Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients

Jääskeläinen, Olli; Solje, Eino; Hall, Anette; Katisko, Kasper; Korhonen, Ville; Tiainen, Mika; Kangas, Antti J.; Helisalmi, Seppo; Pikkarainen, Maria; Koivisto, Anne M.; Hartikainen, Päivi; Hiltunen, Mikko; Ala‐Korpela, Mika; Soininen, Pasi; Haapasalo, Annakaisa; Remes, Anne M.; Herukka, Sanna‐Kaisa

doi:10.3233/jad-190132

Cited by 13 publications

(13 citation statements)

References 60 publications

(79 reference statements)

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“…No additional PUFA were reported in this platform. The results for total PUFA, omega-3, omega-6, and LA and DHA are very robust and have been validated in many publications [110][111][112][113][114][115]. Although we focused our genetic analyses on PUFA, for descriptive reasons, SFA, MUFA, and total fatty acids were also reported.…”

Section: Serum Fatty Acid Determinationssupporting

confidence: 59%

“…Thus, the SNP with the most significant association was rs174537 near FADS1, in determining plasma arachidonic acid (AA) concentrations (p = 5.95 × 10 −46 ). In our study, we did not analyze the association with AA, because the NMR platform used for measuring serum fatty acids [110][111][112][113][114][115][116] did not provide the separate concentration of AA. Therefore, we cannot compare the results and this is a limitation of our study in comparison with other studies providing a more comprehensive profile of fatty acids determined in other platforms (80,81,83,84,86).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

et al. 2020

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Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10−14; FADS1-rs174550, p = 5.35 × 10−14; FADS2-rs1535, p = 5.85 × 10−14; FADS1-rs174546, p = 6.72 × 10−14; FADS2-rs174546, p = 9.75 × 10−14; FADS2-rs174576, p = 1.17 × 10−13; FADS2-rs174577, p = 1.12 × 10−12, among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10−12; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10−12; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10−11). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10−8. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10−7). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA.

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Section: Serum Fatty Acid Determinationssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

et al. 2020

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“…The pathogenesis of C9orf72 is still debated, with proposed mechanisms including repeated RNA-mediated toxicity, dipeptide protein toxicity or haplode ciency [52]. Recently, decreased total serum HDL-C concentration level was observed in C9orf72 repeat expansion carriers, suggesting that the pathogenic mechanism of C9orf72 repeated expansion mutation may be related to abnormal lipid metabolism [53]. Our ndings further con rmed that C9orf72 is an important gene coupling ALS and lipid metabolism from a genetic perspective.…”

Section: Discussionsupporting

confidence: 72%

Shared genetic links between amyotrophic lateral sclerosis and obesity-related traits: a genome-wide association study

Wei

et al. 2021

Neurobiology of Aging

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Background: Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture. Objective: To examine whether there exist genetic enrichment between ALS and eleven obesity-related traits, including body mass index (BMI), waist hip ratio, body fat percentage (BFP), birth weight, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), type 2 diabetes (T2D), fasting glucose, fasting insulin, and identify shared loci among them. Methods: Using the conditional false discovery rate (FDR) statistical framework, we analyzed genome wide association summary statistics for ALS (n=80610) and obesity-related traits, and further conducted functional enrichment analysis. Results: Robust genetic enrichment was observed for ALS conditional on BMI, BFP, HDL-C, LDL-C and T2D, but minimal enrichment on the other traits. 9 shared genetic loci with conjunctional FDR < 0.05 was identi ed, among which 6 were replicated in a second ALS cohort, including rs3849942 (C9orf72), rs170663 (G2E3), rs8018993 (SCFD1), rs978220 (ATXN3), rs62333164 (CLCN3) and rs12603276 (GGNBP2). We further identi ed GGNBP2 as a novel potential ALS risk gene, by integrating cis-expression quantitative trait loci analysis in human brain tissue and summary-data-based Mendelian randomization analysis. Functional analysis indicated the shared risk genes were involved in pathways membrane tra cking and vesicle-mediated transport. Conclusions: Our ndings demonstrate selective genetic overlap between ALS and obesity-related traits, and identi ed new shared risk loci, including novel potential ALS risk gene GGNBP2. These results provide better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.

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“…It is likely that such studies will take place within the context of large cohort studies [see Box 6] avoiding the problems of small sample sizes that are inherent to so many of the published papers so far. Such studies will also pave the way for larger -omics studies which have so far been relatively small and focused on proteomics despite initial evidence for abnormalities in metabolomics [134][135][136] and lipidomics [137][138][139] in FTD as well.…”

Section: The Future -Clinical Trials and Treatment Responsementioning

confidence: 99%

Fluid biomarkers in frontotemporal dementia: past, present and future

Swift

Sogorb‐Esteve

Heller

et al. 2020

J Neurol Neurosurg Psychiatry

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The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer’s disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.

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Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients

Abstract: Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer's disease. Here, we aimed to analyze the lipoprotein profile

Cited by 13 publications

References 60 publications

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

Shared genetic links between amyotrophic lateral sclerosis and obesity-related traits: a genome-wide association study

Fluid biomarkers in frontotemporal dementia: past, present and future

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