What is the clinical evidence from this study?

Study design: Observational. Population: Atrial fibrillation and ischemic stroke (n=8993). Intervention: AGXT2 rs16899974 minor A allele vs. Major allele. Primary outcome: Any atrial fibrillation in patients without structural heart disease (OR 2.07, 95% CI 1.59-2.68, p=3.9 × 10−8).

March 17, 2016Open Access

Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke

ISIlkka SeppäläTampere University of Applied Sciences MKMarcus E. KleberUniversity of Bern SBSteve BevanBroad Institute

Key Result

The minor A allele of the AGXT2 rs16899974 variant was associated with an increased risk of any atrial fibrillation (OR 2.07) in coronary angiography patients without structural heart disease.

Study Design

Type

Observational (n=8,993)

Multicenter

Yes

Structured PICO

Are functional AGXT2 missense variants associated with atrial fibrillation and ischemic stroke?

Population

1,834 individuals with atrial fibrillation (AF) and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing, along with WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls).

Intervention

Presence of functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L)

Comparator

Absence of the minor alleles for the specified AGXT2 variants

Outcome

Atrial fibrillation (any, paroxysmal, and chronic) and ischemic strokehard clinical

The minor A allele of the AGXT2 variant rs16899974 may be associated with an increased risk of atrial fibrillation and ischemic stroke, suggesting a role in age-related thromboembolic complications.

Main Result

Effect estimate: OR 2.07 (95% CI 1.59-2.68)

p-value: p=3.9 × 10−8

Limitations

Some degree of misclassification of AF cases is expected due to reliance on hospital discharge diagnostic codes.
Associations with AF and age at ischemic stroke onset cannot be directly generalized to the general population, other patient groups, or individuals of other ancestral backgrounds.
The rs16899974 variant may be in linkage disequilibrium with the causal variant(s) underlying the associations.
Experimental data for the functional role of rs16899974 is currently lacking.

Abstract

Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.

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