Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study

Abstract

Background The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes. Methods and Results We performed whole exome sequencing in 3,223 African American individuals from the Jackson Heart Study and found a total of 729,666 variant sites with minor allele frequency (MAF) < 5%, including 17,263 null variants and 49,929 missense variants predicted to be damaging by in silico algorithms. We tested null and damaging missense variants within each gene for association with 36 cardiovascular traits. We found three associations that met our pre-specified level of significance (α=1.1×10−7). Null and damaging missense variants in PCSK9 were associated with 36 mg/dl lower low density lipoprotein cholesterol (LDL-C) (p-value=3×10−21). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd-percentile despite a LDL-C of 32 mg/dl. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin (p-value=9×10−13) and rare damaging missense variants in VPS13A with higher red blood cell distribution width (p-value=9.9 × 10−8). Conclusions A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ~3,000 African American individuals.

Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease

“…We were unable to fully resolve the paradox of how the rs11865131-A allele impairs enhancer activity, yet appears to be associated with laboratory and clinical parameters suggesting increased HBA1 / HBA2 expression, which ultimately suggests that regulation within this locus is quite complex and not fully understood. As an example of this emerging complexity, we and others recently discovered a low frequency, loss of function missense variant within HBQ1 that was strongly associated with lower MCH[ 45 ], although HBQ1 is largely thought to be a non-functional α-like globin gene. Here, the common rs11865131-A allele was associated with increased HBQ1 but decreased expression of other proximal genes, including the functional embryonic globin gene HBZ and nearby NPRL3 .…”

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

“…These included the ATVB (Italian Atherosclerosis Thrombosis and Vascular Biology) study (9), the ESP-EOMI (Exome Sequencing Project Early-Onset Myocardial Infarction) study (10), the South German Myocardial Infarction study (11), OHS (Ottawa Heart Study) (12), PROCARDIS (Precocious Coronary Artery Disease Study) (13), PROMIS (Pakistan Risk of Myocardial Infarction Study) (14), the Registre Gironi del COR (Gerona Heart Registry or REGICOR) study (15), the BHF-FHS (British Heart Foundation Family Heart Study) (16), and the Lubeck Myocardial Infarction study (16). Furthermore, we extracted ANGPTL3 sequence data from exome sequencing performed in the Jackson Heart Study (17), the BioImage study (18), and the ARIC (Atherosclerosis Risk in Communities) population-based cohort study (19) in addition to targeted sequencing in the Duke CATHGEN case-control study (20). Loss-of-function mutations included those leading to truncation via a premature stop codon (nonsense), insertions or deletions that scramble protein translation beyond the variant site (frameshift), or point mutations at sites of pre-messenger ribonucleic acid splicing that alter the splicing process (splice-site).…”

Malaria is a cause of iron deficiency in African children

“…Whole blood was used to extract DNA using Puregene reagents (Gentra System, Minneapolis, USA). Genetic studies were conducted as described elsewhere 49 and rs334 genotypes were extracted from exome sequencing datasets as described in Peloso et al 50 .…”