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Alzheimer, proteina C reattiva e lipidi

Studi osservazionali hanno da tempo documentato un'associazione tra colesterolo, proteine infiammatorie e rischio di demenza di Alzheimer. Studi sull'intero genoma hanno dato supporto a queste osservazioni con l'individuazione di polimorfismi genetici implicati nel metabolismo delle lipoproteine e nei processi anti-infiammatori in pazienti con malattia di Alzheimer. Questo nuovo studio, basato sull'analisi dell'intero genoma di oltre 200.000 soggetti, conferma che alcune varianti genetiche sono associate a dislipidemia, ad alti livelli di proteina C reattiva ed al rischio di demenza di Alzheimer. La combinazione di varianti coinvolte nell'infiammazione e nel metabolismo lipidico potrebbe aiutare a identificare i soggetti ad alto rischio di demenza ed a proporre terapie antiinfiammatorie e/o antidislipidemiche come misura preventiva.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.

Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen CH, Karow DS, Brewer JB, Hess CP, Williams J, Sims R, O'Donovan MC, Choi SH, Bis JC, Ikram MA, Gudnason V, DeStefano AL, van der Lee SJ, Psaty BM, van Duijn CM, Launer L, Seshadri S, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Hardy J, Ulstein ID, Aarsland D, Fladby T, White LR, Sando SB, Rongve A, Witoelar A, Djurovic S, Hyman BT, Snaedal J, Steinberg S, Stefansson H, Stefansson K, Schellenberg GD, Andreassen OA, Dale AM; Inflammation Working Group and International Genomics of Alzheimer's Disease Project (IGAP) and DemGene Investigators

Circulation 2015;131:2061-2069

BACKGROUND: Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.
METHODS AND RESULTS: Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.
CONCLUSIONS: We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

Circulation 2015;131:2061-2069