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

ABSTRACT: Vitamin D receptor (VDR) and the megalin gene polymorphism's link with longitudinal cognitive change remains unclear.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.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.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: ? = -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: ? = -0.043, P = 0.006) but to slower decline among men for delayed recall (CVLT-DR: ? > 0, P < 0.0125; both predictions). In women, the Megalin(2) SNPHAP (ACC) was associated with slower decline in category fluency (prediction II: ? = +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.Sex-specific VDR and Megalin gene variations can modify age-related cognitive decline among US adults.

SUBMITTER: Beydoun MA

PROVIDER: S-EPMC3238459 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Beydoun May A MA Ding Eric L EL Beydoun Hind A HA Tanaka Toshiko T Ferrucci Luigi L Zonderman Alan B AB

The American journal of clinical nutrition 20111214 1

<h4>Background</h4>Vitamin D receptor (VDR) and the megalin gene polymorphism's link with longitudinal cognitive change remains unclear.<h4>Objective</h4>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.<h4>Design</h4>Data from 702 non-Hispanic white participants i ...[more]

PMID: 22170372

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Project description: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.

Project description:We examined longitudinal associations of vitamin D receptor (VDR) and megalin (LRP2; LDL receptor-related protein-2) gene polymorphisms with central adiposity. We used data from the Baltimore Longitudinal Study of Aging (BLSA), an ongoing prospective open cohort study. Study participants consisted of non-Hispanic white adults residing in Baltimore city, with one or more visits at age ≥50 years, and complete data (n 609-617). Repeated assessments on waist circumference (WC) and waist:hip ratio (WHR) were available. Multiple linear mixed models were used to estimate mid-follow-up age central adiposity level and annual rate of change with cut-points set at the sex-specific 80th percentile. The four binary outcomes were: 'elevated central adiposity' (ECA-WC and ECA-WHR) and 'significant increase in central adiposity' (SICA-WC and SICA-WHR). SNP for VDR (four SNP: (1) rs11568820 (CdX-2:T/C); (2) rs1544410 (BsmI:G/A); (3) rs7975232 (ApaI:A/C); (4) rs731236 (TaqI:G/A)) and Megalin (three SNP: (1) rs3755166:G/A; (2) rs2075252:C/T; (3) rs4668123:C/T) genes were selected. SNP latent classes (SNPLC) and SNP haplotypes (SNPHAP) were created. Multiple logistic regression analyses indicated that, in men, higher ECA-WHR odds were associated with SNPLC Megalin2:rs3755166[-]/rs2075252[TT]/rs4668123[T-] (v. Megalin1:rs3755166[-]/rs2075252[CC]/rs4668123[-]) (OR 2·87; 95 % CI 1·15, 7·12; P = 0·023) and that SNPLC Megalin3:rs3755166[-]/rs2075252[CT]/rs4668123[-] (v. Megalin1) was linked to lower SICA-WC odds (OR 0·48; 95 % CI 0·26, 0·88; P = 0·019) (P > 0·05 for sex × SNPLC). In women, VDR3 SNPHAP (GAA:bAT) was related to lower odds of ECA-WC (OR 0·37; 95 % CI 0·16, 0·87; P = 0·023) (P < 0·05 for sex × SNPHAP), VDR1 SNPHAP (GCA:baT) was associated with greater odds and VDR3 SNPHAP (GAA:bAT) with lower odds of SICA-WC (P > 0·05 for sex × SNPHAP). Vitamin D-related gene polymorphisms were associated with central adiposity status and change. Future mechanistic studies are needed to confirm those polymorphisms' biological significance to central adiposity.

Project description:Introduction: Recent studies have demonstrated that vitamin D deficiency contributes to the development of metabolic disorders, including obesity and type 2 diabetes mellitus (T2DM). Several vitamin D receptor (VDR) gene polymorphisms had been described to play a role in these conditions since vitamin D receptors were found in many tissues. The aim of this study was to assess the relationship between vitamin D status and VDR gene polymorphisms with metabolic syndrome (MS) parameters in Russian middle-aged women. Materials and Methods: A total of 697 women aged between 30 to 55 years were included in this cross-sectional study. Serum 25-hydroxyvitamin D (25(OH)D) level and four VDR gene polymorphisms rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI), and rs2228570 (FokI) were measured. We applied the International Diabetes Federation (IDF) criteria to identify subjects with MS. Results: 9.3% of subjects had normal vitamin D level, while 90.7% were insufficient or deficient. Abdominal obesity (AO) was seen in 75.5%, impaired glucose tolerance (IGT) or T2DM was observed in 33.3%, reduced high-density lipoprotein cholesterol (HDL-C) level in 32.2% and hypertriglyceridemia in 23.4%. Serum 25(OH)D level in women with or without MS did not differ (48.6 ± 1.8 and 51.1 ± 1.5 nmol/l, p > 0.05). Subjects with vitamin D deficiency showed an increased risk of AO [CI 95% 2.23; 1.15-4.30] and low HDL-C [CI95% 2.60; 1.04-6.49] compared to subjects with normal 25(OH)D level. IGT and T2DM risk was increased only when 25(OH)D concentration was less than 39.0 nmol/l [CI 95% 7.17; 2.99-17.7], but risk of MS did not differ in normal vitamin D status subjects and insufficient/deficient ones (p > 0.05). T allele carriers (A) of rs7975232 had higher total cholesterol and low-density lipoprotein cholesterol levels compared with the GG (aa) genotypes. Similarly, GG (BB) genotype carriers of rs1544410 had higher triglyceride levels than subjects with A (b) allele carriers. However VDR gene polymorphisms did not seem to be associated with an increased risk of MS. Conclusions: Vitamin D deficiency, rs7975232, and rs1544410 VDR gene variants are associated with MS parameters in Russian middle-aged women.

Dataset Information

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

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

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