducci F , Dueker N , Franceschini N , Frank J , Han Y , Hansel NN , Jiang C , Korhonen T , Lind PA , Liu J , Lyytikainen LP , Michel M , Shaffer JR , Short SE , Sun J , Teumer A , Thompson JR , Vogelzangs N , Vink JM , Wenzlaff A , Wheeler W , Yang BZ , Aggen SH , Balmforth AJ , Baumeister SE , Beaty TH , Benjamin DJ , Bergen AW , Broms U , Cesarini D , Chatterjee N , Chen J , Cheng YC , Cichon S , Couper D , Cucca F , Dick D , Foroud T , Furberg H , Giegling I , Gillespie NA , Gu F , Hall AS , Hallfors J , Han S , Hartmann AM , Heikkila K , Hickie IB , Hottenga JJ , Jousilahti P , Kaakinen M , Kahonen M , Koellinger PD , Kittner S , Konte B , Landi MT , Laatikainen T , Leppert M , Levy SM , Mathias RA , McNeil DW , Medland SE , Montgomery GW , Murray T , Nauck M , North KE , Pare PD , Pergadia M , Ruczinski I , Salomaa V , Viikari J , Willemsen G , Barnes KC , Boerwinkle E , Boomsma DI , Caporaso N , Edenberg HJ , Francks C , Gelernter J , Grabe HJ , Hops H , Jarvelin MR , Johannesson M , Kendler KS , Lehtimaki T , Magnusson PK , Marazita ML , Marchini J , Mitchell BD , Nothen MM , Penninx BW , Raitakari O , Rietschel M , Rujescu D , Samani NJ , Schwartz AG , Shete S , Spitz M , Swan GE , Volzke H , Veijola J , Wei Q , Amos C , Cannon DS , Grucza R , Hatsukami D , Heath A , Johnson EO , Kaprio J , Madden P , Martin NG , Stevens VL , Weiss RB , Kraft P , Bierut LJ , Ehringer MA
Ref : Genet Epidemiol , 37 :846 , 2013
Abstract : Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
ESTHER : Stephens_2013_Genet.Epidemiol_37_846
PubMedSearch : Stephens_2013_Genet.Epidemiol_37_846
PubMedID: 24186853

Title : Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies - Grallert_2012_Eur.Heart.J_33_238
Author(s) : Grallert H , Dupuis J , Bis JC , Dehghan A , Barbalic M , Baumert J , Lu C , Smith NL , Uitterlinden AG , Roberts R , Khuseyinova N , Schnabel RB , Rice KM , Rivadeneira F , Hoogeveen RC , Fontes JD , Meisinger C , Keaney JF, Jr. , Lemaitre R , Aulchenko YS , Vasan RS , Ellis S , Hazen SL , van Duijn CM , Nelson JJ , Marz W , Schunkert H , McPherson RM , Stirnadel-Farrant HA , Psaty BM , Gieger C , Siscovick D , Hofman A , Illig T , Cushman M , Yamamoto JF , Rotter JI , Larson MG , Stewart AF , Boerwinkle E , Witteman JC , Tracy RP , Koenig W , Benjamin EJ , Ballantyne CM
Ref : Eur Heart J , 33 :238 , 2012
Abstract : AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 x 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 x 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
ESTHER : Grallert_2012_Eur.Heart.J_33_238
PubMedSearch : Grallert_2012_Eur.Heart.J_33_238
PubMedID: 22003152
Gene_locus related to this paper: human-PLA2G7

Title : Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers - Hartz_2012_Arch.Gen.Psychiatry_69_854
Author(s) : Hartz SM , Short SE , Saccone NL , Culverhouse R , Chen L , Schwantes-An TH , Coon H , Han Y , Stephens SH , Sun J , Chen X , Ducci F , Dueker N , Franceschini N , Frank J , Geller F , Gubjartsson D , Hansel NN , Jiang C , Keskitalo-Vuokko K , Liu Z , Lyytikainen LP , Michel M , Rawal R , Rosenberger A , Scheet P , Shaffer JR , Teumer A , Thompson JR , Vink JM , Vogelzangs N , Wenzlaff AS , Wheeler W , Xiao X , Yang BZ , Aggen SH , Balmforth AJ , Baumeister SE , Beaty T , Bennett S , Bergen AW , Boyd HA , Broms U , Campbell H , Chatterjee N , Chen J , Cheng YC , Cichon S , Couper D , Cucca F , Dick DM , Foroud T , Furberg H , Giegling I , Gu F , Hall AS , Hallfors J , Han S , Hartmann AM , Hayward C , Heikkila K , Hewitt JK , Hottenga JJ , Jensen MK , Jousilahti P , Kaakinen M , Kittner SJ , Konte B , Korhonen T , Landi MT , Laatikainen T , Leppert M , Levy SM , Mathias RA , McNeil DW , Medland SE , Montgomery GW , Muley T , Murray T , Nauck M , North K , Pergadia M , Polasek O , Ramos EM , Ripatti S , Risch A , Ruczinski I , Rudan I , Salomaa V , Schlessinger D , Styrkarsdottir U , Terracciano A , Uda M , Willemsen G , Wu X , Abecasis G , Barnes K , Bickeboller H , Boerwinkle E , Boomsma DI , Caporaso N , Duan J , Edenberg HJ , Francks C , Gejman PV , Gelernter J , Grabe HJ , Hops H , Jarvelin MR , Viikari J , Kahonen M , Kendler KS , Lehtimaki T , Levinson DF , Marazita ML , Marchini J , Melbye M , Mitchell BD , Murray JC , Nothen MM , Penninx BW , Raitakari O , Rietschel M , Rujescu D , Samani NJ , Sanders AR , Schwartz AG , Shete S , Shi J , Spitz M , Stefansson K , Swan GE , Thorgeirsson T , Volzke H , Wei Q , Wichmann HE , Amos CI , Breslau N , Cannon DS , Ehringer M , Grucza R , Hatsukami D , Heath A , Johnson EO , Kaprio J , Madden P , Martin NG , Stevens VL , Stitzel JA , Weiss RB , Kraft P , Bierut LJ
Ref : Arch Gen Psychiatry , 69 :854 , 2012
Abstract : CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD </=10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset </=16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
ESTHER : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedSearch : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedID: 22868939

Title : Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study - Franceschini_2011_Circ.Cardiovasc.Genet_4_661
Author(s) : Franceschini N , Carty C , Buzkova P , Reiner AP , Garrett T , Lin Y , Vockler JS , Hindorff LA , Cole SA , Boerwinkle E , Lin DY , Bookman E , Best LG , Bella JN , Eaton C , Greenland P , Jenny N , North KE , Taverna D , Young AM , Deelman E , Kooperberg C , Psaty B , Heiss G
Ref : Circ Cardiovasc Genet , 4 :661 , 2011
Abstract : BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. METHODS AND
RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 x 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 x 10(-6)), MTHFD1L (rs6922269, P=5.1 x 10(-10)), APOE (rs429358; P=2.7x10(-18)), ZNF627 (rs4804611; P=5.0 x 10(-8)), CXCL12 (rs501120; P=1.4 x 10(-6)) and LPL (rs268; P=2.7 x 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
ESTHER : Franceschini_2011_Circ.Cardiovasc.Genet_4_661
PubMedSearch : Franceschini_2011_Circ.Cardiovasc.Genet_4_661
PubMedID: 22042884

Title : A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease - Wild_2011_Circ.Cardiovasc.Genet_4_403
Author(s) : Wild PS , Zeller T , Schillert A , Szymczak S , Sinning CR , Deiseroth A , Schnabel RB , Lubos E , Keller T , Eleftheriadis MS , Bickel C , Rupprecht HJ , Wilde S , Rossmann H , Diemert P , Cupples LA , Perret C , Erdmann J , Stark K , Kleber ME , Epstein SE , Voight BF , Kuulasmaa K , Li M , Schafer AS , Klopp N , Braund PS , Sager HB , Demissie S , Proust C , Konig IR , Wichmann HE , Reinhard W , Hoffmann MM , Virtamo J , Burnett MS , Siscovick D , Wiklund PG , Qu L , El Mokthari NE , Thompson JR , Peters A , Smith AV , Yon E , Baumert J , Hengstenberg C , Marz W , Amouyel P , Devaney J , Schwartz SM , Saarela O , Mehta NN , Rubin D , Silander K , Hall AS , Ferrieres J , Harris TB , Melander O , Kee F , Hakonarson H , Schrezenmeir J , Gudnason V , Elosua R , Arveiler D , Evans A , Rader DJ , Illig T , Schreiber S , Bis JC , Altshuler D , Kavousi M , Witteman JC , Uitterlinden AG , Hofman A , Folsom AR , Barbalic M , Boerwinkle E , Kathiresan S , Reilly MP , O'Donnell CJ , Samani NJ , Schunkert H , Cambien F , Lackner KJ , Tiret L , Salomaa V , Munzel T , Ziegler A , Blankenberg S
Ref : Circ Cardiovasc Genet , 4 :403 , 2011
Abstract : BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7x10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3x10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4x10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
ESTHER : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedSearch : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedID: 21606135
Gene_locus related to this paper: human-LIPA

Title : Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study - Tang_2010_Circ.Cardiovasc.Genet_3_179
Author(s) : Tang W , Apostol G , Schreiner PJ , Jacobs DR, Jr. , Boerwinkle E , Fornage M
Ref : Circ Cardiovasc Genet , 3 :179 , 2010
Abstract : BACKGROUND: Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined. METHODS AND RESULTS: On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies. Plasma levels of HDL-C and triglycerides were measured at 7 examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326, and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (P<0.005) and with their longitudinal changes over time (P<0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides, but only rs326 and rs13702 were associated with HDL-C (P<0.008). Rs328 showed a stronger association in European Americans than in African Americans, and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans. CONCLUSIONS: Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations, and there is population-related heterogeneity in the longitudinal associations.
ESTHER : Tang_2010_Circ.Cardiovasc.Genet_3_179
PubMedSearch : Tang_2010_Circ.Cardiovasc.Genet_3_179
PubMedID: 20150529

Title : Associations between HDL-cholesterol and polymorphisms in hepatic lipase and lipoprotein lipase genes are modified by dietary fat intake in African American and White adults - Nettleton_2007_Atherosclerosis_194_e131
Author(s) : Nettleton JA , Steffen LM , Ballantyne CM , Boerwinkle E , Folsom AR
Ref : Atherosclerosis , 194 :e131 , 2007
Abstract : Polymorphisms in genes involved in HDL-cholesterol (HDL-C) metabolism influence plasma HDL-C concentrations. We examined whether dietary fat intake modified relations between HDL-C and polymorphisms in hepatic lipase (LIPC-514C-->T), cholesteryl ester transfer protein (CETP TaqIB), and lipoprotein lipase (LPL S447X) genes. Diet (food frequency questionnaire), plasma lipids, and LIPC, CETP, and LPL genotypes were assessed in approximately 12,000 White and African American adults. In both races and all genotypes studied, minor allele homozygotes had highest HDL-C concentrations compared to the other genotypes (P<0.001). However, main effects were modified by usual dietary fat intake. In African Americans - women somewhat more strongly than men -LIPC TT homozygotes with fat intake >or=33.2% of energy had approximately 3-4 mg/dL higher HDL-C concentrations than CC and CT genotypes. In contrast, when fat intake was <33.2% of energy, TT homozygotes had HDL-C concentrations approximately 3.5mg/dL greater than those with the CC genotype but not different from those with the CT genotype (P(interaction)=0.013). In Whites, LPLGG homozygotes had greatest HDL-C at lower total, saturated, and monounsaturated fat intakes but lowest HDL-C at higher intakes of these fats (P(interaction)
ESTHER : Nettleton_2007_Atherosclerosis_194_e131
PubMedSearch : Nettleton_2007_Atherosclerosis_194_e131
PubMedID: 17157861

Title : Influence of lipoprotein lipase gene Ser447Stop and beta1-adrenergic receptor gene Arg389Gly polymorphisms and their interaction on obesity from childhood to adulthood: the Bogalusa Heart Study - Li_2006_Int.J.Obes.(Lond)_30_1183
Author(s) : Li S , Chen W , Srinivasan SR , Boerwinkle E , Berenson GS
Ref : Int J Obes (Lond) , 30 :1183 , 2006
Abstract : OBJECTIVE: To investigate the influence of lipoprotein lipase (LPL) Ser447Stop and beta1-adrenergic receptor (ADRB1) Arg389Gly gene polymorphisms, individually and in combination, on obesity from childhood to adulthood. DESIGN AND SUBJECTS: A community-based cohort of 1331 subjects (30% black and 70% white subjects) was followed over an average period of 23 years from childhood (age range: 4-17 years) to adulthood (age range:18-44 years). MEASUREMENT: Body mass index (BMI, kg/m2) and LPL Ser447Stop and the ADRB1 Arg389Gly genotypes.
RESULTS: The frequency of the ADRB1 Gly389 allele was 0.25 in white subjects vs 0.39 in black subjects (P < 0.001); 0.08 vs 0.05 (P = 0.280) for the LPL Stop447 allele. There was no association between the LPL Stop447 allele and BMI among white and black subjects either in childhood and adulthood levels or annual change from childhood to adulthood. The ADRB1 Gly389 allele was associated with lower BMI only in black adults (P = 0.017). Further, the interaction effect of the LPL Stop447 allele and ADRB1 Gly389 allele on adult BMI or its annual change was significant in white subjects and in the total sample (P = 0.03-0.006). Childhood values tended to show a similar trend. Having both ADRB1 Gly389 allele and LPL Stop447 allele was associated with 71% (95% confidence interval: 26-89%) less odds for developing obesity from childhood to adulthood after adjusting for age, race, sex, and childhood BMI. CONCLUSION: While Gly389 allele of the ADRB1 gene lowers obesity in black subjects, this allele in conjunction with Stop447 allele of the LPL gene lowers obesity in adults and attenuates the development of obesity from childhood to adulthood. These findings underscore the importance of gene-gene interaction in the assessment of genetic influences on complex traits such as obesity.
ESTHER : Li_2006_Int.J.Obes.(Lond)_30_1183
PubMedSearch : Li_2006_Int.J.Obes.(Lond)_30_1183
PubMedID: 16534528

Title : The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke - Fornage_2005_Hum.Mol.Genet_14_2829
Author(s) : Fornage M , Lee CR , Doris PA , Bray MS , Heiss G , Zeldin DC , Boerwinkle E
Ref : Hum Mol Genet , 14 :2829 , 2005
Abstract : Stroke is the leading cause of severe disability and the third leading cause of death, accounting for one of every 15 deaths in the USA. We investigated the association of polymorphisms in the soluble epoxide hydrolase gene (EPHX2) with incident ischemic stroke in African-Americans and Whites. Twelve single nucleotide polymorphisms (SNPs) spanning EPHX2 were genotyped in a case-cohort sample of 1336 participants from the Atherosclerosis Risk in Communities (ARIC) study. In each racial group, Cox proportional hazard models were constructed to assess the relationship between incident ischemic stroke and EPHX2 polymorphisms. A score test method was used to investigate the association of common haplotypes of the gene with risk of ischemic stroke. In African-Americans, two common EPHX2 haplotypes with significant and opposing relationships to ischemic stroke risk were identified. In Whites, two common haplotypes showed suggestive indication of an association with ischemic stroke risk but, as in African-Americans, these relationships were in opposite direction. These findings suggest that multiple variants exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence; some associated with a higher incidence and others with a lower incidence.
ESTHER : Fornage_2005_Hum.Mol.Genet_14_2829
PubMedSearch : Fornage_2005_Hum.Mol.Genet_14_2829
PubMedID: 16115816
Gene_locus related to this paper: human-EPHX2

Title : Polymorphism of the soluble epoxide hydrolase is associated with coronary artery calcification in African-American subjects: The Coronary Artery Risk Development in Young Adults (CARDIA) study - Fornage_2004_Circulation_109_335
Author(s) : Fornage M , Boerwinkle E , Doris PA , Jacobs D , Liu K , Wong ND
Ref : Circulation , 109 :335 , 2004
Abstract : BACKGROUND: Modulation of endogenous epoxide levels by soluble epoxide hydrolase (sEH) in the endothelium represents an important mechanism in the regulation of cardiovascular function. We examined the relationship between a common, functional polymorphism of the human sEH gene and coronary artery calcification (CAC) in young, largely asymptomatic African-American and non-Hispanic white subjects. METHODS AND
RESULTS: Multiple logistic regression and Tobit regression models were used to assess the relationship between the sEH Arg287Gln polymorphism and presence and quantity of CAC. Models adjusting for race (except in race-specific analyses), age, sex, smoking, body mass index, systolic blood pressure, LDL cholesterol, and HDL cholesterol were estimated. Allele and genotype frequency distributions were not significantly different between the 2 ethnic groups (P=0.22; P=0.17, respectively). The Arg287Gln polymorphism of the sEH gene was a significant predictor of CAC status in African-American participants, either alone or after adjusting for other risk factors. African-American subjects with at least 1 copy of the Gln287 allele had a 2-fold greater risk of having CAC compared with those not carrying this allele (95% CI, 1.1 to 2.9; P=0.02). There was no relationship between Arg287Gln polymorphism and the probability of having CAC in white participants (OR, 0.8; 95% CI, 0.5 to 1.3; P=0.49). Inferences from multivariable Tobit regression were similar to those obtained in the logistic regression models, indicating that the Arg287Gln polymorphism was a significant independent predictor of both presence and quantity of CAC in African-American but not white subjects.
CONCLUSIONS: These data suggest an intriguing and possibly novel role for sEH in the pathogenesis of atherosclerosis, which deserves additional investigation.
ESTHER : Fornage_2004_Circulation_109_335
PubMedSearch : Fornage_2004_Circulation_109_335
PubMedID: 14732757
Gene_locus related to this paper: human-EPHX2

Title : Hepatic lipase promoter C-514T polymorphism influences serial changes in HDL cholesterol levels since childhood: the Bogalusa Heart Study - Chen_2003_Atherosclerosis_169_175
Author(s) : Chen W , Srinivasan SR , Boerwinkle E , Berenson GS
Ref : Atherosclerosis , 169 :175 , 2003
Abstract : Hepatic lipase (HL) is an important determinant of high-density lipoprotein (HDL) concentrations. A common C-to-T substitution at position -514 of the promoter region of the HL gene has been shown to be associated with HL activity and HDL cholesterol (HDL-C) levels. The current study examines the influence of this polymorphism on both levels and serial changes of HDL-C from childhood to adulthood in a community-based sample of 707 white and 291 black unrelated individuals aged 4-38 years using a repeated measures analysis. The frequency of the -514T allele was lower in whites than in blacks (0.228 vs. 0.545, P<0.001). After adjusting for age and BMI, the genotype effect on longitudinal profiles of HDL-C levels was significant (P=0.003) in white males with values in the order of T/T>T/C>C/C. Although a similar trend was seen, the genotype effect was not significant in white females and blacks. Further, the slopes of the age trajectories of HDL-C were similar in three genotype groups in blacks and whites. A sex-genotype interaction effect (P=0.043) on longitudinal profiles of HDL-C levels was found in whites, but not in blacks. White males showed a stronger genotype effect (3.6 mg/dl, P=0.003) than white females (0.5 mg/dl, P=0.601). Thus, the -514T variant of the HL gene is consistently associated with higher levels of HDL-C longitudinally since childhood, but not with rate of change over time. These results suggest that the HL gene may play an important role in the regulation of HDL-C levels from childhood to adulthood, especially in white males.
ESTHER : Chen_2003_Atherosclerosis_169_175
PubMedSearch : Chen_2003_Atherosclerosis_169_175
PubMedID: 12860265

Title : Interaction effect of Serine447Stop variant of the lipoprotein lipase gene and C-514T variant of the hepatic lipase gene on serum triglyceride levels in young adults: the Bogalusa Heart Study - Xin_2003_Metabolism_52_1337
Author(s) : Xin X , Srinivasan SR , Chen W , Boerwinkle E , Berenson GS
Ref : Metabolism , 52 :1337 , 2003
Abstract : The opposing effects of lipoprotein lipase (LPL) Serin447Stop (S447X) polymorphism and hepatic lipase (HL) C-514T polymorphism on serum triglyceride (TG) levels have been known. However, little is known about the interaction effect of these 2 functional gene variants on serum triglyceride levels. This aspect was examined in a community-based sample of 902 whites and 389 blacks aged 18 to 41 years, using a repeated measures analysis in a mixed model. The frequency of the LPL X447 allele was higher in whites than blacks (16% v 11%, P <.05); whereas the frequency of HL T-514 allele was higher in blacks than whites (77% v 40%, P <.001). The combined genotype distribution was also different between whites and blacks (P <.001). Although the frequency of carriers of both variants was similar in whites and blacks (7% v 8%), more whites carried the LPL X447 allele only (9% v 3%), and more blacks carried the HL T-514 allele only (70% v 33%). Mean levels of TG adjusted for age, sex, and body mass index (BMI) in carriers versus noncarriers of the LPL X447 allele were lower by 13.5% (P <.0001) in whites, 15.8% (P <.01) in blacks and 16.0% (P <.0001) in the total sample. No such phenotypic effect was noted with respect to HL T-514 allele either in blacks or whites, although the mean level in carriers was marginally (P =.08) higher in the total sample. The interaction effect of LPL and HL variants on TG levels was significant in the total sample (P =.016) and marginal in whites (P =.079). In the total sample, the decrease of TG in carriers versus noncarriers of the LPL X447 was 1.8-fold greater in carriers versus noncarriers of the HL T-514 allele (13.6 mg/dL v 7.4 mg/dL, P =.016). Whites tended to show a similar trend (16.8 mg/dL v 6.1 mg/dL, P =.079). Blacks also showed a similar, but nonsignificant, trend (10.4 mg/dL v 8.6 mg/dL, P =.45). These results by showing modulation of association between S447X variant of the LPL gene and serum TG by C-514T variant of the HL gene underscore the importance of gene-gene interactions in the assessment of genetic effects on complex traits.
ESTHER : Xin_2003_Metabolism_52_1337
PubMedSearch : Xin_2003_Metabolism_52_1337
PubMedID: 14564687

Title : Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats - Fornage_2002_Hypertension_40_485
Author(s) : Fornage M , Hinojos CA , Nurowska BW , Boerwinkle E , Hammock BD , Morisseau C , Doris PA
Ref : Hypertension , 40 :485 , 2002
Abstract : We measured soluble epoxide hydrolase (sEH) renal gene expression in prehypertensive (4 to 5 weeks old) spontaneously hypertensive rats of the Heidelberg SP substrain (SHR [Heid]) and when blood pressure levels entered the hypertensive plateau (17 to 18 weeks old) and compared expression with matched Wistar-Kyoto (WKY [Heid]) rats. Less expression of the gene encoding sEH (EPHX2) was observed in SHR (Heid) than in WKY (Heid). Analysis of sEH protein abundance showed a similar difference. However, no correlation between sEH abundance and blood pressure was observed in the F(2) progeny of a parental strain cross. Measurement of protein abundance in SHR and WKY obtained from Charles River confirmed a recent report that abundance of sEH was greater in SHR (CRiv) than WKY (CRiv) strains. Polymorphisms were detected in EPHX2. Resequencing revealed that 2 alleles of EPHX2 exist in these 4 rat strains, differing by 4 single nucleotide polymorphisms, of which 3 produce nonsynonymous amino acid substitutions. The ancestral allele was shared by SHR (Heid) and WKY (CRiv), and the variant allele was shared by WKY (Heid) and SHR (CRiv). Activity of sEH was greater in animals carrying the variant allele. However, inheritance of this allele was not correlated with blood pressure in the F(2) progeny of a cross between SHR (Heid) and WKY (Heid). These data indicate that sequence variation determining functional alterations in EPHX2 is not likely to contribute to blood pressure levels in SHR.
ESTHER : Fornage_2002_Hypertension_40_485
PubMedSearch : Fornage_2002_Hypertension_40_485
PubMedID: 12364351

Title : The Ser(447)-Stop polymorphism of lipoprotein lipase is associated with variation in longitudinal serum high-density lipoprotein-cholesterol profiles: the Bogalusa Heart Study - Hallman_2001_Metabolism_50_894
Author(s) : Hallman DM , Srinivasan SR , Elkasabany A , Boerwinkle E , Berenson GS
Ref : Metabolism , 50 :894 , 2001
Abstract : The Ser(447)-Stop polymorphism of lipoprotein lipase (LPL) has been associated with altered high-density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) levels at individual measurements, but nothing is known of its associations with lipid profiles derived from serial measurements. We used multilevel statistical models to study effects of this polymorphism on longitudinal lipid profiles in 1,006 Bogalusa Heart Study subjects examined 4 to 9 times between the ages of 4 and 38 years. Stop(447) allele frequencies in African Americans (0.053 +/- 0.011) and whites (0.091 +/- 0.009) differed significantly (chi(2) = 7.595, 1 df, P =.006; Stop(447) homozygotes and heterozygotes combined). Overall, TG levels were lower and HDL-C levels higher in blacks than in whites of the same age and sex. Longitudinal TG profiles were lower in Stop(447) carriers at all ages. However, longitudinal HDL-C profiles differed among genotype groups with age: the Stop(447) allele was associated with higher HDL-C only in subjects above approximately 10 years of age. Genotype-specific HDL-C profiles also differed significantly among race/sex groups. Thus, we found evidence of LPL genotype effects that vary within individuals with age. Possible mechanisms, which could account for age-related changes in the effects of LPL variants, are discussed.
ESTHER : Hallman_2001_Metabolism_50_894
PubMedSearch : Hallman_2001_Metabolism_50_894
PubMedID: 11474476

Title : Influence of lipoprotein lipase serine 447 stop polymorphism on tracking of triglycerides and HDL cholesterol from childhood to adulthood and familial risk of coronary artery disease: the Bogalusa heart study - Chen_2001_Atherosclerosis_159_367
Author(s) : Chen W , Srinivasan SR , Elkasabany A , Ellsworth DL , Boerwinkle E , Berenson GS
Ref : Atherosclerosis , 159 :367 , 2001
Abstract : The effects of the lipoprotein lipase (LPL) Serine 447 Stop (S447X) polymorphism on high-density lipoprotein cholesterol (HDLC) and triglycerides (TG) have been demonstrated. However, little is known about its effect on the tracking of HDLC and TG over time and familial risk of coronary artery disease (CAD). This aspect was examined in black and white individuals (n=829) aged 5-18 year at baseline, followed on average 18.8 yr. The frequency of the X447 allele was lower in Blacks than Whites (0.043 vs. 0.087, P=0.002). Carriers vs. noncarriers of the X447 allele had lower TG (99.3 vs 122.1 mg/dl, P<0.01) and higher HDLC (51.1 vs. 49.7 mg/dl, P<0.05) in adulthood, but not in childhood. The trends in genotype-specific means of childhood and adulthood levels of HDLC and TG in sex or race subgroups were similar to those in the total sample. With respect to tracking over time, of those in the bottom quartile of HDLC in childhood, 46.1% of the noncarriers vs. 23.1% of the carriers remained in this lowest quartile into adulthood (P=0.03); corresponding values for the top quartile of HDLC were 37.5% for the noncarriers vs. 57.1% for the carriers (P=0.03). Although TG tended to track better among the carriers in the bottom quartile and among the noncarriers in the top quartile, this trend was not significant. Carriers showed lower prevalence of parental history of CAD than noncarriers (6.9% vs. 14.1%, P=0.02) independently of lipoprotein variables, adiposity, blood pressure, age, sex and race. Thus, the X447 allele of the LPL gene is associated with an increase in HDLC and a decrease in TG in adults, tracking of HDLC since childhood, and a lower family history of CAD.
ESTHER : Chen_2001_Atherosclerosis_159_367
PubMedSearch : Chen_2001_Atherosclerosis_159_367
PubMedID: 11730816

Title : Analysis of lipoprotein lipase haplotypes reveals associations not apparent from analysis of the constituent loci - Hallman_1999_Ann.Hum.Genet_63_499
Author(s) : Hallman DM , Groenemeijer BE , Jukema JW , Boerwinkle E , Kastelein JJ
Ref : Ann Hum Genet , 63 :499 , 1999
Abstract : Simultaneously analysing genotype effects at several closely-linked loci may be preferable to analysing them separately, but can be difficult, due to multiple genotype classes, small class sizes, and non-independence induced by associations among loci. Analysis of haplotype effects offers an alternative approach. We studied effects of haplotypes comprising 3 loci (5' to 3': PvuII, HindIII, and Ser 447 -Stop) in the lipoprotein lipase (LPL) gene on plasma lipid levels and LPL activity, in 807 Dutch males with coronary atherosclerosis. We analysed haplotype effects in individuals for whom haplotypes could either be determined unequivocally or inferred with high probability, using contrasts suggested by likely evolutionary relationships among the haplotypes. One haplotype was associated with significantly higher total cholesterol, while another was associated with significantly lower triglyceride levels. Though these two haplotypes had generally opposite effects on lipids, both were associated with significantly higher LPL activity. In genotype analyses, the HindIII (-) allele was associated with higher LPL activity; however, one haplotype bearing it had no significant effect on LPL activity. Haplotypes thus provided more information than genotypes alone would have. The two haplotypes with consistently different effects on lipid levels despite similar effects on LPL activity, provide further evidence that aspects of LPL biology, apart from its catalytic function in lipolysis, may mediate its effects on plasma lipids at least in coronary artery disease patients.
ESTHER : Hallman_1999_Ann.Hum.Genet_63_499
PubMedSearch : Hallman_1999_Ann.Hum.Genet_63_499
PubMedID: 11246452

Title : The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease. The Regress Study Group - Kastelein_1998_Clin.Genet_53_27
Author(s) : Kastelein JJ , Groenemeyer BE , Hallman DM , Henderson H , Reymer PW , Gagne SE , Jansen H , Seidell JC , Kromhout D , Jukema JW , Bruschke AV , Boerwinkle E , Hayden MR
Ref : Clin Genet , 53 :27 , 1998
Abstract : Two mutations in the lipoprotein lipase (LPL) gene, a T to G transition at position -93 of the proximal promoter region and an Asp9Asn substitution in exon 2, were examined in 762 Dutch males with angiographically-diagnosed coronary artery disease (CAD) and 296 healthy normolipidemic Dutch males. The two mutations exhibited strong linkage disequilibrium (D' = 0.975). A significantly higher proportion of cases (4.86%) than controls (1.37%) carried the -93G/Asn9 allele (p = 0.008). In the combined sample of cases and controls, adjusted mean plasma total cholesterol (TC) levels were significantly higher in -93G/Asn9 carriers (6.20+/-0.13 mmol/l) than in non-carriers (5.93+/-0.03 mmol/l; p = 0.048), while mean high-density lipoprotein cholesterol (HDL-C) levels were lower in carriers (0.88+/-0.03 mmol/l) than in non-carriers (0.98+/-0.01 mmol/l; p = 0.002). There was a trend towards higher triglyceride (TG) levels in carriers (1.96+/-0.14 mmol/l) compared with non-carriers (1.73+/-0.03 mmol/l) (p = 0.08). Additionally, carrier frequencies in tertiles of TC, HDL-C, TG, and LPL activity, suggested an association of the -93G/Asn9 variant with higher TC and TG levels, and with lower HDL-C and LPL activity levels. Logistic regression revealed a significant odds ratio (OR) for the combined -93G/Asn9 genotype in CAD cases relative to controls (OR: 5.36; 95% CI: 1.57-18.24), with age, body mass index (BMI), smoking, and plasma total- and HDL-cholesterol levels included in the model. In conclusion, we show that the LPL Asp9Asn mutation is in non-random association with a T G substitution at position -93 of the proximal promoter region and that the combined -93G/Asn9 genotype predisposes to decreased HDL-C levels and an increased risk of CAD.
ESTHER : Kastelein_1998_Clin.Genet_53_27
PubMedSearch : Kastelein_1998_Clin.Genet_53_27
PubMedID: 9550358

Title : DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene - Nickerson_1998_Nat.Genet_19_233
Author(s) : Nickerson DA , Taylor SL , Weiss KM , Clark AG , Hutchinson RG , Stengard J , Salomaa V , Vartiainen E , Boerwinkle E , Sing CF
Ref : Nat Genet , 19 :233 , 1998
Abstract : Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.
ESTHER : Nickerson_1998_Nat.Genet_19_233
PubMedSearch : Nickerson_1998_Nat.Genet_19_233
PubMedID: 9662394
Gene_locus related to this paper: human-LPL

Title : Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase - Clark_1998_Am.J.Hum.Genet_63_595
Author(s) : Clark AG , Weiss KM , Nickerson DA , Taylor SL , Buchanan A , Stengard J , Salomaa V , Vartiainen E , Perola M , Boerwinkle E , Sing CF
Ref : American Journal of Human Genetics , 63 :595 , 1998
Abstract : Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed.
ESTHER : Clark_1998_Am.J.Hum.Genet_63_595
PubMedSearch : Clark_1998_Am.J.Hum.Genet_63_595
PubMedID: 9683608
Gene_locus related to this paper: human-LPL

Title : Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group - Groenemeijer_1997_Circulation_95_2628
Author(s) : Groenemeijer BE , Hallman MD , Reymer PW , Gagne E , Kuivenhoven JA , Bruin T , Jansen H , Lie KI , Bruschke AV , Boerwinkle E , Hayden MR , Kastelein JJ
Ref : Circulation , 95 :2628 , 1997
Abstract : BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser447-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n = 820) with normal to mildly elevated total and LDL cholesterol levels. METHODS AND
RESULTS: Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (P = .034), normal postheparin HL activity (P = .453), higher HDL cholesterol levels (P = .013), and lower triglyceride levels (P = .044) than noncarriers. The influence of the Ser447-Stop allele on LPL activity was pronounced in patients using beta-blockers (P = .042) and not significant in those not using them (P = .881), suggesting a gene-environment interaction between the Ser447-Stop mutation and beta-blockers.
CONCLUSIONS: We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on beta-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.
ESTHER : Groenemeijer_1997_Circulation_95_2628
PubMedSearch : Groenemeijer_1997_Circulation_95_2628
PubMedID: 9193431

Title : HindIII DNA polymorphism in the lipoprotein lipase gene and plasma lipid phenotypes and carotid artery atherosclerosis - Chen_1996_Hum.Genet_98_551
Author(s) : Chen L , Patsch W , Boerwinkle E
Ref : Hum Genet , 98 :551 , 1996
Abstract : Lipoprotein lipase (LPL) is the rate limiting enzyme in the hydrolysis of core triglyceride in chylomicron and very low density lipoprotein (VLDL) thus affecting a broad spectrum of plasma lipid levels. In this paper, we investigated the association of a HindIII polymorphism in the LPL gene with plasma lipid levels and carotid artery wall thickness measured by B-mode ultrasonography. A total of 238 Caucasian subjects were selected from the Atherosclerosis Risk In Community (ARIC) study (male = 1.31, female = 107) based on their fasting triglyceride and LDL-cholesterol levels: normolipidemic (n = 48), hypertriglyceridemic (n = 44), hypercholesterolemic (n = 36), and hypertriglyceridemic-hypercholesterolemic (n = 110) groups. We observed a marginally significant association between lipid phenotypes and HindIII genotypes (P = 0.04) in males, with the hypertriglyceridemic and hypercholesterolemic groups having a higher frequency (0.65) of the H+H+ genotype than the other two groups (pooled: 0.55). In males, there was also a significant association between HindIII genotypes and carotid artery wall thickness after considering the effects of age, body mass index, cigarette smoking, lipid phenotype and diabetes status (P = 0.013), with the H+H+ genotype having a higher average value of carotid artery wall thickness (0.84 +/- 0.15 mm) than the other two genotype groups (0.76 +/- 0.14 mm in H+H(+)-genotype class, 0.75 +/- 0.13 mm in H-H- genotype class). In females, no significant associations among LPL HindIII genotype, lipid phenotype and carotid artery wall thickness were observed. These results suggest that the LPL HindIII polymorphism influences LPL-catalyzed, triglyceride-rich lipoprotein metabolism and carotid artery atherosclerosis in a gender-specific manner.
ESTHER : Chen_1996_Hum.Genet_98_551
PubMedSearch : Chen_1996_Hum.Genet_98_551
PubMedID: 8882874

Title : No association of apolipoprotein A-IV codon 347 and 360 variation with atherosclerosis and lipid transport in a sample of mixed hyperlipidemics - Carrejo_1995_Genet.Epidemiol_12_371
Author(s) : Carrejo MH , Sharrett R , Patsch W , Boerwinkle E
Ref : Genet Epidemiol , 12 :371 , 1995
Abstract : Genetic variation at the apolipoprotein (apo) A-I/C-III/A-IV gene cluster on chromosome 11 has been associated with differences in occurrence of atherosclerosis and with variability in lipid levels among hypercholesterolemic-hypertriglyceridemic individuals. The functional cause of the association is not known, but polymorphisms of the apo A-IV gene are of interest because apo A-IV is involved in both triglyceride and cholesterol metabolism. Two mutations in the apo A-IV gene, 347T->S and 360Q->H, are known to cause amino acid substitutions in the mature protein. These polymorphisms were typed in a sample of 119 subjects with high cholesterol and high triglycerides in whom carotid artery wall thickness was previously shown to be strongly associated with silent polymorphic variation in the A-I/C-III/A-IV gene cluster. The relative allele frequencies were 0.83 and 0.17 for codon 347T->, and 0.95 and 0.05 for codon 360Q-> H. These polymorphisms did not show a statistically significant relationship with prevalent hypertension, diabetes, or cardiovascular disease or with plasma lipid levels. Most importantly, these amino acids substitutions in apo A-IV were not associated with carotid artery wall thickness. Therefore, the genetic cause of disease variability in a sample of mixed hyperlipidemics is not amino acid substitutions in codons 347 or 360 of the apoliproteins A-IV gene.
ESTHER : Carrejo_1995_Genet.Epidemiol_12_371
PubMedSearch : Carrejo_1995_Genet.Epidemiol_12_371
PubMedID: 8536954