Genetics of Coronary Artery Disease

Abstract

Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genomewide significance (P<5×10 −8 ) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (q<0.05) and together explain 28% of the estimated heritability of CAD. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome. (Circ Res. 2016;118:564-578.

The developmental biology of genetic Notch disorders

“…ANK, ankyrin repeats; EGF, epidermal growth factor; HD, heterodimerization domain; LNR, Lin-Notch repeats; PEST, proline (P), glutamic acid (E), serine (S) and threonine (T) degradation domain; RAM, Rbp-associated molecule domain; SP, signal peptide; TM, transmembrane domain. diseases, ranging from autism spectrum disorders and schizophrenia to heart disease (McPherson and Tybjaerg-Hansen, 2016;Mitchell, 2011). Recently, the Exome Aggregation Consortium (EXAC) has pooled data and resources to generate the largest database of human sequencing data, including 60,706 individuals (Lek et al, 2016).…”

Asian-Indians: a review of coronary artery disease in this understudied cohort in the United States

“…Furthermore, clustering of CAD in Asian Indian families indicates genetic risk factor/susceptibility (48). Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIOGRAM) study and other genome-wide association studies (GWAS) have found 109 loci associated with CAD and can explain 28% of the heritability (49,50). One likely explanation for the low heritability can be the polygenic nature of CAD.…”

Lipoprotein a: Extreme elevation and genetic polymorphism association with cardiac and vascular lesions evaluated by computed tomography

“…Si bien hubo hallazgos interesantes respecto de este SNP, como la existencia de tres pacientes homocigotas GG con calcificaciones en dos territorios diferentes (coronaria y aorta torácica), su vinculación con la regulación de los niveles Lp(a) recién se está iniciando, ya que fue descubierto en el corriente año (2016). (8,9) Acorde a lo esperado, dado que el bajo número de repeticiones se asocia con niveles altos de Lp(a), se encontró que en el 72% de los pacientes estudiados el número de repeticiones del Kringle IV-2 es menor que el que presentan pacientes con niveles de Lp(a) normales.…”

“…(3-5, 7) Asimismo, a principios del año 2016, mediante estudios de GWAS (Genome Wide Association Study), se ha descripto un nuevo SNP en el gen SLC22A3 (rs2048327) que estaría vinculado a enfermedad vascular coronaria influyendo los niveles de Lp(a). (8,9) En base a los nuevos conocimientos en cuanto a la base genética de la determinación de los niveles de Lp(a), utilizando modernos métodos de biología molecular, es posible estudiar tanto el número de repeticiones del KIV en el gen LPA como los SNP relacionados con mayor riesgo. (5) La tomografía computarizada cardíaca y en especial el puntaje de calcio coronario han demostrado ser los predictores más fuertes de eventos coronarios, posibilitando la reclasificación del riesgo cardiovascular.…”