Genetic Modifiers of Cerebrovascular Large Vessel Stenosis in Sickle Cell Anemia.

Cerebrovascular disease is a common complication in sickle cell anemia (SCA) with overt stroke occuring in 10% of patients and silent stroke in 24% of patients by age 20 years. Etiologies of overt stroke in SCA are heterogenous and include stenosis of large arteries, hemorrhage, hypertensive and hypoxic encephalopathy. Candidate genes identified as possible modifiers of overt stroke in SCA include adenylate cyclase 9 (ADCY9, rs731471 intron C/T), endothelin-converting enzyme (ECE-1, rs212527, intron A/G), Klotho (KL, rs480780, intron C/A), plasminogen activator inhibitor-1 (PAI-1, rs1799768, − 675 4/5,), transforming growth factor beta receptor 3 (TGFBR3, rs284157, intron G/A), tumor necrosis factor alpha (TNF, rs1800629,-308 G/A), and interlukin 4 receptor (IL4R, rs1805015, 503S/P). We examined the association of these candidate genes in a cohort of patients with SCA and stenosis of large cerebral vessels who are followed at a single institution. Patients with stenosis (n = 42, male = 22) were identified as having overt stroke (n = 29) or positive transcranial Doppler (TCD) (n = 13). The mean age at time of stroke or (+) TCD was 7.8 years. All had large vessel stenosis on magnetic resonance angiogram imaging (MRA). A control group of patients with SCA and normal TCD were identified (n = 71, males = 46, mean age = 14.8 years).This control group has passed through the peak years of stroke risk, ages 2–10 years. Single nucleotide polymorphisms (SNPs) were genotypic using novel Taqman assays. Genotypic associations were determined using logistic regression analysis with odds ratios (OR), 95% confidence intervals, and p-values reported. Among the candidate genes only ADYC9 (OR = 2.75, CI 1.2–6.3, p = 0.017) and TGFBR3 (OR = 2.33, CI 1.0–5.3, p = 0.043) had significant association with stenosis of large vessels in SCA. ADYC9 is a membrane-associated enzyme that catalyzes cAMP formation, which is critical for neuronal signaling and survival. TGFBR3 has a role in cardiac endothelial cell transformation to mesenchyme. Genotypic studies of a complex trait such as stroke in SCA will eventually lead to early diagnosis and new or early interventions. However, such genetic studies require clear definitions of phenotypic subtypes based on neuroimaging studies, including MRA.