Vitamin D Receptor and Megalin Gene Polymorphisms Are Associated with Longitudinal Cognitive Change among African-American Urban Adults

Abstract

Background: The link between longitudinal cognitive change and polymorphisms in the vitamin D receptor (VDR) and MEGALIN [or LDL receptor-related protein 2 (LRP2)] genes remains unclear, particularly among African-American (AA) adults.Objectives: We aimed to evaluate associations of single nucleotide polymorphisms (SNPs) for VDR [rs11568820 (Cdx-2:T/C), rs1544410 (BsmI:G/A), rs7975232 (ApaI:A/C), rs731236 (TaqI:G/A)] and LRP2 [rs3755166:G/A,rs2075252:C/T, rs2228171:C/T] genes with longitudinal cognitive performance change in various domains of cognition.Methods: Data from 1024 AA urban adult participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (Baltimore, Maryland) with complete genetic data were used, of whom 660-797 had complete data on 9 cognitive test scores at baseline and/or the first follow-up examination and complete covariate data (∼52% female; mean age: ∼52 y; mean years of education: 12.6 y). Time between examination visits 1 (2004-2009) and 2 (2009-2013) ranged from <1 y to ∼8 y, with a mean ± SD of 4.64 ± 0.93 y. Latent class and haplotype analyses were conducted by creating gene polymorphism groups that were related to longitudinal annual rate of cognitive change predicted from mixed-effects regression models.Results: Among key findings, the rs3755166:G/A MEGALIN SNP was associated with faster decline on the Mini-Mental State Examination overall (β = -0.002, P = 0.018) and among women. VDR₂ (BsmI/ApaI/TaqI: G-/A-/A-) SNP latent class [SNPLC; compared with VDR₁ (ApaI: "AA")] was linked to faster decline on the Verbal Fluency Test, Categorical, in women, among whom the MEGALIN₂ (rs2228171: "TT") SNPLC (compared with MEGALIN₁:rs2228171: "CC") was also associated with a faster decline on the Trailmaking Test, Part B (Trails B), but with a slower decline on the Digit Span Backward (DS-B). Moreover, among men, the VDR₁ SNP haplotype (SNPHAP; GCA:baT) was associated with a slower decline on the Trails B, whereas the MEGALIN₁ SNPHAP (GCC) was associated with a faster decline on the DS-B, reflected as a faster decline on cognitive domain 2 ("visual/working memory").Conclusion:VDR and MEGALIN gene variations can alter age-related cognitive trajectories differentially between men and women among AA urban adults, specifically in global mental status and domains of verbal fluency, visual/working memory, and executive function.

Keywords: MEGALIN; VDR; aging; cognitive change; single nucleotide polymorphism.

FIGURE 1

(A) Schematic representation of the VDR gene. The SNP and gene coordinates are based on NCBI build 36 (hg18, March 2006) with the use of RefSeq gene prediction. The VDR gene on chromosome 12 was composed of ≤11 exons spanning ∼63 kb. (B) Genotype frequencies of selected VDR SNPs of the original sample with complete genetic data (n = 1024). hg, human genome; NCBI, National Center for Biotechnology Information; RefSeq, Reference Sequence; SNP, single nucleotide polymorphism; VDR, vitamin D receptor gene.

FIGURE 2

(A) Schematic representation of the MEGALIN (LRP2) gene. The SNP and gene coordinates are based on NCBI build 36 (hg18, March 2006) with the use of RefSeq gene prediction. The MEGALIN gene on chromosome 2 has 79 exons and is ∼235 kb in size. (B) Genotype frequencies of selected MEGALIN SNPs of the original sample with complete genetic data (n = 1024). hg, human genome; LRP2, LDL receptor–related protein 2; NCBI, National Center for Biotechnology Information; RefSeq, Reference Sequence; SNP, single nucleotide polymorphism.