BACKGROUND: The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single-nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF genes encode two interconnected proteins with fundamental hemostatic functions, the disruption of which may result in thrombosis. OBJECTIVES: To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT. PATIENTS/ METHODS: The protein-coding areas of 186 hemostatic/proinflammatory genes were sequenced by next-generation technology in 94 thrombophilia-negative patients with DVT and 98 controls. Gene-specific information on ADAMTS13 and VWF was used to study the association between DVT and rare coding SNVs of the two genes. RESULTS: More than 70 billion base pairs of raw sequence data were produced to sequence the 700-kb target area with a median redundancy of × 45 in 192 individuals. Most of the 4366 SNVs identified were rare and non-synonymous, indicating pathogenetic potential. Rare (frequency of < 1%) and low-frequency (< 5%) coding SNVs of ADAMTS13 were associated with DVT (prevalence 17% vs. 4%; odds ratio [OR] 4.8 and 95% confidence interval [CI] 1.6-15.0 for rare coding; prevalence 36% vs. 23%, OR 1.9 and 95% CI 1.0-3.5 for low-frequency coding). Patients with rare coding SNVs of ADAMTS13 had lower plasma levels of ADAMTS-13 activity than patients without them. SNVs of VWF were not associated with DVT. CONCLUSIONS: We found an excess of rare coding SNVs of the ADAMTS13 gene in patients with DVT.
BACKGROUND: The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single-nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF genes encode two interconnected proteins with fundamental hemostatic functions, the disruption of which may result in thrombosis. OBJECTIVES: To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT. PATIENTS/ METHODS: The protein-coding areas of 186 hemostatic/proinflammatory genes were sequenced by next-generation technology in 94 thrombophilia-negative patients with DVT and 98 controls. Gene-specific information on ADAMTS13 and VWF was used to study the association between DVT and rare coding SNVs of the two genes. RESULTS: More than 70 billion base pairs of raw sequence data were produced to sequence the 700-kb target area with a median redundancy of × 45 in 192 individuals. Most of the 4366 SNVs identified were rare and non-synonymous, indicating pathogenetic potential. Rare (frequency of < 1%) and low-frequency (< 5%) coding SNVs of ADAMTS13 were associated with DVT (prevalence 17% vs. 4%; odds ratio [OR] 4.8 and 95% confidence interval [CI] 1.6-15.0 for rare coding; prevalence 36% vs. 23%, OR 1.9 and 95% CI 1.0-3.5 for low-frequency coding). Patients with rare coding SNVs of ADAMTS13 had lower plasma levels of ADAMTS-13 activity than patients without them. SNVs of VWF were not associated with DVT. CONCLUSIONS: We found an excess of rare coding SNVs of the ADAMTS13 gene in patients with DVT.
Authors: Eun-Ju Lee; Daniel J Dykas; Andrew D Leavitt; Rodney M Camire; Eduard Ebberink; Pablo García de Frutos; Kavitha Gnanasambandan; Sean X Gu; James A Huntington; Steven R Lentz; Koen Mertens; Christopher R Parish; Alireza R Rezaie; Peter P Sayeski; Caroline Cromwell; Noffar Bar; Stephanie Halene; Natalia Neparidze; Terri L Parker; Adrienne J Burns; Anne Dumont; Xiaopan Yao; Cassius Iyad Ochoa Chaar; Jean M Connors; Allen E Bale; Alfred Ian Lee Journal: Blood Adv Date: 2017-06-29
Authors: Ashish Goel; V Raghupathy; G J Amirtharaj; Aaron Chapla; Aparna Venkatraman; Banumathi Ramakrishna; Anup Ramachandran; Nihal Thomas; K A Balasubramanian; Ian Mackie; Elwyn Elias; Chundamannil E Eapen Journal: Indian J Gastroenterol Date: 2017-10-05
Authors: Maria Teresa Pagliari; Luca A Lotta; Hugoline G de Haan; Carla Valsecchi; Gloria Casoli; Silvia Pontiggia; Ida Martinelli; Serena M Passamonti; Frits R Rosendaal; Flora Peyvandi Journal: PLoS One Date: 2016-11-01 Impact factor: 3.240
Authors: Marcin M Gorski; Luca A Lotta; Emanuela Pappalardo; Hugoline G de Haan; Serena M Passamonti; Astrid van Hylckama Vlieg; Ida Martinelli; Flora Peyvandi Journal: PLoS One Date: 2016-03-16 Impact factor: 3.240
Authors: Laura Martin-Fernandez; Giovana Gavidia-Bovadilla; Irene Corrales; Helena Brunel; Lorena Ramírez; Sonia López; Juan Carlos Souto; Francisco Vidal; José Manuel Soria Journal: PLoS One Date: 2017-04-26 Impact factor: 3.240
Authors: H G de Haan; A van Hylckama Vlieg; L A Lotta; M M Gorski; P Bucciarelli; I Martinelli; T P Baglin; F Peyvandi; F R Rosendaal Journal: J Thromb Haemost Date: 2018-10-16 Impact factor: 5.824