The transforming growth factor-β receptor genes and the risk of intracranial aneurysms

Abstract

Background Mutations in the receptor genes of the transforming growth factor β pathway, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysms, while genetic variants in TGFBR1 and TGFBR2 are associated with abdominal aortic aneurysms. The transforming growth factor-β pathway may be involved in aneurysm development in general. Aims To analyze whether genetics variants in TGFBR1 and TGFBR2 are also involved in the pathogenesis of intracranial aneurysms. Methods Using tag single nucleotide polymorphisms, we analyzed all common genetic variants in TGFBR1 (five single nucleotide polymorphisms) and TGFBR2 (26 single nucleotide polymorphisms) in a Dutch intracranial aneurysm case-control population approach using a two-stage genotyping approach. Results In stage 1, on analyzing 481 patients and 648 controls, two of the five single nucleotide polymorphisms in TGFBR1 were associated with intracranial aneurysm with P<0·10. In an independent cohort of 310 intracranial aneurysm patients and 376 controls, a predominance of the allele of the two single nucleotide polymorphisms found more frequently in patients in stage 1 was also observed in patients of stage 2 but the associations were not statistically significant. On combined analyses of both stages, there was a statistically significant association of both single nucleotide polymorphisms with intracranial aneurysm (single nucleotide polymorphism rs1626340, odds ratio 1·24, 95% confidence intervals 1·05-1·46, P=0·01; single nucleotide polymorphism rs10819634, odds ratio 1·23, 95% confidence intervals 1·03-1·46, P=0·02) but these associations did not hold after multiple testing correction (i.e., P<0·0016, 0·05/31). Also, no differences in the single nucleotide polymorphism frequency were observed for TGFBR2 between patients and controls. Conclusions We found no evidence for TGFBR1 and TGFBR2 as susceptibility genes for intracranial aneurysm in the Dutch population. © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.