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Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities./
作者:	Hoekstra, Mary.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	113 p.
附註:	Source: Masters Abstracts International, Volume: 82-10.
Contained By:	Masters Abstracts International82-10.
標題:	Cardiovascular disease. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383680
ISBN:	9798708717696

Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities.
Hoekstra, Mary.

Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 113 p.

Source: Masters Abstracts International, Volume: 82-10.

Thesis (M.Sc.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Background: Aortic stenosis (AS) is a heart valve disease that is becoming more prevalent with the aging population. Genome-wide association studies (GWAS) of AS in European-ancestry populations have identified the variant rs10455872 in LPA as associated with greater disease risk, an association that has been replicated in both African Americans and Hispanics. This association is mediated by elevated levels of lipoprotein(a) (Lp[a]), which are primarily determined by variation at the LPA locus. The identification of additional risk loci for Lp(a) levels could reveal new targets for Lp(a)- lowering therapies.Apart from LPA, several other risk loci have been identified for AS; however, a genetic risk score (GRS) has never been created to assess the contribution of multiple genetic variants to this disease. Given that Lp(a) is a risk factor for AS with strong genetic determinants, a GRS for Lp(a) may also be effective at explaining variance in AS.Methods: A large-scale GWAS for Lp(a) was performed in White British Individuals from the UK Biobank (N = 293,274). Approximately 93,095,623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. Independent variants reaching genome-wide significance (P ≤ 5 x 10-8) were tested for association in a meta-analysis of two European-ancestry cohorts, as well as additional ethnic groups in the UK Biobank. Results from the Lp(a) GWAS and a previouslyperformed AS GWAS were used to develop genetic risk scores (GRSs) in Non-Hispanic Whites (n = 55,192), African Americans (n = 1,917), and Hispanics (n = 3,482) from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, where the p-value thresholds for the scores were selected based on maximal association with AS in these populations. The proportion of variance explained in AS by the GRSs was assessed in each ethnicity, with and without the most significant variant, rs10455872.Results: A total of 131 independent variants were associated with Lp(a) at genomewide significance, validating previous associations at LPA, APOE, and CETP, and identifying a novel association at APOH. The variant rs8178824 at APOH, encoding beta2-glycoprotein I (β2GPI), was associated with increased Lp(a) levels (β [95% CI] (ln nmol/L), 0.064 [0.047, 0.081]; P = 2.8 x 10-13). This association was replicated in a meta-analysis of 5,465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] (ln mg/dL), 0.16 [0.044, 0.28]; P = 0.0071) but failed to replicate in other ethnicities from the UK Biobank (all P > 0.05). Genetic risk scores constructed from the Lp(a) GWAS contained 263, 1,291, and 11,217 variants when maximized for association in GERA Whites, African Americans, and Hispanics, respectively, while GRSs constructed from an AS GWAS in the same manner contained 3, 10, and 496 variants, respectively. The best-fit (by ethnicity) Lp(a)-GRSs were significantly associated with AS in each ethnicity, but explained a small proportion of variance in AS (Whites: R2 = 0.13%, P = 6.2 x 10-9; African Americans: R2 = 0.56%, P = 0.045; Hispanics: R2 = 0.31%, P = 0.045). The best-fit (by ethnicity) AS-GRSs explained only marginally more phenotypic variance than the Lp(a)-GRSs (Whites: R2 = 0.16%, P = 1.1 x 10-10; African Americans: R2 = 0.63%, P = 0.033; Hispanics: R2 = 0.39%, P = 0.024). When rs10455872 was removed from the Lp(a)-GRSs, the variance explained decreased to 0.076% in Whites, 0.25% in African Americans, and 0.26% in Hispanics. Similarly, excluding rs10455872 from the AS-GRSs decreased the variance explained in Whites (0.063%), African Americans (0.13%), and Hispanics (0.37%).Conclusions: A large-scale GWAS of Lp(a) levels revealed APOH as a novel locus for Lp(a) in individuals of European ancestry, highlighting β2GPI as a potential therapeutic target. An Lp(a)-GRS derived from this GWAS was associated with AS to nearly the same extent as an AS-GRS when assessed in Whites, African Americans, and Hispanics. Both types of GRSs explained only a small proportion of variance in AS, and the LPA variant rs10455872 accounted for a considerable fraction of this in Whites and African Americans, suggesting that the genetic etiology of AS may be predominantly explained by variation at the LPA locus.

ISBN: 9798708717696Subjects--Topical Terms:

3564561
Cardiovascular disease.
Subjects--Index Terms:

Lipoprotein(a)

Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities.
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100 1 $a Hoekstra, Mary. $3 3686264
245 1 0 $a Lipoprotein(a) as a Genetic Risk Factor for Aortic Stenosis across Ethnicities.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 113 p.
500 $a Source: Masters Abstracts International, Volume: 82-10.
500 $a Advisor: Thanassoulis, George;Engert, James.
502 $a Thesis (M.Sc.)--McGill University (Canada), 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Background: Aortic stenosis (AS) is a heart valve disease that is becoming more prevalent with the aging population. Genome-wide association studies (GWAS) of AS in European-ancestry populations have identified the variant rs10455872 in LPA as associated with greater disease risk, an association that has been replicated in both African Americans and Hispanics. This association is mediated by elevated levels of lipoprotein(a) (Lp[a]), which are primarily determined by variation at the LPA locus. The identification of additional risk loci for Lp(a) levels could reveal new targets for Lp(a)- lowering therapies.Apart from LPA, several other risk loci have been identified for AS; however, a genetic risk score (GRS) has never been created to assess the contribution of multiple genetic variants to this disease. Given that Lp(a) is a risk factor for AS with strong genetic determinants, a GRS for Lp(a) may also be effective at explaining variance in AS.Methods: A large-scale GWAS for Lp(a) was performed in White British Individuals from the UK Biobank (N = 293,274). Approximately 93,095,623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. Independent variants reaching genome-wide significance (P ≤ 5 x 10-8) were tested for association in a meta-analysis of two European-ancestry cohorts, as well as additional ethnic groups in the UK Biobank. Results from the Lp(a) GWAS and a previouslyperformed AS GWAS were used to develop genetic risk scores (GRSs) in Non-Hispanic Whites (n = 55,192), African Americans (n = 1,917), and Hispanics (n = 3,482) from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, where the p-value thresholds for the scores were selected based on maximal association with AS in these populations. The proportion of variance explained in AS by the GRSs was assessed in each ethnicity, with and without the most significant variant, rs10455872.Results: A total of 131 independent variants were associated with Lp(a) at genomewide significance, validating previous associations at LPA, APOE, and CETP, and identifying a novel association at APOH. The variant rs8178824 at APOH, encoding beta2-glycoprotein I (β2GPI), was associated with increased Lp(a) levels (β [95% CI] (ln nmol/L), 0.064 [0.047, 0.081]; P = 2.8 x 10-13). This association was replicated in a meta-analysis of 5,465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] (ln mg/dL), 0.16 [0.044, 0.28]; P = 0.0071) but failed to replicate in other ethnicities from the UK Biobank (all P > 0.05). Genetic risk scores constructed from the Lp(a) GWAS contained 263, 1,291, and 11,217 variants when maximized for association in GERA Whites, African Americans, and Hispanics, respectively, while GRSs constructed from an AS GWAS in the same manner contained 3, 10, and 496 variants, respectively. The best-fit (by ethnicity) Lp(a)-GRSs were significantly associated with AS in each ethnicity, but explained a small proportion of variance in AS (Whites: R2 = 0.13%, P = 6.2 x 10-9; African Americans: R2 = 0.56%, P = 0.045; Hispanics: R2 = 0.31%, P = 0.045). The best-fit (by ethnicity) AS-GRSs explained only marginally more phenotypic variance than the Lp(a)-GRSs (Whites: R2 = 0.16%, P = 1.1 x 10-10; African Americans: R2 = 0.63%, P = 0.033; Hispanics: R2 = 0.39%, P = 0.024). When rs10455872 was removed from the Lp(a)-GRSs, the variance explained decreased to 0.076% in Whites, 0.25% in African Americans, and 0.26% in Hispanics. Similarly, excluding rs10455872 from the AS-GRSs decreased the variance explained in Whites (0.063%), African Americans (0.13%), and Hispanics (0.37%).Conclusions: A large-scale GWAS of Lp(a) levels revealed APOH as a novel locus for Lp(a) in individuals of European ancestry, highlighting β2GPI as a potential therapeutic target. An Lp(a)-GRS derived from this GWAS was associated with AS to nearly the same extent as an AS-GRS when assessed in Whites, African Americans, and Hispanics. Both types of GRSs explained only a small proportion of variance in AS, and the LPA variant rs10455872 accounted for a considerable fraction of this in Whites and African Americans, suggesting that the genetic etiology of AS may be predominantly explained by variation at the LPA locus.
520 $a Contexte: La stenose aortique (SA) est une maladie des valves cardiaques de plus en plus repandue en raison du vieillissement de la population. Des etudes d'associations pangenomiques (GWAS) de la SA dans des populations d'ascendance europeenne ont permis d'identifier la variation rs10455872 du locus LPA comme etant associee a un plus grand risque de maladie, une association qui est mediee par des niveaux eleves de lipoproteine(a) (Lp[a]). L'identification de loci de risque additionnels pour les niveaux de Lp(a) pourrait permettre d'identifier de nouvelles cibles pour le developpement de therapies visant a diminuer les niveaux de Lp(a).Outre le locus LPA, plusieurs autres loci de risque ont ete identifies pour la SA. Cependant, jamais un score de risque polygenique (GRS) n'avait ete cree pour mesurer la contribution combinee de multiples variations genetiques a cette maladie.Methodes: Nous avons realise un GWAS a grande echelle chez des Britanniques blancs de la cohorte UK Biobank (n = 293 274 individus). Nous avons teste environ 93 095 623 variations pour evaluer leur association avec les niveaux de Lp(a) transformes en log en utilisant un modele de regression lineaire ajustee pour l'age, le sexe, le lot de genotypage et 20 composantes principales d'ascendance genetique. Les variations atteignant une signification au niveau du genome (P ≤ 5 x 10-8) ont ete testees pour la replication dans une meta-analyse de deux autres cohortes d'ascendance europeenne et d'autres groupes ethniques de la cohorte UK Biobank.Les donnees generees par le GWAS pour la Lp(a) et par un GWAS pour la SA ont ete utilisees pour developper des GRS chez les Blancs non hispaniques (n = 55192), les Afro-Americains (n = 1917) et les Hispaniques (n = 3482) qui font partie de la cohorte GERA (Genetic Epidemiology Research on Adult Health and Aging), ou le seuil de valeur P des scores a ete selectionne pour maximiser l'association avec la SA dans chaque groupe ethnique. La proportion de la variance expliquee de la SA par chaque GRS a ete evaluee avec et sans la variation la plus significative, soit rs10455872.Resultats: Au total, 131 variations independantes ont ete associees de facon statistiquement significative au niveau pangenomique a Lp(a), validant ainsi des associations precedemment etablies avec LPA, APOE et CETP, et identifiant une nouvelle association avec APOH. La variation rs8178824 sur APOH, qui code pour la beta2-glycoproteine I (β2GPI), est associee avec une augmentation des niveaux de Lp(a) (β [95% CI] (ln nmol/L), 0.064 [0.047, 0.081]; P = 2.8 x 10-13). Cette association a ete reproduite dans une meta-analyse de 5465 individus d'ascendance europeenne des cohortes Framingham Offspring Study et Multi-Ethnic Study of Atherosclerosis (β [95% CI] (ln mg/dL), 0.16 [0.044, 0.28]; P = 0.0071), mais l'association n'a pu etre reproduite chez les autres groupes ethniques de la cohorte UK Biobank (tous sont a P > 0.05).Les GRS construits a partir du GWAS de Lp(a) et maximises pour l'association chez les blancs de la cohorte, les Afro-Americains et les Hispaniques de la cohorte GERA comprenaient respectivement 263, 1,291 et 11,217 variants tandis que les GRS construits par la meme methode, a partir du GWAS de SA, comprenaient respectivement 3,10, et 496 variants. Les GRS-Lp(a) optimaux etaient tous associes significativement avec la SA mais expliquaient seulement une petite portion la variance de la SA (Blancs : R2 = 0.13%, P = 6.2 x 10-9; Afro-Americains: R2 = 0.56%, P = 0.045; Hispaniques: R2 = 0.31%, P = 0.045). Les GRS-SA optimaux expliquaient marginalement plus de variance phenotypique que les GRS-Lp(a) (Blancs : R2 = 0.16%, P = 1.1 x 10-10; Afro-Americains: R2 = 0.63%, P = 0.033; Hispaniques: R2 = 0.39%, P = 0.024). Lorsque nous avons retires rs10455872 des GRS-Lp(a) optimaux, la variance expliquee a diminue de 0.076% chez les Blancs, 0.25% chez les Afro-Americains et de 0.26% chez les Hispaniques. Pareillement, si la variation rs10455872 est retiree des GRS-SA optimaux, la variance expliquee diminue respectivement de 0.063%, 0.13% et 0.37%.Conclusions: Un GWAS a grande echelle des niveaux de Lp(a) a permis de reveler APOH comme un nouveau locus pour Lp(a) chez des individus d'ascendance europeenne, revelant β2GPI comme une cible therapeutique potentielle. Un GRS-Lp(a) derive de ce GWAS a egalement ete associe a la SA presque autant qu'un GRS-SA lorsqu'etudie chez les Blancs, les Afro-Americains et les Hispaniques. Les deux types de GRS expliquent seulement une faible proportion de la variance de la SA, la variation LPA rs10455872 representant une fraction considerable de la variance chez les Blancs et les Afro-Americains. Ces resultats suggerent que l'etiologie genetique de la SA peut etre expliquee principalement par des variations au niveau du locus LPA et appuient le role de la Lp(a) en tant que facteur de risque pour la SA dans toutes les groupes ethniques.
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650 4 $a Lipoproteins. $3 605784
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650 4 $a Genomes. $3 592593
650 4 $a Metabolism. $3 541349
650 4 $a Genomics. $3 600531
650 4 $a Lipids. $3 558980
650 4 $a Bioinformatics. $3 553671
650 4 $a Genotype & phenotype. $3 3561790
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650 4 $a Apolipoproteins. $3 2156915
650 4 $a Health risk assessment. $3 546024
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653 $a Aortic stenosis
653 $a Ethnicities
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