Vitamin D receptor and megalin gene polymorphisms and their associations with longitudinal cognitive change in US adults

Abstract

Background: Vitamin D receptor (VDR) and the megalin gene polymorphism's link with longitudinal cognitive change remains unclear.

Objective: The 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 Megalin (rs3755166:G/A; rs2075252:C/T; rs4668123:C/T) genes with longitudinal cognitive performance changes were examined.

Design: Data from 702 non-Hispanic white participants in the Baltimore Longitudinal Study of Aging were used. Longitudinal annual rates of cognitive change (LARCCs) between age 50 y and the individual mean follow-up age were predicted with linear mixed models by using all cognitive score time points (prediction I) or time points before dementia onset (prediction II). Latent class, haplotype, and ordinary least squares (OLS) regression analyses were conducted.

Results: Among key findings, in OLS models with SNP latent classes as predictors for LARCCs, Megalin(2) [rs3755166(-)/rs2075252(TT)/rs4668123(T-)] compared with Megalin(1) [rs3755166(-)/rs2075252(CC)/rs4668123(-)] was associated with greater decline among men for verbal memory (prediction II). Significant sex differences were also found for SNP haplotype (SNPHAP). In women, VDR(1) [BsmI(G-)/ApaI(C-)/TaqI(A-); baT] was linked to a greater decline in category fluency (prediction I: β = -0.031, P = 0.012). The Megalin(1) SNPHAP (GCC) was related to greater decline among women for verbal memory, immediate recall [California Verbal Learning Test (CVLT), List A; prediction II: β = -0.043, P = 0.006) but to slower decline among men for delayed recall (CVLT-DR: β > 0, P < 0.0125; both predictions). In women, the Megalin(2) SNPHAP (ACC) was associated with slower decline in category fluency (prediction II: β = +0.026, P = 0.005). Another finding was that Megalin SNP rs3755166:G/A was associated with greater decline in global cognition in both sexes combined and in verbal memory in men.

Conclusion: Sex-specific VDR and Megalin gene variations can modify age-related cognitive decline among US adults.

FIGURE 1.

A: Gene structure of the VDR gene. The SNP and gene coordinates are based on NCBI build 36 (hg18, March 2006) using RefSeq gene prediction. The VDR gene on chromosome 12 is composed of ≤11 exons spanning ∼63 kb. Note: More than 99% of eligible participants had well-defined SNPLCs that could be summarized by BsmI and TaqI SNP combinations. SNPHAPs were defined on the basis of 3 VDR SNP combinations (BsmI, ApaI, and TaqI) and were expressed as dosage (0 = none, 1 = one copy, 2 = 2 copies) in the main analysis. B: Gene structure of the megalin gene. The SNP and gene coordinates are based on NCBI build 36 (hg18, March 2006) using RefSeq gene prediction. The megalin (LRP2) gene on chromosome 2 has 79 exons and is ∼235 kb in size. Note: More than 96% of eligible participants had well-defined SNPLCs that could be summarized by the genotype of rs4668123. SNPHAPs were defined on the basis of all 3 megalin SNP combinations (rs3755166, rs4668123, and rs2075252) and were expressed as dosage (0 = none, 1 = one copy, 2 = 2 copies) in the main analysis. hg, human genome; LRP2, LDL receptor-related protein 2; NCBI, National Center for Biotechnology Information; RefSeq, reference sequence; SNP, single nucleotide polymorphism; SNPLC, single nucleotide polymorphism latent class; SNPHAP, single nucleotide polymorphism haplotype; VDR, vitamin D receptor gene; vv, variant-variant; wv, wild-type–variant; ww, wild-type–wild-type.