عنوان

Examining the Biological Mechanisms Underlying the Relationship Between Obesity and Multiple Sclerosis Susceptibility

شماره

TL5qt4t8n8

زبان متن نوشتاري يا گفتاري و مانند آن

انگلیسی

عنوان اصلي

Examining the Biological Mechanisms Underlying the Relationship Between Obesity and Multiple Sclerosis Susceptibility

نام عام مواد

[Thesis]

نام نخستين پديدآور

Gianfrancesco, Milena

نام ساير پديدآوران

Barcellos, Lisa F

تاریخ نشرو بخش و غیره

2016

کسي که مدرک را اعطا کرده

Barcellos, Lisa F

امتياز متن

2016

متن يادداشت

Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects over 400,000 Americans and 2.5 million people worldwide. It is characterized by the presence of inflammation, neurodegeneration, and demyelinating lesions of white and gray matter. Both genetic and environmental factors have been implicated in MS etiology. Several genetic variants, including the human leukocyte antigen HLA-DRB1*15:01 allele within the major histocompatibility complex (MHC) and 110 non-MHC variants, have been identified. Environmental risk factors associated with MS onset include exposure to tobacco smoke, Epstein-Barr virus or infectious mononucleosis, low levels of vitamin D, and most recently, obesity. Obesity is a current public health problem around the world; approximately 35% of adults in the U.S. are obese. Further, obesity has more than doubled in children and quadrupled in adolescents over the past 30 years. Studies over the last decade have demonstrated that early childhood and adolescent obesity are significant risk factors for MS susceptibility. Therefore, the increasing prevalence of obesity could potentially be contributing to higher rates of MS in children and adults. Methods In this dissertation, I investigate the association between obesity and MS in several manners in order to understand the causal relationship and underlying biological relationship between these factors. In the first chapter, I examine whether self-reported body size during childhood and adolescence is associated with MS susceptibility, while controlling for several established genetic and environmental risk factors. In the second chapter, I utilize Mendelian randomization to estimate the causal relationship between obesity and MS using a weighted body mass index genetic risk score (BMI GRS) of 97 variants previously identified to be associated with BMI. Additionally, I demonstrate evidence of protein-protein interactions between established gene regions associated with both BMI (n=97) and MS disease susceptibility (n=110), and that a subset of these are significantly associated with MS after adjusting for covariates. In the third chapter, I again examine the causal relationship between obesity and MS onset but instead focus on pediatric-onset MS (disease onset < 18 years). In addition, I examine whether a causal relationship between vitamin D and MS exists in pediatric-onset MS cases and controls, and whether BMI and vitamin D independently contribute to pediatric-onset MS susceptibility. Lastly, in chapter four, I identify genome-wide significant variants associated with serum levels of three adipokines to measure their relationship with MS: plasma soluble leptin receptor, adiponectin, and resistin. Significance This dissertation examines the complex contribution of obesity to MS susceptibility while accounting for other genetic and environmental risk factors for the first time. My findings establish strong evidence for potential underlying biological mechanisms between increased BMI and MS, identify potential genetic pathways that may be targeted for therapeutics, and indicate that interventions focusing on obesity prevention could in turn reduce the incidence of MS in the population.

مستند نام اشخاص تاييد نشده

Wang, Yehong

مستند نام اشخاص تاييد نشده

Gianfrancesco, Milena

مستند نام تنالگان تاييد نشده

UC Berkeley

نام الکترونيکي

فرمت انتشار

p

نوع ماده

[Thesis]

کد کاربرگه

276903

سطح دسترسي

a

تكميل شده

Y