Abstract
To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). For the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only. The mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry. The strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.
Highlights
The strong additive interaction between an updated Systemic lupus erythematosus (SLE) genetic risk score and current/recent smoking suggests smoking may influence specific genes in SLE pathogenesis
Systemic lupus erythematosus (SLE) is a complex and heterogeneous inflammatory autoimmune disease associated with a wide range of symptoms and organ-involvement
SLE genome-wide association studies (GWAS) have identified more than 100 risk loci for SLE susceptibility across populations, adding to our understanding of disease pathogenesis[3,4,5,6,7,8]
Summary
673 SLE cases (1997 American College of Rheumatology criteria) were age-, sex- and race- (first 3 genetic principal components) matched to 3,272 controls. We utilized genetic and epidemiologic data from 1,274 Nurses’ Health Studies (NHS) cohort participants and 2,675 Partners Healthcare Biobank (PHB) participants, including a total of 673 SLE cases and their 3,272 matched control subjects. Participants were asked to report new physician diagnoses of SLE on biennial questionnaires Those indicating a new diagnosis were asked to complete the Connective Tissue Disease Screening Questionnaire[12] and to consent to the release of their medical records. For each case in the NHS, ten NHS controls without any history of reporting a connective tissue disease and with available GWAS data, were selected, matched on age at index date of SLE diagnosis (within five years), self-reported race, and genotyping platform (detailed below). Detailed smoking exposure data for all cases and controls, including age started smoking and updated numbers of cigarettes smoked per day at each two-year time interval, were prospectively reported on every questionnaire. Given our past findings that current and recently quit smokers (within four years before SLE diagnosis) have elevated SLE risk, whereas more distant past and never smokers did not, we defined a binary smoking status variable[9,10]
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