White Matter Hyperintensities Modify CYP2C19 Effect on Stroke Progression in Small Vessel Occlusion

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Acute small vessel occlusion (SVO) ischemic stroke (n=247). Intervention: CYP2C19 loss-of-function (LOF) carrier status (*2 or *3 alleles) modified by white matter hyperintensities (WMH) burden vs. CYP2C19 LOF non-carriers (*1/*1, *1/*17, or *17/*17). Primary outcome: Early neurological deterioration (END), defined as an increase of >= 2 points in total NIHSS score or >= 1 point in motor items within 72 h of admission (aOR 1.22, 95% CI 0.59-2.54, p=0.591).

Q: What does this research mean for the field?

CYP2C19 loss-of-function alleles significantly increase the risk of early neurological deterioration in acute small vessel occlusion stroke patients specifically in the presence of severe white matter hyperintensities. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Xiaoxin Sun; Xinxiu Liu; Lei Wang; Rui Zhu; M Wang; Zhiyong Zhang

doi:10.1002/acn3.70579

November 13, 2026Annals of Clinical and Translational NeurologyOpen Access

White Matter Hyperintensities Modify CYP2C19 Effect on Stroke Progression in Small Vessel Occlusion

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Key result

CYP2C19 loss-of-function alleles linked to higher early neurological deterioration risk in SVO stroke with severe WMH.

aOR 1.22
95% CI 0.59-2.54
P=0.591
n=247

Figures

Why the study?

The association between CYP2C19 loss-of-function alleles and early neurological deterioration in acute small vessel occlusion patients receiving dual antiplatelet therapy remains inconsistent, and whether white matter hyperintensities burden modulates this association was unknown.

Does white matter hyperintensity (WMH) burden modify the association between CYP2C19 loss-of-function (LOF) alleles and early neurological deterioration (END) in acute small vessel occlusion (SVO) stroke patients receiving dual antiplatelet therapy?

Study Design

Type

Cohort (n=247)

Blinding

Blinded outcome adjudication and neuroimaging evaluation

Multicenter

No

Structured PICO

Does white matter hyperintensity (WMH) burden modify the association between CYP2C19 loss-of-function (LOF) alleles and early neurological deterioration (END) in acute small vessel occlusion (SVO) stroke patients receiving dual antiplatelet therapy?

P

Population

247 Chinese adults (median age 67.0 years, 28.7% female) with acute MRI-confirmed small vessel occlusion ischemic stroke admitted within 48 hours of onset and treated with aspirin plus clopidogrel, followed for 90 days.

E

Exposure

CYP2C19 loss-of-function (LOF) carrier status (carrying at least one *2 or *3 allele) stratified by white matter hyperintensities (WMH) burden (mild: Fazekas 0-2 vs. severe: Fazekas 3-6) in patients treated with dual antiplatelet therapy (aspirin plus clopidogrel) and standardized anti-hypertensive and statin therapies

C

Comparator

CYP2C19 non-carriers (without LOF alleles, including *1/*1, *1/*17, or *17/*17) receiving dual antiplatelet therapy (aspirin plus clopidogrel) and standardized anti-hypertensive and statin therapies

O

Outcome

Early neurological deterioration (END), defined as an increase of ≥ 2 points in total NIHSS score or ≥ 1 point in motor items within 72 hours of admission, independently adjudicated by two senior neurologists blinded to clinical and genetic datahard clinical

Main Result

Odds Ratio: 1.22 (95% CI 0.59–2.54)

Absolute Event Rate: 24% vs 18.6%

p-value: p=0.591

In acute small vessel occlusion stroke patients treated with clopidogrel-based dual antiplatelet therapy, CYP2C19 loss-of-function alleles increase the risk of early neurological deterioration over threefold specifically in those with severe white matter hyperintensities, supporting combined genetic and neuroimaging risk stratification.

Limitations

Retrospective, single-center design within a Chinese population and relatively small sample size limiting generalizability and statistical power.
Non-standardized treatment escalation and low frequency of bleeding events precluded direct comparison across antiplatelet strategies.
Use of the visual Fazekas scale rather than volumetric WMH quantification.
SVO criteria (lesion diameter < 20 mm) likely included patients with branch atheromatous disease (BAD).
Focused solely on major CYP2C19 genotypes (*2, *3, and *17) without screening for other variants or performing platelet function testing.
Clinical fluctuations typical of capsular warning syndrome (CWS) were not systematically recorded, and excluding patients unable to complete MRI may have introduced selection bias.
Retrospective, single-center design within a Chinese population and relatively small sample size limiting generalizability and statistical power
Non-standardized treatment escalation and low frequency of bleeding events preventing direct comparison across strategies
Use of the visual Fazekas scale rather than volumetric quantification
SVO criteria (lesion diameter < 20 mm) likely included patients with branch atheromatous disease (BAD), introducing pathophysiological heterogeneity
Focused solely on major CYP2C19 genotypes (*2, *3, and *17) without screening for other variants or performing platelet function testing
Clinical fluctuations typical of capsular warning syndrome (CWS) were not systematically recorded, and residual or unmeasured confounding (as well as selection bias from excluding patients unable to complete MRI) may remain

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Implication

May support combined CYP2C19-WMH stratification for END in SVO on DAPT; leaves open prospective confirmation before clinical use.

Abstract

BACKGROUND: The association between CYP2C19 loss-of-function (LOF) alleles and early neurological deterioration (END) in acute small vessel occlusion (SVO) patients receiving dual antiplatelet therapy (DAPT) remains inconsistent. We hypothesized that white matter hyperintensities (WMH) burden act as a key moderator and investigated whether this modulates the association between CYP2C19 LOF and END. METHODS: We conducted a retrospective study of SVO patients receiving DAPT. CYP2C19 genotypes were classified as LOF carriers or non-carriers. The primary endpoint was END; secondary and safety endpoints included severe END, 90-day mRS 0-2, symptomatic intracranial hemorrhage (sICH), bleeding, and mortality. Multivariable regression and interaction analyzes assessed associations between CYP2C19, WMH, and clinical outcomes. RESULTS: A total of 247 patients (median age 67.0 years; 28.7% female; 60.7% CYP2C19 LOF carriers), 54 (21.9%) experienced END. Multivariable analysis identified infarct diameter (aOR 1.26, 95% CI 1.13-1.39, p < 0.001) and total cerebral small vessel disease (CSVD) burden (aOR 2.02, 95% CI 1.37-2.98, p < 0.001) as independent predictors. A significant multiplicative interaction was observed between CYP2C19 LOF and severe WMH on END risk (aOR 9.34, 95% CI 2.06-48.10, p = 0.005). Stratified analysis showed CYP2C19 LOF significantly increased END risk specifically in patients with severe WMH (aOR 3.44, 95% CI 1.12-10.55, p = 0.030), but not mild WMH. Predicted probability curves suggested a Fazekas score threshold of approximately 2.70. Secondary and safety outcomes were infrequent. CONCLUSIONS: CYP2C19 LOF alleles increase END risk in SVO patients specifically with severe WMH. These findings highlight the value of integrating genetic and neuroimaging markers for risk stratification and personalized antiplatelet therapy.

Discussion

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Cite This Study

Sun et al. (2026) conducted a cohort in Acute small vessel occlusion (SVO) ischemic stroke (n=247). CYP2C19 loss-of-function (LOF) carrier status (*2 or *3 alleles) modified by white matter hyperintensities (WMH) burden vs. CYP2C19 LOF non-carriers (*1/*1, *1/*17, or *17/*17) was evaluated on Early neurological deterioration (END), defined as an increase of >= 2 points in total NIHSS score or >= 1 point in motor items within 72 h of admission (aOR 1.22, 95% CI 0.59-2.54, p=0.591). CYP2C19 loss-of-function alleles interacted with severe WMH to increase early neurological deterioration risk in SVO stroke.

synapsesocial.com/papers/6af9ebcdd393cbc380a0504f https://doi.org/10.1002/acn3.70579

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White Matter Hyperintensities Modify CYP2C19 Effect on Stroke Progression in Small Vessel Occlusion

Figures

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

White Matter Hyperintensities Modify CYP2C19 Effect on Stroke Progression in Small Vessel Occlusion

Figures

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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