期刊
BLOOD ADVANCES
卷 2, 期 3, 页码 235-239出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2017009811
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资金
- Medical Research Council, United Kingdom [G0001249, ID62593]
- Shire Pharmaceuticals
- University College London Hospitals Biomedical Research Centre
- Farr Institute of Health Informatics Research at UCL Partners
- Medical Research Council
- Arthritis Research UK
- British Heart Foundation
- Cancer Research UK
- Chief Scientist Office, Economic and Social Research Council
- Engineering and Physical Sciences Research Council
- National Institute for Health Research
- National Institute for Social Care and Health Research
- Wellcome Trust [MR/K006584/1]
Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and is associated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci would specifically address the benefits of HbF increases in patients. Here, we have applied statistical methods using the most representative variants: rs1427407 and rs6545816 in BCL11A, rs66650371 (3-bp deletion) and rs9376090 in HMIP-2A, rs9494142 and rs9494145 in HMIP-2B, and rs7482144 (Xmn1-HBG2 in the beta-globin locus) to create g(HbF), a genetic quantitative variable for HbF in SCD. Only patients aged >5 years with complete genotype and HbF data were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbS beta(0) thalassemia formed the discovery cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (rs6545816, rs1427407, rs66650371, and rs7482144) each independently contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability (r(2)) in the HbSS or HbS beta(0) patients. The model was replicated with consistent r(2) in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. g(HbF), our 4-variant model, provides a robust approach to account for the genetic component of HbF in SCD and is of potential utility in sickle genetic and clinical studies.
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