rs334
badMag 9.5This is a protein-altering variant in the HBB gene.
Key Literature Trait Associations
Sickle Cell Disease / Malaria Resistance
The HbS mutation (Glu6Val) in beta-globin. Homozygous A/A causes sickle cell disease with chronic anemia, pain crises, and organ damage. Heterozygous carriers (sickle cell trait) have ~90% protection against severe P. falciparum malaria, explaining the high allele frequency in malaria-endemic regions. The classic example of balanced selection in humans.
Chronic kidney disease
Sickle cell trait carriers face substantially elevated risk for renal complications, even in the absence of full sickle cell disease. A study of 45,901 U.S. Army soldiers found SCT associated with OR 2.00 (95% CI 1.39–2.88) for chronic kidney disease and OR 1.74 (95% CI 1.17–2.59) for acute kidney injury. UK Biobank data in 8,019 Black participants showed end-stage renal disease risk dramatically elevated in SCT carriers without diabetes (OR 6.45; 95% CI 1.93–19.61). Mechanisms include sickling in the hypoxic renal medulla causing tubular dysfunction, isosthenuria, hematuria, and progressive nephropathy. Renal medullary carcinoma, a rare but nearly uniformly fatal cancer, is strongly linked to SCT (88% of cases).
Venous thromboembolism
Sickle cell trait carriers (HbAS, rs334-A heterozygotes) have a modestly but significantly elevated risk of venous thromboembolism, particularly pulmonary embolism. A 2024 meta-analysis of over 4 million 23andMe participants found an overall VTE OR of 1.45 (95% CI 1.32–1.60), driven almost entirely by pulmonary embolism (OR 1.95; 95% CI 1.72–2.20) with no significant elevation in isolated DVT. A prospective 22-year cohort study confirmed a 2-fold increase in pulmonary embolism risk (HR 2.05; 95% CI 1.12–3.76). This PE-predominant thrombotic pattern is distinct from Factor V Leiden's DVT-predominant pattern and appears ancestry-independent.
Ischemic stroke
The relationship between rs334-A (sickle cell trait) and ischemic stroke is complex and genotype-dependent. In the homozygous state (HbSS), stroke risk is dramatically elevated due to large-vessel vasculopathy and sickling. However, for heterozygous HbAS carriers, a 2018 meta-analysis of 19,464 African Americans found no significant independent association with ischemic stroke (HR 0.80; 95% CI 0.47–1.35; P=.82), suggesting SCT itself is not a major ischemic stroke driver. UK Biobank data did show association with non-ischemic stroke types in SCT carriers. Clinicians are advised against automatically attributing stroke to SCT without thorough evaluation of conventional stroke risk factors.
Coronary heart disease
Contrary to earlier hypotheses, sickle cell trait (HbAS, rs334-A heterozygous) does not appear to significantly increase coronary heart disease or myocardial infarction risk. A large prospective study of 23,197 African Americans followed from 1987–2016 (including 1,781 SCT carriers) found no significant association of SCT with MI (HR 1.03) or composite CHD outcomes (HR 1.16) after adjustment for conventional cardiovascular risk factors. This finding is clinically important as SCT had previously been suspected as a CHD risk factor, and the data reassure that the modest thrombotic and vascular effects of SCT do not translate to increased coronary event risk.
▶GWAS Catalog Trait Associations (31)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (31)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
HEMOGLOBIN S; Hb SS disease; Malaria, resistance to; not provided; 6 conditions; Inborn genetic diseases; beta Thalassemia; Fetal hemoglobin quantitative trait locus 1; 9 conditions; See cases; Beta-thalassemia HBB/LCRB; HBB-related disorder; Sickle cell-hemoglobin C disease; Malaria, susceptibility to; 8 conditions; Hereditary persistence of fetal hemoglobin; alpha Thalassemia;Heinz body anemia;Beta-thalassemia HBB/LCRB;Hb SS disease;Dominant beta-thalassemia
View on ClinVar →▶Research that mentions this SNP (3)
▶Limited use of interleukin 28B in the setting of response-guided treatment with detailed on-treatment virological monitoringReviewAlessandra Mangia et al.(2011)· Hepatology
This is a special issue of the Italian medical journal BeAdfiles (September 2012) dedicated to genetic conditioning in HIV and hepatitis virus infections. It reviews the major genetic polymorphisms that influence disease progression, treatment response, and drug toxicity in HIV and chronic hepatitis B and C infections, with particular emphasis on IL28B polymorphisms (rs809917 and others) predicting HCV treatment response to interferon-alpha and ribavirin therapy, and ITPA gene variants protecting against ribavirin-induced anemia. The issue also covers pharmacogenetic markers (CYP2B6, ABCB1, HLA-B*5701) and their clinical applications in antiretroviral therapy.
▶A genetic association study in the Gambia using tagging polymorphisms in the major histocompatibility complex class III region implicates a HLA-B associated transcript 2 polymorphism in severe malaria susceptibilityAssociationN=2,162Mahamadou Diakite et al.(2009)· Human Genetics
A case-control association study of 2162 Gambian individuals identified a BAT2 polymorphism (rs1046089) significantly associated with severe malaria (G vs A OR=0.73, P<10⁻⁶ for allelic test; recessive model GG vs GA/AA OR=0.48, P<10⁻⁶). Haplotype analysis confirmed BAT2-associated variants conferred ~40% reduced risk. Secondary findings included AIF1 (rs2259571, OR=0.57, P=0.004) and TNF-238 (rs361525, OR=1.33, P=0.04) associations, though only BAT2 remained significant after Bonferroni correction.
▶Rapid Identification of Hemoglobin Variants by Electrospray Ionization Mass SpectrometryReviewWild BJ et al.(2001)· Blood Cells, Molecules, and Diseases
This review examines how haemoglobin variants affect HbA1c measurement for diabetes diagnosis and monitoring. The paper discusses the clinical significance of haemoglobin variants (HbS, HbC, HbE, HbD, HbF), their prevalence (5.2% in global population), and how different laboratory methods (HPLC, capillary electrophoresis, boronate affinity chromatography) are differentially affected by these variants. In a laboratory cohort of 3,920 HbA1c measurements, 0.71% (n=28) had abnormalities suggesting haemoglobin variants, with 9 confirmed as sickle cell trait.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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