Next generation sequencing to dissect the genetic architecture of KNG1 and F11 loci using factor XI levels as an intermediate phenotype of thrombosis

Abstract

Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia. Among the 110 individuals, a subset of 40 individuals was chosen as a discovery sample for identifying variants. A total of 762 genetic variants were detected. Several significant associations were established among common variants and low-frequency variants sets in KNG1 and F11 with FXI levels using the PLINK and SKAT packages. Among these associations, those of rs710446 and five low-frequency variant sets in KNG1 with FXI level variation were significant after multiple testing correction and permutation. Also, two putative pathogenic mutations related to high and low FXI levels were identified by data filtering and in silico predictions. This study of KNG1 and F11 loci should help to understand the connection between genotypic variation and variation in FXI levels. The functional genetic variants should be useful as markers of thromboembolic risk.

Genetic determinants of activity and antigen levels of contact system factors

“…The latter three SNVs are in moderate LD with rs5030062, with r 2 values of 0.65 (D′ = 1.00), 0.53 (D′ = 0.86) and 0.29 (D′ = 0.75), and represent the same association signal. In addition to FXI:C, rs5030062 was associated with FXI:ag after conditioning on FXI:C. This SNV as well as a tagged missense variant rs710446 have been associated with FXI levels in both pooled activity/antigen GWAS and activity‐only analyses .…”

A case report of vaccine-induced immune thrombotic thrombocytopenia (VITT) with genetic analysis

“…The F11 variant rs116667976 found in heterozygosity in the patient is classified as likely benign by ACMG and presented as having conflicting interpretations of pathogenicity in the ClinVar database. It has been selected as a potentially functional mutation in thrombosis without functional analysis available ( 21 ). The same SNP was described in 2 out of 49 women with heavy menstrual bleeding.…”

Significance of a Family-based Study of Hereditary Thrombosis: A Single-family Case Series of Protein C Deficiency

“…Offering carrier screenings to the general public may help remedy this situation. It may also prevent serious thrombosis-related complications not just in individuals but also in their family members as well as future generations (21,22). Most people are unaware of the genetic risk of thrombophilia and its potentially dire consequences (23).…”