Evolutionary context for the association of γ-globin, serum uric acid, and hypertension in African Americans

BMC Medical Genetics

Research Article

Guanjie Chen¹  Adebowale Adeyemo¹  Ayo P. Doumatey¹  Charles N. Rotimi¹  Jie Zhou¹  Bashira A. Charles¹  Daniel Shriner¹  Amy R. Bentley¹  Griffin P. Rodgers²  Chutima Kumkhaek² 

[1] Center for Research on Genomics and Global Health, National Human Genome Research Institute, Building 12A/Rm 4047, 12 South Dr., 20892, Bethesda, MD, USA;Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA;

关键词: African American;    Ancestry;    Gamma-globin;    Health disparity;    Hypertension;    Malaria;    Uric acid;   

DOI  :  10.1186/s12881-015-0249-z

 received in 2015-02-12, accepted in 2015-10-28,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundHyperuricemia and associated cardio-metabolic disorders are more prevalent in African Americans than in European Americans. We used genome-wide admixture mapping and association testing to identify loci with ancestry effects on serum uric acid levels.MethodsWe analyzed 1,976 African Americans from Washington, D.C, including 1,322 individuals from 328 pedigrees and 654 unrelated individuals, enrolled in the Howard University Family Study. We performed admixture mapping and genome-wide association testing using ~800 k autosomal single-nucleotide polymorphisms (SNPs). We performed fine mapping by dense genotyping. We assessed functionality by a combination of bioinformatic annotation, reporter gene assays, and gel shift experiments. We also analyzed 12,641 individuals enrolled in the National Health and Nutrition Examination Survey.ResultsWe detected a genome-wide significant locus on chromosome 11p15.4 at which serum uric acid levels increased with increasing African ancestry, independent of kidney function. Fine-mapping identified two independent signals in the β-globin locus. The ancestral allele at SNP rs2855126, located upstream of the hemoglobin, gamma A gene HBG1, was associated with increased serum uric acid levels and higher expression of a reporter gene relative to the derived allele. Hyperuricemia was associated with increased risk of hypertension in 3,767 African Americans (Odds Ratio = 2.48, p = 2.71 × 10− 19).ConclusionsGiven that increased expression of γ-globin leads to increased levels of fetal hemoglobin which confers protection against malaria, we hypothesize that evolution in Africa of protection against malaria may have occurred at the cost of increased serum uric acid levels, contributing to the high rates of hyperuricemia and associated cardio-metabolic disorders observed in African Americans.

【 授权许可】

CC BY   
© Shriner et al. 2015

【 图 表 】

12936_2017_2051_Article_IEq86.gif

Fig. 3