Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis

Abstract

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.

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

“…Several studies have shown that obesity in the adolescent years, but not the adult years, is a risk factor for MS 7, 8, 9, 10, 11. This study further emphasizes this trend and confirms a role of obesity in development of pediatric‐onset MS.…”

“…In parallel, there is increasing evidence that obesity during adolescence is associated with a higher risk of MS in adults 7, 8, 9, 10, 11. In children, one study found an effect of obesity in girls but not in boys;12 however, a smaller number of male cases may have limited the ability to detect an effect.…”

Review on Recent Advances in Multiple Sclerosis and Related Disorders

“…Adipose tissue produces and releases a variety of pro-inflammatory cytokines, including leptin, which promotes Th1 responses and reduces regulatory T-cell activity. Researchers have recently published data from a new study comprising two large populations of MS patients and controls, confirming the previously described association between obesity in early life and increased risk of developing MS [4]. Using a Swedish population-based case-control study as well as an American case-control study, the authors observed striking interactions between body mass index status and human leukocyte antigen (HLA)-DRB1*15 allele, the gene most strongly associated with MS, with regards to MS risk.…”

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

“…A couples of studies showed that the presence of HLA-DRB1*15 and absence of HLA-A*02 in obese or smoking patients increases the risk of MS (OR= 16.2 and 13.5, respectively), while the absence of those genotype correlated with a much lower risk (OR=3.7 and 1.4, respectively) [76,77]. If anything, this indicates that the presence of HLA-A*02 may confer resistance to provocative stimulation through obesity or smoking in MS. HLA-C*05 belongs to group 2 of HLA-C alleles that interact with killer immunoglobulin-like receptors (KIR) [78].…”