Background
The idiopathic inflammatory myopathies (IIMs) are a spectrum of rare and heterogeneous autoimmune diseases causing inflammation and weakness of skeletal muscle. Major clinical subgroups are polymyositis (PM) and dermatomyositis (DM). The relative prevalence of PM versus DM varies between populations, and it appears to be dependent on latitude; as latitude increases, the relative prevalence of DM (i.e., DM/DM and PM combined) decreases [
1,
2]. This effect has been attributed to higher ultraviolet (UV) radiation levels increasing the likelihood of the development of DM over PM towards the equator, and also increasing the prevalence of the DM-specific autoantibody anti-Mi-2 [
2‐
4]. UV radiation is thought to play a role in DM owing to skin changes being more prominent on the sun-exposed parts of the face, neck and shoulders, reports of photoaggravation of skin lesions and increased cutaneous photosensitivity compared with healthy control individuals [
5,
6]. UV radiation is used in phototherapy of skin conditions such as psoriasis as well as being a major risk factor for skin cancer owing to its suppression of the immune system. UV radiation affects the immune system in various ways, including DNA damage via production of ROS, induction of cytokine signalling and induction of T-regulatory cells [
7]. Although thought to be linked to the development of some autoimmune disorders, it is unclear how UV radiation contributes to the pathogenesis of conditions such as DM [
2].
Notably, latitude and UV radiation intensity do not perfectly correlate, and UV exposure may depend on the behaviour of individuals, such as whether they work indoors or outdoors. It is possible that the observed differences in DM, PM and anti-Mi-2 prevalence with latitude could additionally be influenced by other factors, such as the different genetic backgrounds of populations. The most strongly associated single-nucleotide polymorphism (SNP) outside the human leucocyte antigen (HLA) gene complex for the PM subgroup in a recent IIM Immunochip study (rs2476601 in
PTPN22) [
8] demonstrates a correlation with latitude, with increasing risk allele frequency from southern to northern Europe [
9]. Similarly, some HLA allele frequencies are known to vary with latitude, such as HLA-B27, associated with ankylosing spondylitis, which is absent in populations around the equator but increases to 40% in populations in the far north and the Arctic [
10].
The aim of this study was to explore the associations of PM and DM prevalence and autoantibody frequencies with latitude. In particular, we investigated whether these “latitude-dependent” associations could instead be attributed to genetic background rather than environmental factors by analysing the distribution of PM and DM risk SNPs in healthy populations.
Discussion
In this study we analysed the associations between latitude and DM relative prevalence and DM-specific autoantibody frequencies in the largest IIM cohort to date. In addition, we analysed the association of latitude with PM- or DM-associated SNP risk allele frequencies and HLA alleles associated with DM autoantibodies in healthy populations. The results confirmed that the proportion of DM increases towards the equator, with a strong negative association with latitude. Furthermore, we showed, for the first time, to our knowledge, that DM-specific anti-TIF1-γ autoantibody frequency was significantly negatively associated with latitude along with HLA alleles associated with anti-TIF1-γ and anti-Mi-2. However, we failed to replicate the increase in the presence of anti-Mi-2 autoantibodies towards the equator which was reported in a previous study (
P = 0.0349) [
2]. The association of anti-Mi-2 with surface UV radiation intensity in that study was more significant (
P = 0.0196) than the association with latitude and later replicated in another study of UV radiation [
2,
3]. In addition, exposing keratinocytes to UV radiation has been shown to increase the expression of Mi-2 protein [
13], supporting the hypothesis that UV radiation may be associated with production of anti-Mi-2 autoantibodies.
In the analysis of PM- and DM-associated non-HLA SNP risk allele frequency, we found that half of the SNPs analysed were significantly associated with latitude and four of five were consistent with the latitude associations of PM or DM prevalence (positive for PM and negative for DM). Effect sizes were modest, but the ORs had tight CIs and were statistically significant.
This study has some limitations, including the assumption that the patients’ location at disease onset and place of birth would be similar to the location of the recruitment centres. The study was limited to one ethnic group because the genetic association study was performed only in Caucasian samples. In addition, samples were collected within a limited range of latitudes, and the cases and controls were not from exactly the same populations. Studies with collection of disease onset and place of birth data along with UV exposure data in a larger multi-ethnic IIM and control cohort spread over a greater range of latitudes could elucidate whether latitude associations are due to population genetic background or environmental factors.
Acknowledgements
The MYOGEN study investigators, in addition to the authors of this article, who contributed to this study are as follows: Ingrid E. Lundberg (Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Frederick W. Miller (Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, MD, USA), Robert G. Cooper (MRC/ARUK Institute of Ageing and Chronic Disease, University of Liverpool, UK), William E. Ollier (Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, UK), Peter K. Gregersen (The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, USA), Jiri Vencovsky (Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic), Katalin Danko (Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary), Vidya Limaye (Rheumatology Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia), Albert Selva-O’Callaghan (Department of Internal Medicine, Vall d’Hebron General Hospital, Barcelona, Spain), Pedro M. Machado, Michael G. Hanna (MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK), Hazel Platt (Centre for Integrated Genomic Medical Research, University of Manchester, UK), Øyvind Molberg (Department of Rheumatology, Oslo University Hospital, Oslo, Norway), Olivier Benveniste (Pitié-Salpêtrière Hospital, UPMC, Assistance Publique – Hôpitaux de Paris, Paris, France), Timothy Radstake (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands), Jan De Bleecker, Boel De Paepe (Department of Neurology, Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium), Britta Maurer (Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland), Leonid Padyukov (Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden), Terrance P. O’Hanlon (Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, MD, USA), Lucy R. Wedderburn (Arthritis Research UK Centre for Adolescent Rheumatology, and Institute of Child Health, University College London, London, UK), Christopher Denton (Royal Free Hospital, London, UK), Herman Mann (Institute of Rheumatology, Prague), David Hilton-Jones (John Radcliffe Hospital, Oxford, UK), Patrick Kiely (St. George’s Hospital, London, UK), Paul H. Plotz (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA), Mark Gourley (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA), Galina Marder (North Shore University Hospital, Great Neck, NY, USA). Neil J. McHugh and Zoe E. Betteridge (Department of Pharmacy and Pharmacology, University of Bath, Bath, UK) generated the autoantibody data used in this study.