The Health Outcome
Stroke is a condition with significant morbidity and mortality. According to the National Institute of Neurological Disorders and Stroke, National Institutes of Health, sickle cell disease (SCD) is a major contributor to the occurrence of stroke in children.
Sickle cell disease is an inherited blood disorder in which red blood cells contain an abnormal subtype of hemoglobin (Hb S allelic variant of the B-globin gene). The disease receives its name from the physical characteristics of the red blood cells that can become sickle (crescent) shaped. These cells may have difficulty passing through small blood vessels, adhere to blood vessel walls, clog and damage blood vessel walls, and also be more readily destroyed. Sickle cell disease as a result is often associated with anemia, and other life-threatening conditions.
Sickle cell disease is an incurable condition and is associated with significant morbidity and mortality (2,3). Published data from the National Center for Health Statistics for states in the United States during 1979-1995 indicated that the age adjusted mortality rates for sickle-cell disease ranged from 0.2 per 1 million persons upwards to 14.6 deaths per 1 million persons. The results of a recent large-scale study of persons with sickle cell anemia conducted in the United States indicated that children were particular at risk for severe complications; stroke was a complication in 11% and silent cerebral infarction in 17-22% of the children in the study population (4).
The etiology of stroke in persons with sickle cell anemia is not well-understood. The authors previously observed an association by HLA subtype with stroke in persons with SCD. The purpose of this study was to study other potential candidate gene polymorphisms in association with stroke in a large, national, multi-center cohort study of sickle cell disease.
In this particular study, the occurrence of stroke was based on the interpretation of magnetic resonance imaging (MRI) results taken from children at ten or more years of age. The determination of stroke via MRI was made by two neurologists who were blinded to patient clinical history and genetic results. (A third neurologist conferred with the two neurologists when there was disagreement on the results.) Children with MRI evidence of stroke were subclassified as having either large vessel ( LV ) or small vessel (SV) disease.
The Finding
The Cooperative Study of Sickle Cell Disease (CSSCD) cohort consists of 3,800 patients from 23 institutions in the United States who in Phase 1 were followed from 1978-1988 and in Phase 2 are followed from 1999 forward (5,6). Four hundred infants were enrolled in this study and followed from 1978 forward, for 13 or more years. These infants received brain MRI scans at 6 years of age and subsequently every 2 years afterwards.
Of the 400 children, 230 children in this population had adequate DNA to be included in a nested case-control study where children with stroke were compared to those whose MRI examination at ten years of age or later did not show evidence of stroke. Children with MRI evidence of stroke were subclassified as having either large vessel ( LV ) or small vessel (SV) disease.
In this study, 106 polymorphisms from 65 candidate genes associated with atherosclerosis, thrombosis, or inflammation were evaluated for associations with stroke. In addition, the authors also included in their analysis HLA-A variants that had been previously found to be associated with stroke. Three of the seven HLA-A variants identified in previous studies were included in the multivariate model, along with those other variables from the current study that were observed to have a p-value <0.10 in a univariate analysis with stroke. The authors reported that the following polymorphisms were independently associated with stroke susceptibility: a) in the LV stroke subgroup:IL4R 503P, TNF(-308)A, ADRB2 27E, HLA-A, TNF(-308)GG homozygosity + IL4R 503P variant carrier status b) in the SV stroke subgroup:VCAM1(-1594), LDLR NcoI.
Public Health Implications
The authors state that the results of the study provide candidate genes for further study in other large patient populations with sickle-cell anemia and that analogous studies in adult populations should also be conducted. As this is a hypothesis generating study, further research is required both to validate the findings in other populations in and outside of the United States and with varying racial and ethnic characteristics, and to explore the potential biologic mechanisms through which the polymorphisms of interest may induce stroke.
References
- Recognition and Treatment of Stroke in Children. The Child Neurology Society Ad Hoc Committee on Stroke in Children: Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke December 12-13, 1996
- What is Sickle Cell Disease. Sickle Cell Disease Association of America.
- Ashley-Koch A. Yang Q. Olney R.S. Sickle Hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. AmJ Epi 2000. 15:839-845.
- Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, EMbury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM. Cerebroavascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288-294.
- Covitz, Wesley MD; Espeland, Mark PhD; Gallagher, Dianne MS; Hellenbrand, William MD; Leff, Sanford MD; Talner, Norman MD. The heart in sickle cell anemia: The Cooperative Study of Sickle Cell Disease (CSSCD). Chest 1995;108:1214-1219.
- Miller ST, Macklin EA, Pegelow CH, Kinney, TR, Sleeper LA, Bello, JA, et al. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr 2001;139:385-390.
