Page 50 - THE EVOLUTION OF EARLY ARTHRITIS AND CARDIOVASCULAR RISK Samina A. Turk

CHAPTER 3
In the following, we present a short overview of genetic and environmental risk factors for RA, with a focus on recent publications. Due to the preclinical phase that many later patients go through, biomarkers of autoimmunity and inflammation can also be used as risk factors or predictors of disease. Recently, several prediction models have been constructed using information from various cohorts of persons at risk of RA.
Genetic risk factors
Approximately 65% of RA risk has been shown to be heritable, and > 100 risk loci are now known. Most of these confer a low risk, and together they explain approximately 16% of total susceptibility(8). It has become clear that ACPA-negative and ACPA-positive disease have a genetically different background (5, 9). The major histocompatibility complex (MHC) class II, DR beta 1 (human leukocyte antigen (HLA)-DRB1) alleles play a central role in the genetic risk of “seropositive” (ACPA and/or rheumatoid factor (RF)-positive) RA, mainly in patients who are ACPA positive(5). Multiple alleles from this complex are associated with RA, which all share a region of similarity termed the shared epitope (SE). Besides these, several non-HLA genes have been identified. Most of the evidence comes from genome-wide association studies (GWAS)(10). Until now, most GWAS investigating RA have been performed in seropositive individuals with a European background(10). Recently, a review was published of specific genetic risk in Asian populations(11). Although most single-nucleotide polymorphisms (SNPs) have the same effect sizes for developing RA in European and Asian people, some differences are found, mainly for PADI4 and PTPN22, which are more strongly associated with RA in Asian populations. Furthermore, the genetic risk in certain high-risk populations of North American Natives has been described, showing that most of the risk is conferred by a high prevalence of the SE in this population(12). Evidence is lacking for many other populations. However, it seems that common SNPs found in ACPA-positive individuals with a European background also make individuals with a different ethnicity more susceptible to developing RA(9). This was also shown, to a lesser extent, for ACPA- negative patients.
A disadvantage of the GWAS method is that the implicated SNPs are not necessarily causally linked to the development of RA itself. Moreover, until now, they cannot be used for individual prediction because of their low effect sizes. Most have odds ratios (ORs) for developing ACPA-positive RA of 1.1-1.2, with a few exceptions having an individual OR of around 2.0 (e.g., locus 1p13 on the PTPN22 gene, and 6p21 on the HLA*04 genes)(9).
Genetic risk scores
Given the many involved genes with small effect sizes, genetic risk scores (GRS) have been developed to help individual prediction of RA by adding up multiple validated genetic risk loci. In the next step these can be combined with environmental factors in prediction models. GRS for RA usually take both the number of alleles an individual possesses and the effect size of the alleles into account. Published GRS prediction
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