Clinical trial NCT05515653: Impact of the Genetic Background as a Risk Factor for Atherosclerotic Cardiovascular Disease in the Brazilian Population
Official title: Impact of the Genetic Background as a Risk Factor for Atherosclerotic Cardiovascular Disease in the Brazilian Population
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Cardiovascular Diseases
Acute MI
Stroke
Peripheral Arterial Disease
Genetic Predisposition to Disease
Keywords: case-control study
Polymorphism genetic
cardiovascular disease
observational study
Lead sponsor: Hospital Alemão Oswaldo Cruz
Sponsor class: OTHER
Collaborators: name: Grupo Fleury
name: Ministry of Health, Brazil
First posted: 2022-08-25
Enrollment: 3974
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: In-hospital patients with the first atherosclerotic event will be enrolled (Cases). Patients being attended in the same hospitals without cardiovascular events or without any overt disease will be the controls. The sample size calculation assumed a dominant inheritance pattern, within a non-matched case-control study design 1:1. A sample of 1867 cases and 1867 controls would have a statistical power of 90% to detect a genetic OR of 1.3, assuming an allelic frequency of 10%, considering an unpaired control 1:1 of the genetic factor.

A prevalence of 10% of the disease in the target population was considered, an alpha significance level of 5%, bilateral hypothesis test.

Brief summary: The main objective of this project is to evaluate the genomic information previously associated with cardiovascular diseases (CVD) and its importance as an independent risk predictor (expressed in Odds Ratio) when adjusted for traditional risk factors (smoking, diabetes, arterial hypertension, obesity , anxiety and depression, inadequate diet, physical inactivity, alcohol consumption and apolipoprotein B/A1 ratio (ApoB/ApoA1).

An unpaired case-control study of individuals over 18 years of age will be carried out. Cases (N = 1867) will be enrolled right after the occurrence of the first atherosclerotic cardiovascular event (Acute Myocardial Infarction, Stroke and Peripheral Artery Thrombotic-Ischemic Events). The ratio between cases and controls will be 1:1. The controls (N = 1867) will be adult individuals over 18 years of age who sought medical care at the same locations for other clinical reasons (no CVD) or individuals without any overt disease. The genetic evaluation will be performed through the association of Low-covering Whole Genome Sequencing (coverage 0.5-5x) and Whole Exome Sequencing (average coverage 30x).

Detailed description: The study will be carried out in about 50 centers, comprising the five Brazilian regions. The study will be conducted from July 2022 to December 2023. Data collection will be performed at each center consecutively, for cases and controls, through electronic Case Report Form (CRF).

Cases (N = 1867) will be selected by the occurrence of the first atherosclerotic cardiovascular event (Acute Myocardial Infarction, Stroke and Peripheral Arterial Thrombotic-Ischemic Events) during the hospitalization phase for the management of the acute atherothrombotic event. The ratio between cases and controls will be 1:1. Controls (N = 1867) will be adult individuals over 18 years of age who sought medical care at the same locations for other clinical reasons (no CVD) or individuals without any overt disease. The definitions of acute atherothrombotic events follow classic clinical and complementary exam criteria and are based on national and international guidelines. The complete project was submitted to the local Institutional Review Board (IRB)/National Research Ethics Commission (CONEP) system and has ethical approval (CAAE: 56482922.2.1001.0070). All cases and controls will be invited to participate and, if they agree, an Informed Consent Form will be obtained.

Investigators will assess exposures to traditional risk factors in combination with genomic data (polygenic risk score) in both cases and controls, and these exposures will be expressed as odds ratios. Multiple logistic regression models will be built to adjust and determine the strengths of association between demographic variables, traditional risk factors and genetic data: gender, age, ethnicity, weight, body mass index, smoking, diabetes, hypertension, obesity, anxiety and depression, inadequate diet, physical inactivity, alcohol consumption and apolipoprotein B/A1 ratio (ApoB/ApoA1). For each association variable with a greater chance of cardiovascular disease (significant OR), an attributable risk will be calculated to estimate the fraction of risk attributable to the genetic component (Polygenic Risk Score) and to other clinical and demographic variables.

The polygenic risk score will be calculated through a hybrid approach by taking into account the following features: effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the Polygenic Risk Score, and the number of nonmissing SNPs in the sample. Each risk allele will be given points in the risk score, and the total score will range between 0 (absence of risk alleles) and the maximum value (yet to be defined), based on the distribution of risk alleles that will be identified in the population included in the study. The scale will be interpreted in a direct (positive) association, i.e., the higher the score, the higher the number of alleles and respective weighted effect sizes. Finally, the polygenic risk score will be adjusted to previously reported traditional risk factors for atherosclerotic cardiovascular disease to determine the attributable risk fraction associated with the genomic profile.

Eligibility criteria: Inclusion Criteria:

* Cases: adults over 18 years with first atherosclerotic cardiovascular event (Acute Myocardial Infarction, Stroke and Peripheral Artery Thrombotic-Ischemic Events)
* Controls: adult individuals over 18 years of age who sought medical care at the same locations for other clinical reasons (no CVD) or individuals without any overt disease

Exclusion Criteria:

* Previous occurrence of Cardiovascular Event (Myocardial Infarction, Stroke or Peripheral Artery Thrombotic Events
* Patients already recruited in another study linked to the GENOMA Brazil Program.

Primary outcomes:
measure: Population attributable risk fraction measured for the Polygenic Risk Score. Scale will range from 0 to maximum number of risk alleles. The higher the score, the higher the number of risk alleles (worse).
timeFrame: through study completion, an average of 1 year
measure: Polymorphisms genes as an independent risk factor for the occurrence of Acute Myocardial infarction (AMI), stroke and peripherical arterial thrombotic-ischemic events
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Rio Branco
country: Brazil
facility: Acurácia Serviços Médicos
state: AC
city: Maceió
country: Brazil
facility: Centro de Pesquisas Clínicas Dr. Marco Mota HCOR
state: Alagoas
city: Ipiaú
country: Brazil
facility: Hospital e Clínica São Roque
state: Bahia
city: Salvador
country: Brazil
facility: Instituto Cárdio Pulmonar da Bahia
state: Bahia
city: Barbalha
country: Brazil
facility: Hospital Maternidade São Vicente de Paulo
state: Ceará
city: Aracaju
country: Brazil
facility: Centro de Pesquisa Clínica do Coração
state: CE
city: Vila Velha
country: Brazil
facility: Hospital Evangélico de Vila Velha
state: ES
city: Vitória
country: Brazil
facility: Hospital Universitário Cassiano Antônio de Moraes
state: ES
city: Goiânia
country: Brazil
facility: Universidade Federal de Goiás - UFG
state: GO
city: São Luís
country: Brazil
facility: Hospital Universitário da Universidade Federal do Maranhão/HU/UFMA
state: MA
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte
state: MG
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
state: MG
city: Uberaba
country: Brazil
facility: Hospital de Clínicas da Universidade Federal do Triângulo Mineiro
state: MG
city: Cuiabá
country: Brazil
facility: Hospital Geral Filantrópico Universitário - Assoc. de Proteção à Maternidade e Infância de Cuiabá
state: Mount
city: Campo Grande
country: Brazil
facility: Hospital Universitário Maria Aparecida Pedrossian
state: MS
city: Recife
country: Brazil
facility: Real Hospital Português de Beneficência em Pernambuco
state: PE
city: Teresina
country: Brazil
facility: Hospital Universitário da Universidade Federal do Piauí
state: PI
city: Campina Grande Do Sul
country: Brazil
facility: Hospital e Maternidade Angelina Caron
state: PR
city: Curitiba
country: Brazil
facility: Núcleo de Pesquisa Clínica S/S
state: PR
city: Bento Gonçalves
country: Brazil
facility: Associação Dr. Bartholomeu Tacchini
state: Rio Grande Do Sul
city: Natal
country: Brazil
facility: Instituto Atena de Pesquisa Clínica
state: RN
city: Passo Fundo
country: Brazil
facility: Associacao Hospitalar Beneficente Sao Vicente de Paulo
state: RS
city: Pelotas
country: Brazil
facility: Santa Casa de Misericórdia de Pelotas
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora Da Conceicao Sa
state: RS
city: Porto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
state: RS
city: Santa Maria
country: Brazil
facility: Hospital Universitário de Santa Maria
state: RS
city: Blumenau
country: Brazil
facility: Maestri e Kormann Consultoria Medico Cientifica
state: Santa Catarina
city: Joinville
country: Brazil
facility: H&W Cardiologia LTDA
state: Santa Catarina
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
state: Sao Paulo
city: Aracaju
country: Brazil
facility: Hospital Cirurgia
state: SE
city: Barueri
country: Brazil
facility: Hospital Municipal de Barueri
state: SP
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clínica de Campinas
state: SP
city: Campinas
country: Brazil
facility: Scentryfar Pesquisa Clínica
state: SP
city: São José Do Rio Preto
country: Brazil
facility: Fundação Faculdade de Medicina de São José do Rio Preto
state: SP
city: São Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
state: SP
city: São Paulo
country: Brazil
facility: Instituto de Cardiologia HCFMUSP
state: SP
city: São Paulo
country: Brazil
facility: Instituto de Pesquisa GNDI
state: SP
city: Matão
country: Brazil
facility: Hospital Carlos Fenando Malzoni
state: São Paulo
city: São José Do Rio Preto
country: Brazil
facility: Braile Hospital Dia Ltda
state: São Paulo
city: São Paulo
country: Brazil
facility: Hospital Santa Paula
Study officials:
affiliation: Hospital Alemão Oswaldo Cruz
name: Álvaro Avezum, MD, PhD
role: STUDY_CHAIR
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