Genetic Markers Associated With Plasma Protein C Level in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Protein C is an endogenous anticoagulant protein with anti-inflammatory properties. Single-nucleotide polymorphisms (SNPs) affect the levels of circulating protein C in European Americans. We performed a genome-wide association (GWA) scan of plasma protein C concentration with approximately 2.5 million SNPs in 2,701 African Americans in the Atherosclerosis Risk in Communities Study. Seventy-nine SNPs from the 20q11 and 2q14 regions reached the genome-wide significance threshold of 5 × 10−8. A missense variant rs867186 in the PROCR gene at 20q11 is known to affect protein C levels in individuals of European descent and showed the strongest signal (P = 9.84 × 10−65) in African Americans. The minor allele of this SNP was associated with higher protein C levels (β = 0.49 μg/ml; 10% variance explained). In the 2q14 region, the top SNPs were near or within the PROC gene: rs7580658 (β = 0.15 μg/ml; 2% variance explained, P = 1.7 × 10−12) and rs1799808 (β = 0.15 μg/ml; 2% variance explained, P = 2.03 × 10−12). These two SNPs were in strong linkage disequilibrium (LD) with another SNP rs1158867 that resides in a biochemically functional site and in weak to strong LD with the top PROC variants previously reported in individuals of European descent. In addition, two variants outside the PROC region were significantly and independently associated with protein C levels: rs4321325 in CYP27C1 and rs13419716 in MYO7B. In summary, this first GWA study for plasma protein C levels in African Americans confirms the associations of SNPs in the PROC and PROCR regions with circulating levels of protein C across ethnic populations and identifies new candidates for protein C regulation.

Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism

“…Two of these regions (2q13-q14/ PROC and 20q11/ PROCR ) were the same as those identified by the previous GWAS of protein C with HapMap imputation in the ARIC Study 8 . In the 2q13-q14 region, the top SNP on the IBC Array was in the 3’UTR of MAP3K2 (rs423353; P=7.2×10 −11 ), while a low frequency variant in CYP27C1 (rs140608390) had the most significant association in the 1000G GWAS (p=6.7×10 −24 ).…”

“…In European Americans, associations with common variants [minor allele frequency (MAF) > 0.05] were found in four genomic regions located near PROCR (protein C receptor), PROC, GCKR , and BAZ1B , with a possible second independent association found at EDEM2 , located close to PROCR . In African Americans, genome-wide significant associations were found at PROCR and PROC , but not at GCKR or BAZ1B 8 . Genome-wide association studies (GWAS) in French 5 and Spanish 9 populations have also identified significant associations in the PROCR region.…”

“…Recent genome-wide association analyses in the ARIC Study identified 504 single nucleotide polymorphisms (SNPs) associated with protein C levels in European Americans 7 and 79 SNPs associated with protein C in African Americans 8 , respectively. In European Americans, associations with common variants [minor allele frequency (MAF) > 0.05] were found in four genomic regions located near PROCR (protein C receptor), PROC, GCKR , and BAZ1B , with a possible second independent association found at EDEM2 , located close to PROCR .…”

Coagulation Status and Venous Thromboembolism Risk in African Americans: A Potential Risk Factor in COVID-19

“… 55 – 57 However, some genetic studies identify potential single-nucleotide polymorphisms (SNPs) that may affect the level of circulating protein C in multiple groups, including increased levels of protein C in African Americans. 58 While FV Leiden mutation, which results in activated protein C resistance, is a well-characterized mechanism of thrombosis in Caucasian populations, direct changes in protein C, protein S, and thrombomodulin have been found in some African Americans (as described above). African Americans also have increased levels of lipoprotein (a), which is known to play a role in the development of atherosclerosis and the predisposition to thrombosis due to its similarity to plasminogen, as well as through platelet activation.…”

Dissecting the genetic determinants of hemostasis and thrombosis

“…More recently, a study of the African American subset of the ARIC cohort (N = 2701) reported associations in PROCR, PROC and an intergenic region near PROC that collectively explained ~14% of the variance in protein C levels. (42)…”