Smoking and its interaction with genetics in MS etiology.

The etiology of multiple sclerosis (MS) involves multifaceted interactions between genetic loci and environmental factors. Smoking is an important risk factor for MS that overall increases the risk of the disease with approximately 50%. However, the precise effects of smoking on MS development vary considerably in different contexts and in different populations. This review focuses on the influence of smoking on MS risk and its interaction with genetics in MS etiology. The possible biological mechanisms are presented in this paper. Further research is needed to establish the mechanisms of causality and to explore preventive strategies.

Incorporating machine learning approaches to assess putative environmental risk factors for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) incidence has increased recently, particularly in women, suggesting a possible role of one or more environmental exposures in MS risk. The study objective was to determine if animal, dietary, recreational, or occupational exposures are associated with MS risk. METHODS: Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of exposures with potential relevance to disease in a large population-based (Kaiser Permanente Northern California [KPNC]) case-control study. Variables with non-zero coefficients were analyzed in matched conditional logistic regression analyses, adjusted for established environmental risk factors and socioeconomic status (if relevant in univariate screening),± genetic risk factors, in the KPNC cohort and, for purposes of replication, separately in the Swedish Epidemiological Investigation of MS cohort. These variables were also assessed in models stratified by HLA-DRB1*15:01 status since interactions between risk factors and that haplotype have been described. RESULTS: There was a suggestive association of pesticide exposure with having MS among men, but only in those who were positive for HLA-DRB1*15:01 (OR pooled = 3.11, 95% CI 0.87, 11.16, p = 0.08). CONCLUSIONS: While this finding requires confirmation, it is interesting given the association between pesticide exposure and other neurological diseases. The study also demonstrates the application of LASSO to identify environmental exposures with reduced multiple statistical testing penalty. Machine learning approaches may be useful for future investigations of concomitant MS risk or prognostic factors.

Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors.

OBJECTIVE: To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. METHODS: Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. RESULTS: In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (p<0.01). Estimates trended in the same direction for males, but were not significant. BMI in 20s demonstrated a linear relationship with MS (p-trend=9.60×10(-4)), and a twofold risk of MS for females with a BMI≥30kg/m(2) was observed (OR=2.15, 95% CI 1.18, 3.92). Significant associations between BMI in 20s and MS in males were not observed. Multivariate modelling demonstrated that significant associations between BMI or body size with MS in females persisted after adjusting for history of infectious mononucleosis and genetic risk factors, including HLA-DRB1*15:01 and established non-HLA risk alleles. INTERPRETATION: Results show that childhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors.

Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.

BACKGROUND: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers. METHODS: A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden. RESULTS: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17-12.33]). CONCLUSIONS: We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.

High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women.

In a Swedish population-based case-control study (1571 cases, 3371 controls), subjects with different body mass indices (BMIs) were compared regarding multiple sclerosis (MS) risk, by calculating odds ratios (OR) with 95% confidence intervals (95% CI). Subjects whose BMI exceeded 27 kg/m(2) at age 20 had a two-fold increased risk of developing MS compared with normal weight subjects. Speculatively, the obesity epidemic may explain part of the increasing MS incidence as recorded in some countries. Measures taken against adolescent obesity may thus be a preventive strategy against MS.

Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis.

OBJECTIVE: The aim of this study was to estimate the influence of tobacco smoking and Swedish snuff use on the risk of developing multiple sclerosis (MS). METHODS: A population-based case-control study was performed in Sweden, using incident cases of MS (902 cases and 1,855 controls). A case was defined as a subject from the study base who had received a diagnosis of MS, and controls were randomly selected from the study base. The incidence of MS among smokers was compared with that of never-smokers. We also investigated whether the use of Swedish snuff had an impact on the risk of developing MS. RESULTS: Smokers of both sexes had an increased risk of developing MS (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2-1.7 for women, and OR 1.8, 95% CI 1.3-2.5 for men). The increased risk was apparent even among subjects who had previously smoked moderately (< or =5 pack-years) prior to index, and the risk increased with increasing cumulative dose (p < 0.0001). The increased risk for MS associated with smoking remained up to 5 years after stopping smoking. In contrast, taking Swedish snuff for more than 15 years decreased the risk of developing MS (OR 0.3, 95% CI 0.1-0.8). CONCLUSIONS: Smokers of both sexes run an increased risk of developing multiple sclerosis (MS), and the risk increases with cumulative dose of smoking. However, the use of Swedish snuff is not associated with elevated risk for MS, which may indicate that nicotine is not the substance responsible for the increased risk of developing MS among smokers.