Abstract 29: Effects of a Novel Structural Variant in Hemoglobin on Racial Differences in Hemoglobin A1c

Background: Studies have found higher hemoglobin A1c (HbA1c) at similar levels of glucose for adults who self-identify as Black vs. White, but the mechanism for this difference is poorly understood. Genetic variants that are more common in persons of African descent that affect hemoglobin (Hb) or red cell turnover may explain some of this difference. A recently discovered deletion in a non-coding region of the HBA2 gene is common in persons of African descent and may contribute to differences in Hb and HbA1c. Methods: We evaluated 5178 participants (mean age 56 years, 18% Black, 55% female) who attended Visit 2 (1990-1992) of the Atherosclerosis Risk in Communities Study without diagnosed diabetes and BMI <30 kg/m 2 . We compared the distributions of Hb and HbA1c in Black and White participants by the number of deletions in the HBA2 region (zero, one, or two). We used linear regression to evaluate the extent to which this genetic variant explained glucose-independent Black-White differences in HbA1c and Hb. Results: Deletions in the HBA2 region were common in Black participants (30% one, 4% two) but rare in White participants (1%: one, 0%: two). Mean Hb was lower in Black participants with one (-0.38 g/dL, p<0.001) and two deletions (-0.76 g/dL, p=0.002) and HbA1c was higher (one: +0.11%, p<0.001; two deletions: +0.13%, p=0.11) ( Figure ). Results were similar in White participants with one deletion (N=38), but non-significant. In a regression model adjusted for age, sex, fasting glucose, and BMI, the differences in HbA1c and Hb comparing Blacks vs White adults were +0.2% and -0.6 g/dL, respectively. Additional adjustment for HBA2 deletions explained 16% of the difference in HbA1c and 19% of the difference in Hb. Conclusions: A variation in the non-coding region of the HBA2 gene common in those with African ancestry results in significantly lower Hb and significantly higher HbA1c, partially explaining the small observed racial differences in HbA1c. Other undiscovered variants could more fully explain observed racial differences in HbA1c.