DRB1–environment interactions in multiple sclerosis etiology: results from two Swedish case–control studies

ObjectiveWe aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01.MethodsUsing population-based case–control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.ResultsThe effect of each DRB1*15:01 allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01 and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01 alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01 carriers without the protective A*02:01 allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01 homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).ConclusionsThe strikingly increased MS risk among DRB*15:01 homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

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The influence of human leukocyte antigen-DRB115:01 and its interaction with smoking in MS development is dependent on DQA101:01 status

Multiple Sclerosis Journal ◽

10.1177/1352458519877685 ◽

2019 ◽

Vol 26 (13) ◽

pp. 1638-1646 ◽

Cited By ~ 1

Author(s):

Anna Karin Hedström ◽

Ola Hössjer ◽

Jan Hillert ◽

Pernilla Stridh ◽

Ingrid Kockum ◽

...

Keyword(s):

Multiple Sclerosis ◽

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Population Based ◽

Case Control ◽

Case Control Studies ◽

Swedish Population ◽

Leukocyte Antigen ◽

Smoking Interaction ◽

Additive Scale

Background: HLA-DRB1*15:01, absence of HLA-A*02:01, and smoking interact to increase multiple sclerosis (MS) risk. Objective: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB1*15:01 and absence of A*02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA1*01:01 allele, which confers a protective effect only in the presence of DRB1*15:01. Methods: In two Swedish population-based case–control studies (5838 cases, 5412 controls), subjects with different genotypes and smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals employing logistic regression. Interaction on the additive scale between different genotypes and smoking was evaluated. Results: The DRB1*08:01 allele interacted with smoking to increase MS risk. The interaction between DRB1*15:01 and both the absence of A*02:01 and smoking was confined to DQA1*01:01 negative subjects, whereas no interactions occurred among DQA1*01:01 positive subjects. Conclusion: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB1*15:01 and its interaction with the absence of A*02:01 and smoking is dependent on DQA1*01:01 status which may be due to differences in the responding T-cell repertoires.

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Breastfeeding is associated with reduced risk of multiple sclerosis in males, predominantly among HLA-DRB1*15:01 carriers

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217320928101 ◽

2020 ◽

Vol 6 (2) ◽

pp. 205521732092810

Author(s):

AK Hedström ◽

C Adams ◽

X Shao ◽

C Schaefer ◽

T Olsson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Protective Factor ◽

Meta Analysis ◽

Population Based ◽

Case Control ◽

Carrier Status ◽

Case Control Studies ◽

Biologic Effect ◽

The Impact ◽

Reduced Risk

Background Breastfeeding as an infant appears protective against later development of some autoimmune diseases, but research into its influence on multiple sclerosis (MS) risk has yielded inconclusive results. Objective We investigated the possible impact of breastfeeding on MS risk. Methods We used two population-based case–control studies comprising 3670 cases and 6737 matched controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between MS and exposure to prolonged breastfeeding (4 months or longer) versus reduced breastfeeding (less than 4 months). A meta-analysis of case–control studies that assessed the impact of breastfeeding on MS risk among women and men was conducted. Results Prolonged breastfeeding was associated with reduced MS risk among men (OR 0.7, 95% CI 0.5–0.9) but not among women (OR 0.9, 95% CI 0.8–1.1). Among men, a synergistic effect was observed between HLA-DRB1*15:01 carrier status and reduced breastfeeding. Conclusions Findings from the current study add to accumulating evidence that breastfeeding may be a modifiable protective factor for reducing the risk of MS in offspring. When possible, mothers should be supported to breastfeed their infants; however, the mechanism of a sex-specific biologic effect of breastfeeding on MS risk is unclear.

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Nicotine might have a protective effect in the etiology of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512471879 ◽

2013 ◽

Vol 19 (8) ◽

pp. 1009-1013 ◽

Cited By ~ 49

Author(s):

AK Hedström ◽

J Hillert ◽

T Olsson ◽

L Alfredsson

Keyword(s):

Multiple Sclerosis ◽

Immune Responses ◽

Protective Effect ◽

Lower Risk ◽

Population Based ◽

Case Control ◽

Case Control Studies ◽

Swedish Population ◽

Moist Snuff ◽

High Doses

Objective: The use of moist snuff is common in Sweden and leads to exposure to high doses of nicotine. Recent studies indicate that exposure to nicotine could modulate immune responses. The aim of this study was to investigate the influence of snuff use on the risk of developing multiple sclerosis (MS), taking smoking habits into consideration. Methods: In two Swedish population-based, case-control studies (7883 cases, 9437 controls), subjects with different snuff use habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Results: Snuff-takers have a decreased risk of developing MS compared with those who have never used moist snuff (OR 0.83, 95% CI 0.75–0.92), and we found clear evidence of an inverse dose-response correlation between cumulative dose of snuff use and the risk of developing the disease. We further observed that subjects who combined smoking and snuff use had a significantly lower risk for MS than smokers who had never used moist snuff, also after adjustment for amount of smoking. Conclusions: Our results add evidence to the hypothesis that nicotine exerts anti-inflammatory and immune-modulating effects in a way that might decrease the risk of developing MS.

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Estimating the Marginal Causal Effect and Potential Impact of Waterpipe Smoking on Multiple Sclerosis Using Targeted Maximum Likelihood Estimation Method: a Large Population-Based Incident Case-Control Study

American Journal of Epidemiology ◽

10.1093/aje/kwab036 ◽

2021 ◽

Author(s):

Ibrahim Abdollahpour ◽

Saharnaz Nedjat ◽

Amir Almasi-Hashiani ◽

Maryam Nazemipour ◽

Mohammad Ali Mansournia ◽

...

Keyword(s):

Multiple Sclerosis ◽

Maximum Likelihood ◽

Case Control Study ◽

Population Based ◽

Case Control ◽

Waterpipe Smoking ◽

Case Control Studies ◽

Incident Case ◽

Targeted Maximum Likelihood ◽

Control Study

Abstract There are few if any reports regarding the role of lifetime waterpipe smoking in multiple sclerosis (MS) etiology. The authors investigated the association between waterpipe and MS, adjusted for confounders. This was a population-based incident case-control study conducted in Tehran, Iran. Cases (n=547) were 15–50-year-old patients identified from the Iranian Multiple Sclerosis Society between 2013 and 2015. Population-based controls (n=1057) were 15–50-year old recruited by random digit telephone dialing. A double robust estimator method known as targeted maximum likelihood estimator (TMLE) was used to estimate the marginal risk ratio and odds ratio between waterpipe and MS. The both estimated RR and OR was 1.70 (95% CI: 1.34, 2.17). The population attributable fraction was 21.4% (95% CI: 4.0%, 38.8%). Subject to the limitations of case-control studies in interpreting associations causally, this study suggests that waterpipe use, or its strongly related but undetermined factors, increases the risk of MS. Further epidemiological studies including nested case-control studies are needed to confirm these results.

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Etiological research in pediatric multiple sclerosis: A tool to assess environmental exposures (PEDiatric Italian Genetic and enviRonment ExposurE Questionnaire)

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/20552173211059048 ◽

2021 ◽

Vol 7 (4) ◽

pp. 205521732110590

Author(s):

Silvy Pilotto ◽

Jessica Gencarelli ◽

Stefania Bova ◽

Leonardo Gerosa ◽

Damiano Baroncini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Environmental Factors ◽

Pediatric Population ◽

Environmental Exposures ◽

Case Control ◽

Italian Population ◽

Case Control Studies ◽

Environment Exposure ◽

Perceived Relevance ◽

Pediatric Onset

Background The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics. Objectives To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented. Methods PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population. Results PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%. Conclusion PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research.

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Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Cancers ◽

10.3390/cancers13061378 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1378

Author(s):

Tú Nguyen-Dumont ◽

James G. Dowty ◽

Jason A. Steen ◽

Anne-Laure Renault ◽

Fleur Hammet ◽

...

Keyword(s):

Breast Cancer ◽

Cumulative Risk ◽

Population Based ◽

Case Control ◽

Cancer Information ◽

Case Control Studies ◽

Breast Cancer Family ◽

Pathogenic Variants ◽

Increased Risk ◽

Control Family

Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

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Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: a meta-analysis of case–control studies

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319190 ◽

2019 ◽

Vol 90 (9) ◽

pp. 1059-1067 ◽

Cited By ~ 14

Author(s):

Sarah-Jane Martin ◽

Sarah McGlasson ◽

David Hunt ◽

James Overell

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Light Chain ◽

Meta Analysis ◽

Grey Literature ◽

Case Control ◽

Disease Stage ◽

Case Control Studies ◽

Neurofilament Light Chain ◽

Neurofilament Light

ObjectiveNeurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS). We conducted a systematic review and meta-analysis of case–control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other.MethodsGuidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Electronic databases were searched for published and ‘grey’ literature, with 151 hits. Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis.ResultsCSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001). Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108). CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001).ConclusionsCSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS. Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease ‘activity’ rather than as a marker of disability or disease stage.

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