Genetic Factors in Antiphospholipid Syndrome: Preliminary Experience with Whole Exome Sequencing

Abstract

As in many autoimmune diseases, the pathogenesis of the antiphospholipid syndrome (APS) is the result of a complex interplay between predisposing genes and triggering environmental factors, leading to a loss of self-tolerance and immune-mediated tissue damage. While the first genetic studies in APS focused primarily on the human leukocytes antigen system (HLA) region, more recent data highlighted the role of other genes in APS susceptibility, including those involved in the immune response and in the hemostatic process. In order to join this intriguing debate, we analyzed the single-nucleotide polymorphisms (SNPs) derived from the whole exome sequencing (WES) of two siblings affected by APS and compared our findings with the available literature. We identified genes encoding proteins involved in the hemostatic process, the immune response, and the phospholipid metabolism (PLA2G6, HSPG2, BCL3, ZFAT, ATP2B2, CRTC3, and ADCY3) of potential interest when debating the pathogenesis of the syndrome. The study of the selected SNPs in a larger cohort of APS patients and the integration of WES results with the network-based approaches will help decipher the genetic risk factors involved in the diverse clinical features of APS.

Relationship Between Gender Differences and Clinical Outcome in Patients With the Antiphospholipid Syndrome

“…Although epidemiological data on APS remain limited, and the gender ratio varies widely across studies, ranging from 10:1 to 1:1 (24), in our study we found a female predominant ratio of approximately 3:1. The causes of this predominance are certainly multifactorial, mainly linked to the X chromosome and to different genes expressed exclusively on this chromosome, such as TLR7, FOX-P3, CD40L (25) and other genes involved in the process of immune response (26). Indeed, there are multiple hypotheses about the genetic mechanisms of autoimmune diseases, such as X monosomy until inactivation of X chromosome that could explain gender difference (27).…”

Genetic variation in toll-like receptor 4 gene with primary antiphospholipid syndrome susceptibility: a cohort of Egyptian patients

“…The present study cohort was comprised of females only, which corroborates the results of previous studies. This female predominance is likely multifactorial; however, a number of X-linked genes, such as FOX-P3 and CD40L, play important roles in immune responses [37,38]. Further, sex hormones and pregnancy, likely due to increased progesterone levels, are known to influence the immune system.…”

High-throughput sequencing technology facilitates the discovery of novel biomarkers for antiphospholipid syndrome

“…Barinotti A et al found two siblings with APS and carried out whole exome sequencing to analyze single nucleotide polymorphisms (SNPS), and found that there were many sites involved in hemostasis, immune response and protein coding of phospholipid metabolism. However, the correlation with APS is weak (27). In Meta-analysis, Islam et al showed that 16 genes related to thrombolic APS (TAPS), and the proteins encoded by these genes were interrelated, mainly involved in two processes of coagulation cascade and immune response (28).…”