Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these ...nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors - high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein-Barr virus (EBV) infection - strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors - smoking, EBV infection and obesity - interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene-environment interactions.
Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology. It has been shown that ...genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors. Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality. Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data. The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design. In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis. We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions. The application of MR design in the field of rheumatology remains limited. Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found. Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results. Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers). As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered. Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates. To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.
Elevated apolipoprotein B (apoB) and elevated apoB/apoA-1 ratio increase the risk of myocardial infarction (MI) and stroke, whereas high apoA-1 is protective. We study how these apolipoproteins are ...associated with major adverse cardiovascular events (MACEs), whether apoA-1 contributes to this association, and whether abnormal values occur decades before such events develop.
In the Swedish AMORIS (Apolipoprotein-related MOrtality RISk) cohort study, 137,100 men and women aged 25-84 years were followed an average 17.8 years. ApoB, apoA-1, and the apoB/apoA-1 ratio were analysed in relation to MACEs (non-fatal MI, stroke, and cardiovascular CV mortality), yielding 22,473 events. Hazard ratios (HRs) were estimated using Cox regression. Kaplan-Meier estimates were used to investigate the relationship of MACEs with increasing quintiles of the apoB/apoA-1 ratio in all age groups for both sexes. In nested case-control analyses, cases were randomly matched to age- and sex-matched controls, yielding population trajectories for apolipoproteins. Increased level of apoB and increased apoB/apoA-1 ratio were associated with risk of MACE and all clinical sub-components in both men and women across all ages (10th versus first decile in both sexes combined: HR 1.7 for MACE and 2.7 for non-fatal MI). Decreased values of apoA-1 potentiated the impact of apoB at all levels of apoB (on average across apoB range: 40% increase in HR for MACE and 72% increase in HR for non-fatal MI), indicating that the apoB/apoA-1 ratio covers a broader range of persons with dyslipidaemia at risk than apoB alone. In both men and women, MACEs occurred earlier on average for each increasing quintile of the apoB/apoA-1 ratio. Individuals with the highest levels of apoB/apoA-1 ratio experienced CV events on average several years earlier than those with lower ratios. Higher apoB/apoA-1 ratio in cases of MACE versus controls was seen already about 20 years before the event. A limitation of this study was that adjustment for tobacco smoking and hypertension was only possible in a small validation study.
An imbalance between apoB and apoA-1 resulting in an increased apoB/apoA-1 ratio is strongly associated with the outcome MACE and its sub-components, in both men and women of all ages. An increased apoB/apoA-1 ratio already 2 decades before events calls for early recognition and primary prevention. Simple evidence-based cut values should be considered in future cardiovascular guidelines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with ...common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody-associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG (P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Mediterranean diet has been associated with lower mortality and lower risk of cardiovascular diseases and cancer. Although its components have been analysed in several studies, only one study has ...specifically investigated the association between Mediterranean diet and risk of rheumatoid arthritis (RA), and reported no association.
Data on 1721 patients with incident RA (cases) and 3667 controls, matched on age, gender and residential area, from the Swedish epidemiological investigation of RA (EIRA), a population-based case-control study, were analysed using conditional logistic regression. The Mediterranean diet score, ranging from 0 to 9, was calculated from a 124-item food frequency questionnaire.
In the EIRA study (median age of participants 53 years), 24.1% of the patients and 28.2% of the controls had high adherence to the Mediterranean diet (a score between 6 and 9). After adjustments for body mass index, educational level, physical activity, use of dietary supplements, energy intake, and smoking, high adherence reduced the odds of developing RA by 21% (OR 0.79; 95% CI 0.65-0.96) as compared to low adherence (a score between 0 and 2). The OR was even lower among men (OR 0.49; 95% CI 0.33-0.73), but no significant association was found among women (OR 0.94; 95% CI 0.74-1.18). An association between high diet score and low risk of RA was observed in rheumatoid factor (RF)-positive (OR 0.69; 95% CI 0.54-0.88), but not RF-negative RA (OR 0.96; 95% CI 0.68-1.34), and in RA characterised by presence of antibodies to citrullinated peptides (ACPA), but not in ACPA-negative RA.
In this large population-based case-control study, the Mediterranean diet score was inversely associated with risk of RA. However, an association was only found among men and only in seropositive RA.
The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of ...the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective:
There is some evidence implicating diet in the development of inflammatory diseases. We aimed to study the influence of dietary habits on the risk of developing multiple sclerosis (MS).
...Methods:
We used a population-based case–control study recruiting incident cases of MS (1953 cases, 3557 controls). Subjects with different dietary habits 5 years prior to MS diagnosis were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Adjustment was made for a large number of environmental and lifestyle habits, including ancestry, smoking, alcohol consumption, body mass index, physical activity, and sun exposure habits.
Results:
Mediterranean diet was associated with lower risk of developing MS (adjusted OR = 0.54, 95% CI: 0.34–0.86, p = 0.009), compared with Western-style diet. There was no significant association between vegetarian/vegan diet and MS risk (adjusted OR = 0.96, 95% CI: 0.75–1.24, p = 0.976), nor between diet with low glycemic index and MS risk (adjusted OR = 0.93, 95% CI: 0.60–1.42, p = 0.518).
Conclusions:
Mediterranean diet may exert a protective influence regarding the risk of subsequently developing MS compared with Western-style diet.
Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, ...MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case-control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend < 0.0001). A potentiating effect was observed between non-drinking and presence of DRB1*15:01 (AP 0.3, 95% CI 0.2-0.5) which was of similar magnitude irrespective of smoking habits. Non-drinking also interacted with smoking to increase MS risk (AP 0.2, 95% CI 0.06-0.4). Non-drinking interacts with DRB1*15:01 and smoking to increase the risk of MS. Better understanding of the mechanisms behind our findings may help to define ways to achieve protection against MS by other means than alcohol consumption.
Smoking is one of the most established risk factors for rheumatoid arthritis (RA). The aim of this study was to estimate how age at smoking debut, smoking cessation, duration, intensity, and ...cumulative dose of smoking influence the risk of developing anti-citrullinated peptide antibodies (ACPA) positive and ACPA negative RA. The present report is based on a Swedish population-based, case-control study with incident cases of RA (3655 cases, 5883 matched controls). Using logistic regression models, subjects with different smoking habits were compared regarding risk of developing the two variants of RA, by calculating odds ratios (OR) with 95% confidence intervals (CI). Smoking increased the risk of developing both ACPA positive (OR 1.9, 95% CI 1.7–2.1) and ACPA negative RA (OR 1.3, 95% CI 1.2–1.5). For both subsets of RA, there seemed to be a threshold ( ~ 2.5 pack years for ACPA positive RA and ~ 5 pack years for ACPA negative RA) below which no association between smoking and RA occurred. A dose-response association was observed between cumulative dose of smoking and risk of developing ACPA positive RA (p value for trend < 0.0001). Duration of smoking had a higher influence on the association between smoking and RA than did intensity of smoking. For both subsets of RA, the detrimental effect of smoking decreased after smoking cessation. Twenty years after smoking cessation, there was no longer an association between smoking and risk of ACPA negative RA, whereas the association between smoking and ACPA positive RA risk persisted and was dependent on the cumulative dose of smoking. Smoking increases the risk of both subsets of RA with a more pronounced influence on the risk of ACPA positive RA. Preventive measures in order to reduce smoking are essential and may result in a decline in RA incidence.
Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects.
We examined this hypothesis in ...1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis.
Hazard ratios per 5-kg/m2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66–0.77), 0.94 (0.89–0.99), and 1.16 (1.05–1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis.
The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.
•Data from 1.3 million adults from 39 prospective cohort studies were pooled for the analyses.•Higher BMI was associated with increased risk of dementia when the follow-up was long.•When follow-up was short, lower BMI was linked to increased dementia risk probably due to reverse causation.
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