Further Investigation of the Role of Factor XIII in Priapism Associated with SCD.
Authors: Khatib Aya El , Ashley-Koch Allison , Kail Melanie , Collins Ann , Jonassaint Jude , Adam Soheir S. , Ataga Kenneth I. , Eckman James R. , Orringer Eugene P. , Greenberg Charles S. , Telen Marilyn J. 
Published: October 2019

Abstract
Genetic risk factors may contribute to the incidence of certain sickle cell disease (SCD) complications. Priapism, a painful, unwanted and sustained erection, is caused by decreased venous drainage in the penile vessels. Our previous work suggested an association between multiple non-coding polymorphisms in the A1 subunit of coagulation Factor XIII (F13A1) gene and a history of priapism (Elliott et al., 2007). The purpose of this study was to further investigate the possible association of polymorphisms in the A1 and B (F13B) subunits of the Factor XIII gene with priapism in order to better understand how differences in the coagulation pathway might affect the risk for priapism. The larger data set from which this study was derived included 524 unrelated patients with any form of SCD. These individuals had been recruited at three southeastern US medical centers. A subset of 186 males from this study population was used in the current analysis. These patients all had a diagnosis of Hb SS, had provided a DNA sample for genetic analysis and had responded to a standardized questionnaire regarding the history of priapism. The patients had a mean age of 32.4 years, and 78 (42%) reported a positive history of priapism. Four coding single nucleotides polymorphism (SNPs) in the F13A1 gene and 10 SNPs (2 coding, 8 non-coding) in the F13B gene were genotyped in our dataset. Genotyping was performed using Applied Biosystems Taqman Allelic Discrimination Assays. For quality control, blinded duplicate and CEPH samples were included on all gels and required to match 100%. Further, the genotypes of at least 95% of the samples had to be called with certainty to be considered for statistical analysis. Deviations from Hardy-Weinberg equilibrium (HWE) were identified using exact tests implemented by the Genetic Data Analysis program; no markers in F13A1 or F13B significantly deviated from HWE. For each SNP, exact tests of association for the genotypes by occurrence of priapism were performed using SAS. No SNPs in F13B were associated with priapism, and two F13A polymorphisms previously associated with risk for thrombosis (rs5985 and rs6003) were also not associated with risk for priapism in our data set. However, a single coding SNP in F13A1 (rs5988) was strongly associated with priapism (global p-value of 0.03). The odds that males with the C/C genotype suffered from priapism were 2.43 times higher than for those with the C/G genotype. This SNP resides in the C- terminus of FXIIIA. This area of the protein functions to prevent substrates from gaining access to the Factor XIII active site. While there is no evidence that this area directly regulates catalysis, it may play a role in aligning the substrate with the active site. Factor XIII could modify fibrin formation and alter red cell interaction with the vasculature. We plan to express the molecule encoded by the allele associated with risk to see if it has altered activity. In conclusion, identification of risk groups for priapism by genetic studies may lead to investigation of newly identified pathophysiologic mechanisms for this complication of SCD.
Priapism Genotype Frequencies for rs5988 Negative History Positive History Total C/C 68 61 129 C/G 38 14 52 G/G 2 3 5 Total 108 78 186