Both genetic and environmental factors display low or modest associations with multiple sclerosis. Hypothetically, gene-environment interactions may exert much stronger effects. In this study, we investigated potential interactions between genetic risk factors and smoking in relation to risk of developing multiple sclerosis. A population-based case-control study involving incident cases of multiple sclerosis (843 cases, 1209 controls) was performed in Sweden. Cases and controls were classified according to their smoking status and human leukocyte antigen DRB1 as well as human leukocyte antigen A genotypes. Subjects with different genotypes and smoking habits were compared with regard to incidence of multiple sclerosis, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. A significant interaction between two genetic risk factors, carriage of human leukocyte antigen DRB1*15 and absence of human leukocyte antigen A*02, was observed among smokers whereas such an interaction was absent among non-smokers. There were considerable differences in odds ratios between the various groups. Compared with non-smokers with neither of the genetic risk factors, the odds ratio was 13.5 (8.1-22.6) for smokers with both genetic risk factors. The odds ratio for smokers without genetic risk was 1.4 (0.9-2.1) and the odds ratio for non-smokers with both genetic risk factors was 4.9 (3.6-6.6). Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors. The risk of developing multiple sclerosis associated with human leukocyte antigen genotypes may be strongly influenced by smoking status. The findings are consistent with our hypothesis that priming of the immune response in the lungs may subsequently lead to multiple sclerosis in genetically susceptible people.
Our findings suggest that patients with low baseline lymphocyte counts and underweight women in which fingolimod treatment will be initiated should possibly be monitored more closely.
FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.
Background
In multi-site HIV observational cohorts, clustering of observations often occur within sites. Ignoring clustering may lead to “Simpson's paradox” (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox-regression models.
Methods
Survival time from combination antiretroviral therapy (cART) initiation was analysed using four Cox models: (i) no site adjustment; (ii) site as a fixed effect; (iii) stratification through site; and (iv) shared frailty on site.
Results
A total of 6454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (i) shows the hazard ratio (HR) for years 2010-2014 was higher than the HR for 2006-2009, compared to 2003-2005 (HR = 0.68 vs 0.61). Models (ii)-(iv) consistently implied greater improvement in survival for those who initiated in 2010-2014 than 2006-2009 contrasting findings from Model (i). The effects of other significant covariates on survival were similar across four models.
Conclusions
Ignoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.