Novel exomic rare variants associated with venous thrombosis

Q: What are the key findings of this study?

Clustered chromosome 17p13.1 MYH rare missense variants and FAM134B (rs78314670) were associated with recurrent VTE in adults under 55.

Q: What is the clinical evidence from this study?

Study design: Case-Control. Population: Venous thromboembolism (VTE) (n=315). Intervention: Exomic rare variant polymorphisms (including F5, FAM134B, and chr17p13.1 MYH rare SNPs) vs. Healthy controls (<55 years old) without VTE. Primary outcome: Recurrent venous thromboembolism (VTE) associated with 7 rare missense MYH variants (p=2.70 x10-16).

Q: What does this research mean for the field?

Clustered chromosome 17p13.1 MYH rare missense variants and the FAM134B rs78314670 variant are significantly associated with recurrent venous thromboembolism in adults under 55. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Hiroshi Deguchi; Meenal Shukla; Mohammed Hayat; Ali Torkamani; Darlene J. Elias; John H. Griffin

doi:10.1111/bjh.16613

March 30, 2020British Journal of HaematologyOpen Access

Novel exomic rare variants associated with venous thrombosis

View Full Paper

Ask AI

Bookmark

Share

Key result

Rare chromosome 17p13.1 MYH missense variants linked to recurrent VTE in younger adults.

P=2.70 x10-16
n=315

Why the study?

Genetic or acquired risk factors have not been identified for a substantial percentage of VTE cases, and recently discovered common variants often lack functional associations with coagulation regulation. Exomic rare variant analysis in a younger VTE population was undertaken to discover unknown genetic risk factors.

Are rare exomic missense variants in genes such as FAM134B and chromosome 17p13.1 skeletal muscle myosin (MYH) associated with venous thromboembolism and recurrent VTE in patients under 55 years of age?

Key Points

To identify novel rare genetic variants and explore biological mechanisms underlying venous thromboembolism risk in young patients.
Genotyped exomic rare variant polymorphisms using the Axiom Exome Genotyping Array in 104 venous thrombosis cases and 211 controls aged under 55 years from the Scripps Venous Thrombosis Registry.
Conducted subgroup and rare variant collapsing association analyses across chromosome 17p13.1 skeletal myosin heavy chain genes in 32 recurrent venous thrombosis cases versus 211 controls.
Tested the in vivo procoagulant activity of skeletal muscle myosin using an anti-factor VIII antibody-induced hemophilic mouse tail clip bleeding model.
Recurrent venous thrombosis was significantly associated with FAM134B rs78314670 and MYH8 rs111567318 (false discovery rate-adjusted p < 0.05), with 7 of 8 FAM134B rs78314670 carriers displaying plasma anticoagulant glucosylceramide levels below the 10th percentile of controls (p < 0.0001).
Collapsing analysis of 7 rare missense MYH variants revealed a cumulative frequency of 0.156 in recurrent cases versus 0 in controls (p = 2.70 x 10^-16), and 0.063 versus 0 in all cases (p = 2.11 x 10^-7).
Intravenous administration of skeletal muscle myosin exerted procoagulant effects in hemophilic mice, reducing tail clip blood loss from 6.9 to 2.3 μL/gm (p < 0.0001).

Study Design

Type

Case-Control (n=315)

Multicenter

No

Structured PICO

Are rare exomic missense variants in genes such as FAM134B and chromosome 17p13.1 skeletal muscle myosin (MYH) associated with venous thromboembolism and recurrent VTE in patients under 55 years of age?

P

Population

315 adults aged under 55 years (104 VTE cases, including 32 recurrent VTE cases, and 211 controls) from the Scripps Venous Thrombosis Registry.

E

Exposure

Exomic rare variant polymorphisms (~300,000 interrogated via Axiom Exome Genotyping Array), specifically focusing on FAM134B (rs78314670, Arg127Cys), MYH8 (rs111567318, Glu1838Ala), clustered chromosome 17p13.1 MYH rare SNPs, and F5 SNPs; intravenous skeletal muscle myosin in the mouse model.

C

Comparator

211 control subjects aged <55 years without VTE from the Scripps Venous Thrombosis Registry.

O

Outcome

Association of rare exomic variants with all VTE and recurrent VTE.hard clinical

Main Result

Absolute Event Rate: 15.6% vs 0%

p-value: p=2.70 x10-16

Limitations

Small sample size (particularly for recurrent VTE subgroup) resulting in diminished statistical power
Associations of variants with VTE may be tenuous or false and require replication in larger cohorts
Potential confounding clinical variables such as lipids, body mass index, and blood pressure could not be evaluated
Functional influences of the identified gene mutations require further demonstration
Small number of subjects in this pilot study, especially in the recurrent VTE subgroup, reducing statistical power
Reported genetic associations may be tenuous or false and require extensive replication studies in other VTE cohorts
Inability to evaluate potential confounding clinical variables such as lipids, body mass index, and blood pressure due to small sample size
More information is needed to demonstrate and understand the functional influences of these gene mutations

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

This study identifies novel rare genetic variants in FAM134B and chromosome 17p13.1 skeletal muscle myosin (MYH) genes associated with recurrent VTE in younger adults, supported by functional links to low anticoagulant glucosylceramide levels and in vivo procoagulant activity of myosin.

Abstract

Summary Exomic rare variant polymorphisms (c. 300 000) were analysed in the Scripps Venous Thrombosis (VTE) registry (subjects aged <55 years). Besides coagulation factor V (F5) single nucleotide polymorphisms (SNPs), family with sequence similarity 134, member B (FAM134B; rs78314670, Arg127Cys) and myosin heavy chain 8 (MYH8; rs111567318, Glu1838Ala) SNPs were associated with recurrent VTE (n = 34 cases) (false discovery rate‐adjusted P < 0·05). FAM134B (rs78314670) was associated with low plasma levels of anticoagulant glucosylceramide. Analysis of 50 chr17p13.1 MYH rare SNPs (clustered skeletal myosin heavy chain genes) using collapsing methods was associated with recurrent VTE (P = 2·70 ×10−16). When intravenously injected, skeletal muscle myosin was pro‐coagulant in a haemophilia mouse tail bleeding model. Thus, FAM134B and MYH genetic variants are plausibly linked to VTE risk.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Deguchi et al. (2020) conducted a case-control in Venous thromboembolism (VTE) (n=315). Exomic rare variant polymorphisms (including F5, FAM134B, and chr17p13.1 MYH rare SNPs) vs. Healthy controls (<55 years old) without VTE was evaluated on Recurrent venous thromboembolism (VTE) associated with 7 rare missense MYH variants (p=2.70 x10-16). Clustered chromosome 17p13.1 MYH rare missense variants and FAM134B (rs78314670) were associated with recurrent VTE in adults under 55.

synapsesocial.com/papers/6a905941109970a0fe90a483 https://doi.org/10.1111/bjh.16613

View Full Paper

Ask AI

Bookmark

Share

Novel exomic rare variants associated with venous thrombosis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Novel exomic rare variants associated with venous thrombosis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading