Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

Training-related and competition-related risk factors for respiratory tract and gastrointestinal infections in elite cross-country skiers

This paper was accepted for publication in the British Journal of Sports Medicine. The definitive version is available at: http://dx.doi.org/10.1136/bjsports-2015-095398Aim To examine symptoms indicative of respiratory tract and gastrointestinal infections and determine risk factors for such symptoms in elite cross-country skiers. Methods Self-reported training and symptom data for 37 elite cross-country skiers from 2007 to 2015 were analysed using multilevel logistic regression equations with symptom incidence and duration as outcome variables, and sex, performance level, season, competition, air travel, altitude exposure and training characteristics as independent variables. Results Data for 7016 person-weeks were analysed, including 464 self-reported infection events and 110 959 h of training. Athletes reported median (range) 3 (1–7) respiratory tract and/or gastrointestinal events per year, with symptoms lasting 5 (1–24) days. During the winter, symptoms occurred more frequently (OR 2.09, p<0.001) and lasted longer (b=0.043, p<0.001) compared with summer. Competition and air travel increased the risk of symptoms, with ORs of 2.93 (95% CI 2.24 to 3.83) and 4.94 (95% CI 3.74 to 6.53), respectively (p<0.001). Athletes with higher training monotony had lower risk of symptoms (OR 0.87 (95% CI 0.73 to 0.99), p<0.05). Other training variables were not associated with symptoms. Athletes who had won an Olympic/World Championship medal reported shorter symptom duration compared with less successful athletes (b=−0.019, p<0.05) resulting in significantly fewer symptomatic days/year (14 (6–29) vs 22 (8–43) days/year). Conclusions Air travel and competition are major risk factors for acute respiratory tract and gastrointestinal symptoms in this population. Athletes who have large fluctuations in training load experience such symptoms more frequently. Shorter duration of symptoms appears to be associated with success in cross-country skiing