Causal Association between Rheumatoid Arthritis with the Increased Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

Young Ho Lee; Gwan Gyu Song

doi:10.4078/jrd.2019.26.2.131

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Lee and Song: Causal Association between Rheumatoid Arthritis with the Increased Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

Original Article

J Rheum Dis 2019;26(2):131-136.

Published online: 30 April 2019

DOI: https://doi.org/10.4078/jrd.2019.26.2.131

Causal Association between Rheumatoid Arthritis with the Increased Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

Young Ho Lee, Gwan Gyu Song

Department of Rheumatology, Korea University College of Medicine, Seoul, Korea

Corresponding to: Young Ho Lee http://orcid.org/0000-0003-4213-1909 Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail: lyhcgh@korea.ac.kr

Received 10 December 20184 January 2019 Accepted 23 January 2019

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with type 2 diabetes (T2D).

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 a genomewide association studies (GWAS) meta-analysis of 5,539 autoantibody-positive individuals with RA and 20,169 controls of European descent, and a GWAS dataset of 10,247 individuals with T2D and 53,924 controls, overwhelmingly of European descent as outcomes.

Results

We selected 10 single-nucleotide polymorphisms from GWAS data on RA as instrumental variables to improve the inference. The IVW method supported a causal association between RA and T2D (β=0.044, standard error [SE]=0.022, p=0.047). The MR-Egger analysis showed a causal association between RA and T2D (β=0.093, SE=0.033, p=0.023). In addition, the weighted median approach supported a causal association between RA and T2D (β=0.056, SE=0.025, p=0.028). The association between RA and T2D was consistently observed using IVW, MR Egger, and weighted median methods. Cochran's Q test indicated no evidence of heterogeneity between instrumental variable estimates based on individual variants and MR-Egger regression revealed that directional pleiotropy was unlikely to have biased the results (in-tercept=−0.030; p=0.101).

Conclusion

MR analysis supports that RA may be causally associated with an increased risk of T2D.

Keywords: Rheumatoid arthritis, Type 2 diabetes, Mendelian randomization

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Figure 1.

Forest plot of the causal effects of rheumatoid arthri-tis-associated single-nucleotide polymorphisms on type 2 diabetes. MR: Mendelian randomization, IVW: inverse-variance weighted.

Figure 2.

Scatter plots of the genetic associations of rheumatoid arthritis against those of type 2 diabetes. The slopes of each line represent the causal association for each method. Blue line represents the inverse-variance weighted estimate, green line represents the weighted median estimate, and dark blue line represents the MR-Egger estimate. SNP: single-nucleotide polymorphism.

Table 1.

Instrumental single-nucleotide polymorphisms associated with RA and T2D GWASs

Instrumental SNP	Gene	Chromosome loci	Effect allele	Exposure (RA)			Outcome (T2D)
Instrumental SNP	Gene	Chromosome loci	Effect allele	Beta	SE	p-value	Beta	SE	p-value
rs10040327	IL6ST	5	A	−0.288	0.044	6.65E-11	−0.037	0.039	0.344
rs3087243	CTLA4	2	A	−0.139	0.023	2.24E-08	0.014	0.023	0.534
rs396458	CYP21A2	6	G	−0.528	0.035	9.15E-50	0.043	0.033	0.195
rs460568	C6orf120	6	T	0.262	0.031	3.81E-16	0.027	0.032	0.391
rs4810485	CD40	20	T	−0.163	0.030	5.69E-09	0.016	0.026	0.538
rs6679677	DCLRE1B	1	A	0.663	0.038	4.39E-70	−0.007	0.036	0.855
rs6920220	LOC102723649	6	A	0.199	0.029	2.49E-12	−0.008	0.028	0.777
rs9268145	C6orf10	6	G	1.058	0.027	＜5.00E-08	0.089	0.028	0.001
rs9277412	HLA-DPB1	6	T	−0.357	0.029	1.80E-39	0.014	0.025	0.564
rs9784876	TAP2	6	A	0.668	0.047	2.40E-46	0.067	0.042	0.110

RA: rheumatoid arthritis, T2D: type 2 diabetes, GWAS: genomewide association study, SNP: single-nucleotide polymorphism, Beta: beta coefficient, SE: standard error, IL6ST: interleukin 6 signal transducer, CTLA4: cytotoxic T-lymphocyte-associated protein 4, CYP21A2: cytochrome P450 family 21 subfamily A member 2, C6orf120: chromosome 6 open reading frame 120, CD40: cluster of differentiation 40, DCLRE1B: DNA crosslink repair 1B, LOC102723649: uncharacterized LOC102723649, C6orf10: chromosome 6 open reading frame 10, HLA-DPB1: major histocompatibility complex, Class II, DP Beta 1, TAP2: transporter 2, ATP binding cassette subfamily B member.

Table 2.

MR estimates from each method used to determine the causal effect of rheumatoid arthritis on the risk of type 2 diabetes

MR method	Number of SNPs	Beta coefficient	Standard error	Association p-value	Cochran Q-statistic	Heterogeneity p-value
Inverse variance weighted	10	0.044	0.022	0.047	12.14	0.206
MR-Egger	10	0.093	0.033	0.023	8.50	0.387
Weighted median	10	0.056	0.025	0.028	NA	NA

MR: Mendelian randomization, SNP: single-nucleotide polymorphism, NA: not available.

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