HLA genetics in multiple sclerosis

Multiple sclerosis (MS) is a chronic disease in which both genetic and environmental risk factors contribute to disease susceptibility. MS patients suffer from inflammatory lesions in the central nervous system which results in demyelination of nerve cells, reduced neuronal activity and finally neurodegeneration. The immune system has a central role in MS pathogenesis and human leukocyte antigen (HLA) molecules are key players. The genes encoding HLA class I and II molecules are highly polymorphic isotypically and allotypically which makes it problematic to identify which variants affect disease susceptibility. The strongest genetic risk factor for MS is a haplotype of HLA class II alleles, DRB1*15:01,DRB5*01:01,DQA1*01:02,DQB1*06:02 (below referred to as DRB1*15) which increases the risk of MS 3-fold compared with the general Swedish population where the lifetime risk of MS is 0.2%. Our group pioneered the identification of a protective effect of the HLA class I region, by discovering that HLA-A*02 decreases the risk of MS by 40%. The main focus in this thesis has been to identify additional HLA factors, if any, that influence MS susceptibility. In papers I and II we genotyped 1,784 Swedish and Norwegian MS patients and 1,660 controls, for HLADRB1, HLA-A, HLA-C, and eventually also HLA-B, and applied several statistical methods, mainly logistic regression analyses. We conclude that, in addition to the roles played by DRB1*15 and HLA-A*02, additional influence on susceptibility is exerted by HLA-DRB1*01, HLA-DRB1*07 and HLA-B*12, which are negatively associated with MS and HLA-B*14 which increases the risk of MS. Analysis based on haplotypes, rather than on alleles, showed that a haplotype carrying HLA-A*02, HLA-C*05 and HLA-B*12 is markedly protective, reducing the risk of MS 2.4-fold, also outweighing the risk of HLA-DRB1*15 when present on the same haplotype. Paper III focuses on a possible interaction between genetic background (DRB1*15) and an environmental influence, a month-of-birth effect on MS risk. We demonstrate that patients born in April have a higher risk of being DRB1*15 positive. On the contrary, patients born in November have a lower risk of being DRB1*15 positive. We hypothesize that pregnancies exposed to a lower degree of sunlight thus lower levels of Vitamin D, confer an increased risk for a DRB1*15 positive child to later develop MS. In paper IV the influence of HLA genes on the risk of developing neutralizing antibodies (NAbs) to interferon beta (IFN-β) treatment was studied. We show that the risk allele for MS, HLA-DRB1*15, is also a risk factor for development of NAbs in patients treated with high dose subcutaneously administered IFN-β 1-a, but not for IFN-β 1-b. DRB1*15 is also a risk factor for developing antibody titers high enough to abolish the effect of treatment. Thus, the genetic risk of NAbs varies with IFN-β formulation. This thesis adds several pieces of information to the large MS genetics puzzle and suggests several roles of HLA genes and molecules that should be further investigate

Genetic Basis for Sex Differences in Obesity and Lipid Metabolism

Men and women exhibit significant differences in obesity, cardiovascular disease, and diabetes. To provide better diagnosis and treatment for both sexes, it is important to identify factors that underlie the observed sex differences. Traditionally, sex differences have been attributed to the differential effects of male and female gonadal secretions (commonly referred to as sex hormones), which substantially influence many aspects of metabolism and related diseases. Less appreciated as a contributor to sex differences are the fundamental genetic differences between males and females, which are ultimately determined by the presence of an XX or XY sex chromosome complement. Here, we review the mechanisms by which gonadal hormones and sex chromosome complement each contribute to lipid metabolism and associated diseases, and the current approaches that are used to study them. We focus particularly on genetic approaches including genome-wide association studies in humans and mice, -omics and systems genetics approaches, and unique experimental mouse models that allow distinction between gonadal and sex chromosome effects

Technology Challenge

The 1998 MTTA Technology ChallengeThe MTTA (The Machine Tool Technologies Association) Technology Challenge featured 37 schools and partner companies working together on manufacturing-based projects throughout the year. Each school teamed up with a local company to work on the Challenge, starting off their projects with industrial visits. The children that took part in the Challenge were aged between 8-11 years, the aim being to excite the younger generation about the opportunities available to them in engineering. MTTA supports the view that it is important to ensure that teachers have the knowledge to further inspire and nurture the children's interest. Teacher training days are organised to assist this, enabling teachers to experience the importance of engineering skills to industry

Metabolic impact of sex chromosomes.

Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement-independently from gonadal sex-plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease

Metabolic impact of sex chromosomes

Obesity and associated metabolic diseases are sexually dimorphic. To provide better diagnosis and treatment for both sexes, it is of interest to identify the factors that underlie male/female differences in obesity. Traditionally, sexual dimorphism has been attributed to effects of gonadal hormones, which influence numerous metabolic processes. However, the XX/XY sex chromosome complement is an additional factor that may play a role. Recent data using the four core genotypes mouse model have revealed that sex chromosome complement—independently from gonadal sex—plays a role in adiposity, feeding behavior, fatty liver and glucose homeostasis. Potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. Here we review recent data in mice and humans concerning the potential impact of sex chromosome complement on obesity and metabolic disease

Cell-autonomous sex determination outside of the gonad

The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes. Results: Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high-fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes. Conclusions: Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

ObjectiveWe sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.MethodsWe conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.ResultsFindings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.ConclusionsThese results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors

Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes

Objective— The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. Approach and Results— We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male–female gonadal sex and XX–XY chromosome complement. Gonadectomy of adult mice revealed that the male–female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male–female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. Conclusions— We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results

Antibodies; Interferon beta; Multiple sclerosisAnticossos; Interferó beta; Esclerosi múltipleAnticuerpos; Interferón beta; Esclerosis múltipleAntibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA