Luis R Macias-Kauffer1, Hugo Villamil-Ramírez2, Paola León-Mimila2, Leonor Jacobo-Albavera3, Carlos Posadas-Romero4, Rosalinda Posadas-Sánchez4, Blanca E López-Contreras2, Sofía Morán-Ramos2, Sandra Romero-Hidalgo5, Víctor Acuña-Alonzo6, Blanca E Del-Río-Navarro7, Maria-Cátira Bortolini8, Carla Gallo9, Gabriel Bedoya10, Francisco Rothhammer11, Rolando González-Jose12, Andrés Ruiz-Linares13, Christopher R Stephens14, Rafael Velazquez-Cruz15, Cecilia Fernández Del Valle-Laisequilla16, Juan G Reyes-García17, Lina M Barranco Garduño18, Miriam Del C Carrasco-Portugal18, Francisco J Flores-Murrieta19, Gilberto Vargas-Alarcón20, Carlos A Aguilar-Salinas21, Teresa Villarreal-Molina22, Samuel Canizales-Quinteros23. 1. Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico. 2. Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico. 3. Laboratorio de Enfermedades Cardiovasculares, INMEGEN, Mexico City, Mexico. 4. Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico. 5. Departamento de Genómica Computacional, INMEGEN, Mexico City, Mexico. 6. Escuela Nacional de Antropología e Historia, Mexico City, Mexico. UCL Genetics Institute, University College London, London WC1E 6BT, UK. 7. Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico. 8. Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil. 9. Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru. 10. GENMOL (Genetica Molecular), Universidad de Antioquia, Medellin 5001000, Colombia. 11. Instituto de Alta Investigación, Universidad de Tarapacá e ICBM Facultad de Medicina Universidad de Chile, 1000009, Chile. 12. Instituto Patagónico de Ciencias Sociales y Humanas (CENPAT-CONICET), U9120ACD Puerto Madryn, Argentina. 13. Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China; Aix-Marseille Univ, CNRS, EFS, ADES, Marseille, France. 14. C3-Centro de Ciencias de la Complejidad e Instituto de Ciencias Nucleares, UNAM, Ciudad de México, Mexico. 15. Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico. 16. Investigación Clínica y Farmacovigilancia, Productos Medix, S.A. de C.V., Mexico City, Mexico. 17. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico. 18. Unidad de Investigación en Farmacología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico. 19. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico; Unidad de Investigación en Farmacología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico. 20. Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico. 21. Unidad de Investigación en Enfermedades Metabólicas and Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey, N.L., Mexico. 22. Laboratorio de Enfermedades Cardiovasculares, INMEGEN, Mexico City, Mexico. Electronic address: mvillareal@inmegen.gob.mx. 23. Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico. Electronic address: cani@unam.mx.
Abstract
BACKGROUND: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS: Only two loci were associated with SUA levels: SLC2A9 (β = -0.47 mg/dl, P = 1.57 × 10-42 for lead SNP rs7678287) and ABCG2 (β = 0.23 mg/dl, P = 2.42 × 10-10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS: SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD.
BACKGROUND: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS: Only two loci were associated with SUA levels: SLC2A9 (β = -0.47 mg/dl, P = 1.57 × 10-42 for lead SNP rs7678287) and ABCG2 (β = 0.23 mg/dl, P = 2.42 × 10-10 for lead SNP rs2231142). No significant interaction between SLC2A9rs7678287 and ABCG2rs2231142 genotypes and obesity was observed. However, a significant ABCG2rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS:SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD.
Authors: Paola León-Mimila; Hugo Villamil-Ramírez; Luis R Macías-Kauffer; Leonor Jacobo-Albavera; Blanca E López-Contreras; Rosalinda Posadas-Sánchez; Carlos Posadas-Romero; Sandra Romero-Hidalgo; Sofía Morán-Ramos; Mayra Domínguez-Pérez; Marisol Olivares-Arevalo; Priscilla López-Montoya; Roberto Nieto-Guerra; Víctor Acuña-Alonzo; Gastón Macín-Pérez; Rodrigo Barquera-Lozano; Blanca E Del-Río-Navarro; Israel González-González; Francisco Campos-Pérez; Francisco Gómez-Pérez; Victor J Valdés; Alicia Sampieri; Juan G Reyes-García; Miriam Del C Carrasco-Portugal; Francisco J Flores-Murrieta; Carlos A Aguilar-Salinas; Gilberto Vargas-Alarcón; Diana Shih; Peter J Meikle; Anna C Calkin; Brian G Drew; Luis Vaca; Aldons J Lusis; Adriana Huertas-Vazquez; Teresa Villarreal-Molina; Samuel Canizales-Quinteros Journal: Arterioscler Thromb Vasc Biol Date: 2021-07-08 Impact factor: 10.514
Authors: Federica Piani; Fumihiko Sasai; Petter Bjornstad; Claudio Borghi; Ashio Yoshimura; Laura G Sanchez-Lozada; Carlos Roncal-Jimenez; Gabriela E Garcia; Ana Andres Hernando; Gabriel Cara Fuentes; Bernardo Rodriguez-Iturbe; Miguel A Lanaspa; Richard J Johnson Journal: J Bras Nefrol Date: 2021 Oct-Dec