Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis.
OBJECTIVE
We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).


METHODS
We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression. Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction.


RESULTS
In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5-35.2) compared to nonobese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13.8 (95% CI 4.1-46.8).


CONCLUSIONS
We observed striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule-restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.
From the Institute of Environmental Medicine (A.K.H.), Neuroimmunology Unit, Department of Clinical Neuroscience (I.L.B., I.K.), and the Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm, Sweden; Genetic Epidemiology and Genomics Lab (L.B., M.G.), Division of Epidemiology, School of Public Health, University of California, Berkeley; Kaiser Permanente Division of Research (C.S.), Oakland, CA; Center for Molecular Medicine (I.K.) and Neuroimmunology Unit, Department of Clinical Neuroscience and Center for Molecular Medicine (T.O.), Karolinska Institutet at Karolinska University Hospital, Solna; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
Anna Karin
AK
Hedström
Izaura
I
Lima Bomfim
Lisa
L
Barcellos
Milena
M
Gianfrancesco
Catherine
C
Schaefer
Ingrid
I
Kockum
Tomas
T
Olsson
Lars
L
Alfredsson
D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015789:HLA-A2 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D063766:Pediatric Obesity / Q000453:epidemiology / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
D015789:HLA-A2 Antigen; D059811:HLA-DRB1 Chains