Hall AS

References (5)

Title : Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease - Khera_2017_JAMA_317_937
Author(s) : Khera AV , Won HH , Peloso GM , O'Dushlaine C , Liu D , Stitziel NO , Natarajan P , Nomura A , Emdin CA , Gupta N , Borecki IB , Asselta R , Duga S , Merlini PA , Correa A , Kessler T , Wilson JG , Bown MJ , Hall AS , Braund PS , Carey DJ , Murray MF , Kirchner HL , Leader JB , Lavage DR , Manus JN , Hartzel DN , Samani NJ , Schunkert H , Marrugat J , Elosua R , McPherson R , Farrall M , Watkins H , Lander ES , Rader DJ , Danesh J , Ardissino D , Gabriel S , Willer C , Abecasis GR , Saleheen D , Dewey FE , Kathiresan S
Ref : Jama , 317 :937 , 2017
Abstract : Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305699 individuals of the Global Lipids Genetics Consortium and up to 120600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32646 control participants (0.32%) and 83 of 14245 participants with early-onset CAD (0.58%). Compared with 46703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 x 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
ESTHER : Khera_2017_JAMA_317_937
PubMedSearch : Khera_2017_JAMA_317_937
PubMedID: 28267856
Gene_locus related to this paper: human-LPL

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 : 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 : 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 : The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease - Talmud_2007_Clin.Sci.(Lond)_112_617
Author(s) : Talmud PJ , Flavell DM , Alfakih K , Cooper JA , Balmforth AJ , Sivananthan M , Montgomery HE , Hall AS , Humphries SE
Ref : Clinical Science (Lond) , 112 :617 , 2007
Abstract : LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08-0.19] compared with 0.07 (95% CI, 0.05-0.10) respectively; odds ratio, 2.52 (95% CI, 1.17-5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23-1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13-2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53-3.45) for X447+ (P<0.0001)] and had a significant interaction with hypertension in CHD risk determination (P=0.007). In conclusion, hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects.
ESTHER : Talmud_2007_Clin.Sci.(Lond)_112_617
PubMedSearch : Talmud_2007_Clin.Sci.(Lond)_112_617
PubMedID: 17291198