Association of the Haptoglobin Gene Polymorphism With Cognitive Function and Decline in Elderly African American Adults With Type 2 Diabetes: Findings From the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Study

JAMA Netw Open. 2018 Nov 2;1(7):e184458. doi: 10.1001/jamanetworkopen.2018.4458.


Importance: African American individuals have higher dementia risk than individuals of white race/ethnicity. They also have higher rates of type 2 diabetes, which may contribute to this elevated risk. This study examined the association of the following 2 classes of alleles at the haptoglobin (Hp) locus that are associated with poor cognition, cardiovascular disease, and mortality: Hp 1-1 (associated with poor cognition and cerebrovascular disease) and Hp 2-1 and Hp 2-2 (associated with greater risk of myocardial infarction and mortality). An additional polymorphism in the promoter region of the Hp 2 allele, restricted to individuals of African descent, yields a fourth genotype, Hp 2-1m. African American adults have a higher prevalence of Hp 1-1 (approximately 30%) compared with individuals of white race/ethnicity (approximately 14%), but the potential role of the Hp genotype in cognition among elderly African American individuals with type 2 diabetes is unknown.

Objective: To assess the association of the Hp genotypes with cognitive function and decline in elderly African American adults with type 2 diabetes.

Design, setting, and participants: This cohort study used publicly available data and specimens from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) study to investigate the association of the Hp genotypes with cognitive function and decline in 466 elderly African American participants with type 2 diabetes. The hypothesis was that the Hp 1-1 genotype compared with the other genotypes would be associated with more cognitive impairment and faster cognitive decline in elderly African American adults with type 2 diabetes. The initial ACCORD trial was performed from October 28, 1999, to September 15, 2014. This was a multicenter clinical study performed in an academic setting.

Exposures: The Hp genotypes were determined from serum samples by polyacrylamide gel electrophoresis and by enzyme-linked immunosorbent assay.

Main outcomes and measures: The Mini-Mental State Examination (MMSE) was used to measure cognitive function and change after 40 months. The MMSE score ranges from 0 to 30 points; higher scores represent better cognition. Associations were examined with analysis of covariance and linear regression, adjusting for age, sex, education, baseline glycated hemoglobin level, systolic blood pressure, diastolic blood pressure, cholesterol level, creatinine level, and treatment arm (intensive vs standard). The cognitive change model adjusted also for the baseline MMSE score.

Results: Among 466 African American study participants (mean [SD] age, 62.3 [5.7] years), 64.8% were women, and the genotype prevalences were 29.4% (n = 137) for Hp 1-1, 36.1% (n = 168) for Hp 2-1, 10.9% (n = 51) for Hp 2-1m, and 23.6% (n = 110) for Hp 2-2. The groups differed in their baseline MMSE scores (P = .006): Hp 1-1 had the lowest MMSE score (mean [SE], 25.68 [0.23]), and Hp 2-1m had the highest MMSE score (mean [SE], 27.15 [0.36]). Using the least squares method, the 40-month decline was significant for Hp 1-1 (mean [SE], -0.41 [0.19]; P = .04) and for Hp 2-2 (mean [SE], -0.68 [0.21]; P = .001). However, the overall comparison across the 4 groups did not reach statistical significance for the fully adjusted model. The interaction of age with the Hp 1-1 genotype on MMSE score decline estimate per year change was significant (mean [SE], -0.87 [0.37]; P = .005), whereas it was not significant for Hp 2-1 (mean [SE], 0.06 [0.37]; P = .85), Hp 2-1m (mean [SE], -0.06 [0.51]; P = .89), and Hp 2-2 (mean [SE], -0.44 [0.41]; P = .29), indicating that cognitive decline in Hp 1-1 carriers was accentuated in older ages, whereas it was not significant for the other Hp genotypes.

Conclusions and relevance: In this study, the Hp 1-1 genotype, which is 2-fold (approximately 30%) more prevalent among African American individuals than among individuals of white race/ethnicity, was associated with poorer cognitive function and greater cognitive decline than the other Hp genotypes. The Hp gene polymorphism may explain the elevated dementia risk in African American adults. The neuropathological substrates and mechanisms for these associations merit further investigation.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • African Americans / genetics*
  • Age Factors
  • Aged
  • Alleles
  • Cardiovascular Diseases / genetics
  • Cognition Disorders / ethnology
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics*
  • Cognition*
  • Cohort Studies
  • Dementia / ethnology
  • Dementia / genetics
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / ethnology
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Progression
  • Female
  • Genotype*
  • Haptoglobins / genetics*
  • Humans
  • Male
  • Memory
  • Mental Status and Dementia Tests
  • Middle Aged
  • Polymorphism, Genetic*
  • Risk Factors


  • Haptoglobins