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Causal association between rheumatoid arthritis and a decreased risk of Alzheimer’s disease

A Mendelian randomization study

Kausalzusammenhang zwischen rheumatoider Arthritis und vermindertem Risiko für M. Alzheimer

Eine Mendel-Randomisierungsstudie

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Abstract

Objective

This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with Alzheimer’s disease (AD).

Methods

We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from three-stage trans-ethnic genome-wide association studies (GWAS) meta-analyses of 29,880 RA cases and 73,758 controls as exposures and a meta-analysis of 4 GWAS datasets consisting of 17,008 AD cases and 37,154 controls of European descent as outcomes.

Results

We selected 80 single nucleotide polymorphisms (SNPs) from GWAS data on RA as instrumental variables (IVs), 60 of which were associated with RA on a genome-wide significance level. The IVW method showed evidence to support an inverse causal association between RA and AD (β = −0.039, standard error [SE] = 0.017, P = 0.021). MR-Egger regression revealed that directional pleiotropy was unlikely to be a source of bias in the results (intercept = 0.002; P = 0.649). The MR-Egger analysis showed no causal association between RA and AD (β = −0.050, SE = 0.030, P = 0.096). However, the weighted median approach showed that RA and AD were causally linked (β = −0.078, SE = 0.024, P = 0.001). The funnel plot did not show heterogeneity between IV estimates based on the individual variants.

Conclusions

The MR analysis supports that RA was causally associated with a reduced risk of AD.

Zusammenfassung

Ziel

Die vorliegende Studie zielte darauf ab zu untersuchen, ob rheumatoide Arthritis (RA) in einem kausalen Zusammenhang mit M. Alzheimer stehe.

Methoden

Dazu wurde die Analyse einer 2‑Stichproben-Mendel-Randomisierung (MR) unter Einsatz von Verfahren mit inverser Varianzgewichtung (IVW), gewichtetem Mittel und der MR-Egger-Regression durchgeführt. Die Autoren verwendeten die Metaanalysen der öffentlich zugänglichen zusammenfassenden statistischen Datensätze von dreistufigen transethnischen genomweiten Assoziationsstudien (GWAS) mit 29.880 RA-Fällen und 73.758 Kontrollen als Exposition und eine Metaanalyse von 4 GWAS-Datensätzen mit 17.008 AD(Alzheimer’s disease)-Fällen und 37.154 Kontrollen europäischer Abstammung als Endpunkte.

Ergebnisse

Als instrumentelle Variablen (IV) wurden 80 Einzelnukleotidpolymorphismen (SNPs) aus den GWAS-Daten zur RA ausgewählt, von denen 60 auf einem genomweiten Signifikanzniveau mit RA assoziiert waren. Die IVW-Methode erbrachte Belege für die Stützung eines inversen Kausalzusammenhangs zwischen RA und AD (β = −0,039; Standardfehler, „standard error“, SE: 0,017, p = 0,021). Anhand der MR-Egger-Regression zeigte sich, dass es unwahrscheinlich war, dass die direktionale Pleiotropie eine Quelle für Bias in den Ergebnissen darstellte („intercept“ = 0,002; p = 0,649). Die MR-Egger-Analyse ergab keinen Kausalzusammenhang zwischen RA und AD (β = −0,050; SE = 0,030; p = 0,096). Allerdings zeigte der Ansatz unter Verwendung des gewichteten Mittels, dass RA und AD kausal verknüpft waren (β = −0,078; SE = 0,024; p = 0,001). Der Funnel Plot ergab keine Heterogenität zwischen IV-Schätzwerten auf der Basis der individuellen Varianten.

Schlussfolgerung

Die MR-Analyse lieferte Hinweise darauf, dass die RA kausal mit einem verminderten Risiko für M. Alzheimer verknüpft sei.

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Acknowledgements

This study was supported in part by a grant from the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI15C2958).

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Authors and Affiliations

  1. Department of Rheumatology, Hospital for Rheumatic Diseases, Hanyang University, Seoul, Korea (Republic of)

    S.-C. Bae

  2. Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, 02841, Seoul, Korea (Republic of)

    Y. H. Lee MD, PhD

Authors
  1. S.-C. Bae
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Correspondence to Y. H. Lee MD, PhD.

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S.-C. Bae and Y.H. Lee declare that they have no competing interests.

This article does not contain any studies with human participants or animals performed by any of the authors.

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U. Müller-Ladner, Bad Nauheim

U. Lange, Bad Nauheim

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Bae, SC., Lee, Y.H. Causal association between rheumatoid arthritis and a decreased risk of Alzheimer’s disease. Z Rheumatol 78, 359–364 (2019). https://doi.org/10.1007/s00393-018-0504-8

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  • DOI: https://doi.org/10.1007/s00393-018-0504-8

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