Roles of Genes in the Susceptibility to and Severity of Rheumatoid Arthritis - A Review

Rheumatoid arthritis (RA) is a chronic heterogeneous autoimmune disorder of unknown etiology. Genetic factors play an important role in susceptibility to RA as the heritability of RA is between 50% and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. It is conceivable that there is more than one susceptible gene(s) operative in RA, and an interaction of the relevant genes may predispose the offspring to develop the disease under certain conditions .Outside the major histocompatibility complex (MHC) region, some additional risk loci have been identified and validated including PTPN22, STAT4, PADI4, CTLA4 and others Genetic factors are also important in RA pharmacotherapy due to the gene-dependent activity of enzymes involved in the pharmacokinetics and/or pharmacodynamics of RA medications. Indeed, there is great variability in drug efficacy as well as adverse events associated with any anti-rheumatic therapy and genetics is thought to contribute significantly to this inter-individual variability in response. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. DOI: http://dx.doi.org/10.3329/jom.v13i1.10048 JOM 2012; 13(1): 51-54

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Faculty Opinions recommendation of Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1108099.564084 ◽

2008 ◽

Author(s):

Zoltán Szekanecz ◽

Zoltan Szabo

Keyword(s):

Rheumatoid Arthritis ◽

Cohort Study ◽

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Large Cohort ◽

Age At Diagnosis ◽

Leukocyte Antigen ◽

Large Cohort Study ◽

Autoantibody Status

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Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis

Seminars in Arthritis and Rheumatism ◽

10.1053/sarh.2002.32552 ◽

2002 ◽

Vol 31 (6) ◽

pp. 355-360 ◽

Cited By ~ 100

Author(s):

Miguel A. Gonzalez-Gay ◽

Carlos Garcia-Porrua ◽

Ali H. Hajeer

Keyword(s):

Rheumatoid Arthritis ◽

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Leukocyte Antigen

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Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response

BioMed Research International ◽

10.1155/2019/3494937 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Muhammad M. Aslam ◽

Peter John ◽

Attya Bhatti ◽

Sidrah Jahangir ◽

M. I. Kamboh

Keyword(s):

Rheumatoid Arthritis ◽

Vitamin D ◽

Immune Responses ◽

Molecular Mechanisms ◽

Genetic Factors ◽

Autoimmune Disorder ◽

Serum Levels ◽

Principal Factor ◽

Phosphate Homeostasis ◽

Low Serum

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

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Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.092312 ◽

2008 ◽

Vol 68 (1) ◽

pp. 107-109 ◽

Cited By ~ 14

Author(s):

K A Guthrie ◽

N R Tishkevich ◽

J L Nelson

Keyword(s):

Rheumatoid Arthritis ◽

Human Leukocyte Antigen ◽

Age Of Onset ◽

Human Leukocyte ◽

Paternal Allele ◽

Hla Alleles ◽

Leukocyte Antigen ◽

The North ◽

Significant Difference ◽

Hla Genotype

Objectives:Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.Methods:We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).Results:Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.Conclusions:Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

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