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Effect of genetic variation in LRRTM3 on risk of Alzheimer disease.

ABSTRACT: OBJECTIVE:To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies. METHODS:First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer's Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplotype analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing. RESULTS:One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio, -0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer's Disease data set or the Caribbean Hispanic data set. The corresponding haplotypes were also associated with AD risk (.01 < P < .05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P < .05 to P < .01) compared with the scrambled small-hairpin RNA condition. CONCLUSIONS:These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate ?-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.

SUBMITTER: Reitz C

PROVIDER: S-EPMC3391336 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Effect of genetic variation in LRRTM3 on risk of Alzheimer disease.

Reitz Christiane C Conrad Christopher C Roszkowski Katherine K Rogers Robert S RS Mayeux Richard R

Archives of neurology 20120701 7

<h4>Objective</h4>To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.<h4>Methods</h4>First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer's Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker ...[more]

PMID: 22393166

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Project description:Background and objectivesPrevious studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear.MethodsA 2-sample mendelian randomization study design was applied to examine the association between genetic variation in the targets of 4 antidiabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, whereas summary statistics for AD were retrieved from previous genome-wide association studies comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes mellitus (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables.ResultsIn the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (odds ratio [OR] = 0.38 per 1 mmol/L decrement in blood glucose, 95% CI 0.19-0.72, p = 0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR = 0.35 per 1 mmol/L decrement in blood glucose, 95% CI 0.15-0.82, p = 0.016). An association between genetic variations in the glucagon-like peptide 1 (GLP-1) analogue target and a lower risk of AD was also observed (OR = 0.32 per 1 mmol/L decrement in blood glucose, 95% CI 0.13-0.79, p = 0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive.DiscussionGenetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD.

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Effect of genetic variation in LRRTM3 on risk of Alzheimer disease.

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Effect of genetic variation in LRRTM3 on risk of Alzheimer disease.

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