Genetic Studies of Rheumatoid Arthritis: Progress and Challenges

Changsoo Kang

doi:10.4078/jrd.2015.22.5.274

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Kang: Genetic Studies of Rheumatoid Arthritis: Progress and Challenges

Review Article

J Rheum Dis 2015;22(5):274-281.

Published online: 31 October 2015

DOI: https://doi.org/10.4078/jrd.2015.22.5.274

Genetic Studies of Rheumatoid Arthritis: Progress and Challenges

Changsoo Kang

Department of Biology, Research Institute of Basic Sciences, College of Natural Sciences, Sungshin Women's University, Seoul, Korea

Corresponding to: Changsoo Kang, Department of Biology, Research Institute of Basic Sciences, College of Natural Sciences, Sungshin Women's University, 55 Dobong-ro, 76ga-gil, Gangbuk-gu, Seoul 01133, Korea. E-mail: ckang@sungshin.ac.kr

Received 8 August 2015 Revised 20 September 2015 Accepted 21 September 2015

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

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with both genetic and environmental factors. The DRB1 gene at the human leukocyte antigen (HLA) locus of chromosome 6p21.3 was the first genetic factor associated with RA to be identified in the 1980s; however, identification of causative genes other than those at the HLA locus has been challenging for geneticists because of the strong linkage disequilibrium in this locus and the non-Mendelian inheritance pattern of RA. Recent advances in high-throughput single nucleotide polymorphism genotyping technologies and bioinformatic analysis tools have facilitated the identification of positive associations of hundreds of genes with RA using family-based linkage analyses and genome wide association studies. Some of the RA associated genes at non-HLA loci are as follows: PADI4, PTPN22, STAT4, and TNFAIP3. In this paper, we describe the pathological mechanisms mediated by these genes. In addition, we review results of previous genetic studies of RA and future challenges in connecting the dots of missing heritability in the post-genomewide association study era.

Keywords: Rheumatoid arthritis, Genetics, Mutation, Linkage, Association

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Figure 1.

Conversion of arginine residue to citrulline by peptidyl arginine deiminase, type IV (PADI4).

Table 1.

Notable genetic studies of rheumatoid arthritis

Reference	Method	Summary of finding	Gene or chromosome
[8]	Serological testing in 80 RA patients and controls	B-cell alloantigen HLA-DRw4 were statistically more frequent in patients (70%) than in normal controls (28%)	6p21.3
[10]	DNA sequencing	Found association of DRB1 SE alleles with RA	HLA-DRB1
[17,18]	Case and control study by genotyping SNPs in MHC locus	Suggested nominal association of the intronic and promoter SNPs with RA independently of DRB1 SE	MICA, HLA-DQB2, IkBL
[11,12]	GWAS	Identified three major causative variants in DRB1 with RA	HLA-DRB1
[19-26]	Family-based linkage analysis	Identified significant linkage of RA to the markers in several chromosomes	1p36, 2q33, 2q35, 3q13, 6p21.3, 14, 16p13– q12.2, 18q22-23
[27]	Association study of candidate region (1p36)	Revealed functional PADI4 haplotypes are associated with RA by increasing autoantibodies against citrullinated peptides	PADI4
[29]	Association study of candidate region (2q33)	Found association of haplotype in the intronic region of STAT4 with both RA and SLE	STAT4
[34]	Association study of candidate genes	Identified a missense mutation in PTPN22 and found risk allele increase systemic autoimmunity	PTPN22
[37]	GWAS	Found a intergenic SNP associated with RA	TNFAIP3
[40]	GWAS	Identified 7 risk loci for RA in the Caucasian population	IL6ST, SPRED2, RBPJ, CCR6, IRF5, PXK, IL2RA, CCL21, AFF3
[39]	GWAS	Identified 9 loci associated with RA in the Japanese population	B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4, PTPN2

GWAS: genomewide association study, HLA: human leukocyte antigen, MHC: major histocompatibility complex, RA: rheumatoid arthritis, SE: shared epitope, SNP: single nucleotide polymorphism, SLE: systemic lupus erythematosus, STAT4: signal transducer and activator of transcription 4, TNFAIP3: tumor necrosis factor-α-induced protein 3.

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