Journal of thrombosis and haemostasis : JTH · 2026
Plasma level of human epididymis protein 4 is associated with risk of future venous thromboembolism-the Trøndelag Health study.
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Cathro Celina Janene, Wulff Eilertsen Ellen-Sofie, Nøst Therese H, Hindberg Kristian D, Tang Weihong, Guan Weihua, Folsom Aaron R, Jonasson Christian, Thomas Laurent, Hveem Kristian, Brækkan Sigrid K, Hansen John-Bjarne
Аннотация
BACKGROUND: Plasma human epididymis protein 4 (HE4) levels have been associated with the risk of future venous thromboembolism (VTE) in a proteome-wide study.
OBJECTIVES: We aimed to investigate whether plasma HE4 levels were (i) correlated with growth differentiation factor-15 (GDF-15), a marker of oxidative stress, (ii) associated with VTE risk after adjustment for potential confounders, and (iii) genetically regulated, as assessed by protein quantitative trait loci analyses.
METHODS: A case-cohort was derived from the Trøndelag Health Study (N = 50 800), including 294 incident VTE cases over 5 years of follow-up and a randomly sampled age- and sex-weighted subcohort (n = 1066). HE4 and GDF-15 levels were measured using an aptamer-based method in plasma collected at baseline. Weighted Cox regression was used to estimate hazard ratios for VTE, with 95% CIs based on quartiles (Q1-4) of HE4 levels.
RESULTS: HE4 levels correlated with GDF-15 levels (r = .71; P = 3.42 × 10-211), and both proteins were elevated in smokers. Participants with HE4 levels in the highest quartile (Q4) had a 2.5-fold higher risk of future VTE (hazard ratio, 2.54; 95% CI, 1.60-4.03) than those in the lowest quartile (Q1), after adjustment for age, sex, and sample batch. The risk remained after multivariable adjustments. Two genetic variants in trans, with genome-wide significance, explained only 1.6% of the variability in plasma HE4.
CONCLUSION: HE4 levels were associated with an increased risk of future VTE after adjustment for major confounders and did not appear to be strongly genetically regulated. Our findings suggest that HE4 levels may reflect an underlying condition, eg, oxidative stress, that predisposes to VTE.
OBJECTIVES: We aimed to investigate whether plasma HE4 levels were (i) correlated with growth differentiation factor-15 (GDF-15), a marker of oxidative stress, (ii) associated with VTE risk after adjustment for potential confounders, and (iii) genetically regulated, as assessed by protein quantitative trait loci analyses.
METHODS: A case-cohort was derived from the Trøndelag Health Study (N = 50 800), including 294 incident VTE cases over 5 years of follow-up and a randomly sampled age- and sex-weighted subcohort (n = 1066). HE4 and GDF-15 levels were measured using an aptamer-based method in plasma collected at baseline. Weighted Cox regression was used to estimate hazard ratios for VTE, with 95% CIs based on quartiles (Q1-4) of HE4 levels.
RESULTS: HE4 levels correlated with GDF-15 levels (r = .71; P = 3.42 × 10-211), and both proteins were elevated in smokers. Participants with HE4 levels in the highest quartile (Q4) had a 2.5-fold higher risk of future VTE (hazard ratio, 2.54; 95% CI, 1.60-4.03) than those in the lowest quartile (Q1), after adjustment for age, sex, and sample batch. The risk remained after multivariable adjustments. Two genetic variants in trans, with genome-wide significance, explained only 1.6% of the variability in plasma HE4.
CONCLUSION: HE4 levels were associated with an increased risk of future VTE after adjustment for major confounders and did not appear to be strongly genetically regulated. Our findings suggest that HE4 levels may reflect an underlying condition, eg, oxidative stress, that predisposes to VTE.