rs11549407 (HBB): Hemoglobin & Hematocrit Variant
Key takeaways
- rs11549407 is a rare variant in HBB, the gene encoding hemoglobin's beta-subunit, linked to lower hemoglobin and hematocrit levels.
- The association was found in roughly 21,700 Hispanic/Latino individuals at genome-wide significance.
- Inheriting two copies of this variant is known to cause anemia.
- Standard genetic panels could not detect this variant until a 100,000+ genome, diversity-inclusive reference panel became available.
Key takeaways
- rs11549407 is a rare variant in HBB, the gene encoding hemoglobin's beta-subunit, linked to lower hemoglobin and hematocrit levels.
- The association was found in roughly 21,700 Hispanic/Latino individuals at genome-wide significance.
- Inheriting two copies of this variant is known to cause anemia.
- Standard genetic panels could not detect this variant until a 100,000+ genome, diversity-inclusive reference panel became available.
What the research says
rs11549407 is a rare variant in HBB - which encodes the beta-subunit of hemoglobin, the oxygen-carrying protein in red blood cells - and was identified at genome-wide significance for lower hemoglobin (HGB; p = 1.5×10^-¹²) and lower hematocrit (HCT; p = 8.8×10^-¹^0) in approximately 21,700 Hispanic/Latino participants, a discovery made possible by the NHLBI TOPMed whole-genome sequencing reference panel PMID 31856170. Neither association would have reached genome-wide significance using the 1000 Genomes Project Phase 3 or Haplotype Reference Consortium panels, which lacked sufficient Hispanic/Latino ancestry coverage for accurate imputation of this rare variant PMID 31856170. Independent whole-genome sequencing of up to 62,653 ethnically diverse TOPMed participants confirmed that HBB locus rare variants - including those representing the carrier state for coding and splice-site loss-of-function changes causing inherited red blood cell disorders - are associated with quantitative red blood cell traits PMID 34597586.
Reported associations
- Hemoglobin (HGB) levels: Lower HGB in Hispanic/Latino individuals (p = 1.5×10^-¹², n ≈ 21,700; per-allele effect size not reported in available study text) PMID 31856170
- Hematocrit (HCT): Lower HCT in Hispanic/Latino individuals (p = 8.8×10^-¹^0, n ≈ 21,700; per-allele effect size not reported in available study text) PMID 31856170
- Anemia (homozygous state): The discovery study reports that of the two HBB rare variants identified, the variant associated with lower hemoglobin is described as known to cause anemia when both copies are inherited; rs11549407 is the hemoglobin-lowering variant among the pair PMID 31856170
- Inherited red blood cell disorders (carrier state): HBB locus rare variants identified in a whole-genome sequencing cohort (n ≤ 62,653 ethnically diverse individuals) represent the carrier state for known coding, promoter, or splice-site loss-of-function variants that cause inherited red blood cell disorders PMID 34597586
Evidence quality
The primary evidence comes from a single study of approximately 21,700 Hispanic/Latino individuals where the variant reached genome-wide significance for both HGB (p = 1.5×10^-¹²) and HCT (p = 8.8×10^-¹^0) PMID 31856170. Per-allele effect sizes (beta coefficients) were not reported in the available study text, limiting direct quantitative interpretation. Detection relied entirely on the TOPMed reference panel; with standard panels the imputation quality was insufficient for significance, meaning the finding is contingent on the availability of diversity-inclusive sequencing resources PMID 31856170. Notably, the discovery paper identified two HBB rare variants and states that one of them was replicated in an independent sample, but does not specify which - leaving the independent variant-level replication status of rs11549407 ambiguous PMID 31856170. At the broader HBB locus level, associations with red blood cell phenotypes were replicated in independent GWAS data imputed to the TOPMed panel within a whole-genome sequencing study of up to 62,653 ethnically diverse participants, providing supporting locus-level evidence PMID 34597586. All direct evidence for this specific variant is limited to Hispanic/Latino individuals; generalizability to other populations is not established by the studies available here.
Lifestyle considerations
No lifestyle considerations on file for this variant.
Lifestyle context
Concrete actions anchored to the cited research. We do not prescribe, we describe.
Bloodwork
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complete blood count with hemoglobin and hematocrit Moderate
The variant causes loss-of-function in hemoglobin beta, resulting in reduced hemoglobin production and mild anemia in heterozygous carriers (thalassemia minor).
Annual or biennial testing to monitor hemoglobin and hematocrit levels
Discuss with your doctor
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beta-thalassemia genetic status and health implications High
This stop-gain variant is the major genetic cause of beta-thalassemia in some populations; carriers may be at risk for various health-related complications.
Discuss genetic diagnosis, family implications, and recommended screening with physician
Frequently asked questions
What does the HBB gene do?
HBB encodes the beta-subunit of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Variants in HBB can reduce or alter hemoglobin function, affecting how efficiently oxygen is delivered to tissues.
Is rs11549407 linked to anemia?
Population studies in Hispanic/Latino individuals found rs11549407 significantly associated with lower hemoglobin and hematocrit levels. When two copies are inherited (homozygous state), this variant is known to cause anemia directly.
Which populations carry rs11549407?
Genome-wide significant associations have been detected specifically in Hispanic/Latino populations. Because it is a rare variant, its frequency and effects in other ancestries have not been established in the available research.
Why was rs11549407 not found in earlier genetic studies?
Earlier reference panels lacked sufficient representation of Hispanic/Latino ancestry to accurately impute this rare variant. The NHLBI TOPMed panel, built from over 100,000 deeply sequenced genomes across diverse ancestries, provided the coverage needed for detection.
What is the measured effect of rs11549407 on hemoglobin?
The discovery study found statistically strong signals (p = 1.5×10^-¹² for hemoglobin; p = 8.8×10^-¹^0 for hematocrit) in approximately 21,700 Hispanic/Latino individuals. The per-allele effect size in standard units was not reported in the available study text.