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Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults : A Population-Based Cohort Study

Manderstedt, Eric LU ; Halldén, Christer LU ; Lind-Halldén, Christina LU ; Elf, Johan LU ; Svensson, Peter J. LU ; Engström, Gunnar LU ; Melander, Olle LU orcid ; Baras, Aris ; Lotta, Luca A. and Zöller, Bengt LU orcid (2022) In Thrombosis and Haemostasis 122(8). p.1326-1332
Abstract

Background The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Methods The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function... (More)

Background The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Methods The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) <0.1%. Results Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9). Conclusion Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
genetics, PROCR, protein C receptor, venous thromboembolism
in
Thrombosis and Haemostasis
volume
122
issue
8
pages
1326 - 1332
publisher
Schattauer GmbH
external identifiers
  • pmid:35021256
  • scopus:85125723523
ISSN
0340-6245
DOI
10.1055/a-1738-1564
language
English
LU publication?
yes
id
a0276dd9-1b21-4608-ac1b-838f74eba231
date added to LUP
2022-04-26 11:46:59
date last changed
2024-04-18 07:17:55
@article{a0276dd9-1b21-4608-ac1b-838f74eba231,
  abstract     = {{<p>Background The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Methods The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) &lt;0.1%. Results Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9). Conclusion Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.</p>}},
  author       = {{Manderstedt, Eric and Halldén, Christer and Lind-Halldén, Christina and Elf, Johan and Svensson, Peter J. and Engström, Gunnar and Melander, Olle and Baras, Aris and Lotta, Luca A. and Zöller, Bengt}},
  issn         = {{0340-6245}},
  keywords     = {{genetics; PROCR; protein C receptor; venous thromboembolism}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1326--1332}},
  publisher    = {{Schattauer GmbH}},
  series       = {{Thrombosis and Haemostasis}},
  title        = {{Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults : A Population-Based Cohort Study}},
  url          = {{http://dx.doi.org/10.1055/a-1738-1564}},
  doi          = {{10.1055/a-1738-1564}},
  volume       = {{122}},
  year         = {{2022}},
}