Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

Association between sun exposure habits and disease progression in multiple sclerosis.

BACKGROUND AND PURPOSE: Higher latitude has been associated with increased occurrence of multiple sclerosis (MS) and with more severe disease. The aim was to study the impact of sun exposure habits on MS disease progression and health-related quality of life. METHODS: Patients from a population-based case-control study were categorized based on sun exposure habits at diagnosis and were followed up to 15 years post-diagnosis through the Swedish MS registry (n = 3314) with regard to changes in Expanded Disability Status Scale (EDSS). Linear mixed models were used to analyse long-term changes, while Cox regression models, with 95% confidence intervals, were used to investigate outcomes, including 24-week confirmed diasability worsening, EDSS3, EDSS4, and physical worsening as measured by the physical component of the Multiple Sclerosis Impact Scale 29. RESULTS: Compared to average sun exposure (median value), low exposure to sunlight was associated with faster EDSS progression, increased risk of confirmed disability worsening (hazard ratio [HR] 1.48, 95% CI 1.21-1.81), increased risk of reaching EDSS 3 (HR 1.35, 95% CI 1.02-1.79), EDSS 4 (HR 1.47, 95% CI 1.01-2.20) and self-reported physical worsening (HR 1.27, 95% CI 1.00-1.62). Significant trends revealed a lower risk of unfavourable outcomes with increasing sun exposure. CONCLUSIONS: Very low levels of sun exposure are associated with worse disease progression and health-related quality of life in patients with MS.

Medically unexplained symptoms are common in women in tertiary neurological healthcare center: A survey cohort study of persons investigated for suspected multiple sclerosis.

BACKGROUND: A significant proportion of individuals with suspicious onset of multiple sclerosis (MS) does not fulfill the diagnostic criteria. Although some receive other diagnoses, many remain undiagnosed and lack healthcare follow-up. This study aimed to characterize persons with undetermined diagnosis (PwUD) through a questionnaire. METHODS: Incident cases with suspected MS were consecutively admitted to a tertiary neurological healthcare center in a prospective cohort study. Those who remained undiagnosed after 40 months (mean, range 31-52) were considered PwUD. They completed a modified questionnaire, previously used in a population-based case-control study of incident MS cases. Their responses were compared with two control cohorts, persons with MS (PwMS) and healthy controls, randomly selected from national registries, matched by age, gender, and area of residence. RESULTS: Out of 271 patients with suspected MS onset, 72 (20.3%) were PwUD with a female majority (79%). The response rate was 83% and 39% reported persisting MS-like symptoms. Compared to controls (n = 548) and PwMS (n = 277), fewer PwUD were currently smoking (p = .4 and p = .03), consumed less alcohol (p = .04 and p = .01), and had children (p = .02 and p = .002). PwUD reported occurrence of other autoimmune disease in 29%, higher compared to PwMS and controls (p < .001 and p < .001). CONCLUSIONS: UD is common among persons investigated for suspected MS, in particular among female parents. Our data suggest that PwUD can be characterized as nonsmokers with low alcohol consumption and a higher prevalence of autoimmune disease, in particular thyroid disease.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans.

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

OBJECTIVES: To discover autoantibodies to non-modified proteins associated with the presence/absence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). METHODS: The autoantibody repertoire of 80 ACPA negative and 80 ACPA positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls. The relationship between the four autoantibodies and lung abnormalities on high-resolution computed tomography (HRTC) was examined in 93 early RA patients from LURA cohort. Association between the autoantibodies, smoking and MHC class II alleles was assessed by logistic regression analysis. RESULTS: : Anti-ANOS1 and anti-MURC IgG levels were associated with ACPA-positive status (OR = 3.02; 95% CI 1.87-4.89; and OR = 1.86; 95% CI 1.16-2.97, respectively) and increased in ACPA-positive patients compared with controls. Anti-ANOS1 IgG was associated with smoking habit (OR = 2.11; 95% CI 1.22-3.69) and anti-MURC IgG with the presence of the MHC class II "shared-epitope" genes (OR = 1.95; 95% CI 1.11-3.46). Anti-TSPYL4 IgG was associated with ACPA-negative (OR = 0.41; 95% CI 0.19-0.89). Anti-TSPYL4 IgG and anti-MAP2K6 IgG levels were increased in the ACPA-negative patients compared with controls. Presence of anti-MAP2K6 IgG and anti-TSPYL4 IgG correlated negatively with HRCT-defined lung abnormalities. CONCLUSIONS: These four autoantibodies may be useful in diagnostics and in predicting clinical phenotypes of RA.

Head trauma results in manyfold increased risk of multiple sclerosis in genetically susceptible individuals.

BACKGROUND: Large register-based studies have reported an association between head trauma and increased risk of multiple sclerosis (MS). We aimed to investigate possible interactions between head trauma and MS-associated HLA genes in relation to MS risk. METHODS: We used a Swedish population-based case-control study (2807 incident cases, 5950 matched controls with HLA genotypes available for 2057 cases, 2887 controls). Subjects with and without a history of self-reported head trauma were compared regarding MS risk, by calculating ORs with 95% CIs using logistic regression models. Additive interaction between head trauma, HLA-DRB1*1501 and absence of HLA-A*0201, was assessed by calculating the attributable proportion (AP) due to interaction. RESULTS: A history of head trauma was associated with a 30% increased risk of subsequently developing MS (OR 1.34, 95% CI 1.17 to 1.53), with a trend showing increased risk of MS with increasing number of head impacts (p=0.03). We observed synergistic effects between recent head trauma and HLA-DRB1*15:01 as well as absence of HLA*02:01 in relation to MS risk (each AP 0.40, 95% CI 0.1 to 0.7). Recent head trauma in individuals with both genetic risk factors rendered an 18-fold increased risk of MS, compared with those with neither the genetic risk factors nor a history of head trauma (OR 17.7, 95% CI 7.13 to 44.1). CONCLUSIONS: Our findings align with previous observations of a dose-dependent association between head trauma and increased risk of MS and add a novel aspect of this association by revealing synergistic effects between recent head trauma and MS-associated HLA genes.

In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.

OBJECTIVES: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis. METHODS: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline. RESULTS: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained. CONCLUSION: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria.

Prevention vs treatment of rheumatoid arthritis.

Whether a yet chronic and not curable disease like rheumatoid arthritis (RA) can be subject to prevention or whether available resources should be focused on treatment is a classical dilemma. Similar to the case in most other chronic diseases, the focus in research as well as in clinical practice has been on the treatment of established diseases, resulting in drugs that are efficient in eliminating most joint damage but not able to cure the disease or stop needs for continuous treatment of the disease. Less effort has been spent on identifying and implementing ways to prevent the disease. We argue in this review that knowledge concerning the longitudinal evolvement of the major, 'seropositive' subset of RA has now come to a stage where prevention should be a large part of the research agenda and that we should prepare for prevention as part of clinical practice in RA. We describe briefly the knowledge basis for broad public health-based prevention as well as for a 'precision prevention' strategy. In the latter, individuals at high risk for RA will be identified, monitored, and ultimately provided with advice on how to change lifestyle/environment or be given treatment with drugs able to delay and ultimately stop the development of RA. Whether this potential of precision prevention for RA will change the broader clinical practice will depend on whether specific and long-lasting interference with disease-inducing immunity, ultimately 'tolerance therapy', will become a reality.

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes.

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82-0.89, p = 1.22 × 10-29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66-0.76, p = 9.07 × 10-17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

A genome-wide cross-trait analysis identifies genomic correlation, pleiotropic loci, and causal relationship between sex hormone-binding globulin and rheumatoid arthritis.

BACKGROUND: Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. METHODS: Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; Noverall = 368,929; Nmen = 180,094; Nwomen = 188,908), crude SHBG (Noverall = 370,125; Nmen = 180,726; Nwomen = 189,473), and RA (Ncase = 22,350; Ncontrol = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. RESULTS: Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ([Formula: see text] = 0.11, P = 1.0 × 10-4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01-1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997-1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. CONCLUSION: Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.

Genome-wide investigation of persistence to treatment with methotrexate in early rheumatoid arthritis.

OBJECTIVES: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy. METHODS: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. RESULTS: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. CONCLUSIONS: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.

Inverse association between Mediterranean diet and risk of multiple sclerosis.

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.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which and Epstein-Barr virus (EBV) infection is a likely prerequisite. Due to the homology between Epstein-Barr nuclear antigen 1 (EBNA1) and alpha-crystallin B (CRYAB), we examined antibody reactivity to EBNA1 and CRYAB peptide libraries in 713 persons with MS (pwMS) and 722 matched controls (Con). Antibody response to CRYAB amino acids 7 to 16 was associated with MS (OR = 2.0), and combination of high EBNA1 responses with CRYAB positivity markedly increased disease risk (OR = 9.0). Blocking experiments revealed antibody cross-reactivity between the homologous EBNA1 and CRYAB epitopes. Evidence for T cell cross-reactivity was obtained in mice between EBNA1 and CRYAB, and increased CRYAB and EBNA1 CD4+ T cell responses were detected in natalizumab-treated pwMS. This study provides evidence for antibody cross-reactivity between EBNA1 and CRYAB and points to a similar cross-reactivity in T cells, further demonstrating the role of EBV adaptive immune responses in MS development.

Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression.

We aimed to study the influence of smoking habits, exposure to passive smoking and snuff use on disease progression, cognitive performance and quality of life in patients with multiple sclerosis (MS). METHOD: Patients from two population-based case-control studies were categorised based on tobacco exposure at diagnosis and were followed up to 15 years post diagnosis through the Swedish MS registry (n=9089) regarding changes in Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale 29 and Symbol Digit Modalities Test. We used linear mixed models to analyse long-term changes, and Cox regression models with 95% CI using 24-week confirmed disability worsening, reaching EDSS 3 and EDSS 4, respectively, physical and psychological worsening and cognitive disability worsening as end points. The influence of smoking cessation post diagnosis was also investigated. RESULTS: Compared with non-smokers, current smokers had a faster EDSS progression (ßcurrent smoking×time=0.03, 95% CI 0.02 to 0.04). A faster EDSS progression was also associated with passive smoking (ßcurrent passive smoking×time=0.04, 95% CI 0.03 to 0.06). Smoke exposure negatively impacted all secondary outcomes. Those who continued smoking had worse outcomes than those who stopped smoking post diagnosis. Snuff users had a more favourable EDSS progression, compared with never users. CONCLUSIONS: Our findings indicate that both smoking and passive smoking have a negative influence on MS and that smoking cessation post diagnosis may be an important secondary preventive measure. Snuff use was associated with slower disease progression, suggesting that nicotine replacement therapy could be an attractive way to increase the chance of quitting smoking among patients with MS.

Incidence of LADA and Type 2 Diabetes in Relation to Tobacco Use and Genetic Susceptibility to Type 2 Diabetes and Related Traits: Findings From a Swedish Case-Control Study and the Norwegian HUNT Study.

OBJECTIVE: Smoking and Swedish smokeless tobacco (snus) are associated with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Our aim was to investigate whether genetic susceptibility to T2D, insulin resistance (IR), and insulin secretion (IS) aggravate these associations. RESEARCH DESIGN AND METHODS: We used data from two population-based Scandinavian studies with case subjects with LADA (n = 839) and T2D (n = 5,771), matched control subjects (n = 3,068), and 1,696,503 person-years at risk. Pooled, multivariate relative risks (RR) with 95% CI were estimated for smoking/genetic risk scores (T2D-GRS, IS-GRS, and IR-GRS), and ORs for snus or tobacco/GRS (case-control data). We estimated additive (proportion attributable to interaction [AP]) and multiplicative interaction between tobacco use and GRS. RESULTS: The RR of LADA was elevated in high IR-GRS heavy smokers (≥15 pack-years; RR 2.01 [CI 1.30, 3.10]) and tobacco users (≥15 box/pack-years; RR 2.59 [CI 1.54, 4.35]) compared with low IR-GRS individuals without heavy use, with evidence of additive (AP 0.67 [CI 0.46, 0.89]; AP 0.52 [CI 0.21, 0.83]) and multiplicative (P = 0.003; P = 0.034) interaction. In heavy users, there was additive interaction between T2D-GRS and smoking, snus, and total tobacco use. The excess risk conferred by tobacco use did not differ across GRS categories in T2D. CONCLUSIONS: Tobacco use may confer a higher risk of LADA in individuals with genetic susceptibility to T2D and insulin resistance, whereas genetic susceptibility does not seem to influence the increased T2D incidence associated with tobacco use.