Collectively autoimmune diseases constitute a major burden to society. Though the etiology of autoimmune diseases remain largely unknown, evidence supports a substantial genetic component. For many autoimmune diseases, twin studies demonstrate a dramatically higher disease concordance rate in monozygotic twins than in dizygotic twins. Genes in the major histocompatibility complex (MHC) region on the short arm of chromosome 6, particularly the human leukocyte antigen (HLA) class II genes, are strongly associated with risk of developing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D).

The MHC class II transactivator gene (CIITA, also called MHC2TA), located on the short arm of chromosome 16, encodes an important transcription factor (CIITA) regulating the genes required for HLA class II MHC-restricted antigen presentation. Thus CIITA is a strong biological candidate for studies of autoimmune disease. Directly adjacent to CIITA lies the C-type lectin domain family 16, member A gene (CLEC16A, previously called KIAA0350). CLEC16A is a sugar binding receptor containing a putative immunoreceptor and was recently identified as a novel T1D and MS susceptibility locus through genomewide association (GWA) studies.

HLA may also influence susceptibility to autoimmune disease through other inherited and noninherited mechanisms, in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA compatibility and differences in both maternal vs. paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen (NIMA) effects) in autoimmune diseases have been reported.

The investigation described in this dissertation tested hypotheses that (1) the CIITA -168A/G promoter polymorphism (rs3087456) influences susceptibility to RA (Chapter 2); (2) common genetic variation in CIITA influences susceptibility to RA in a case-control study (Chapter 3); (3) common genetic variation in CIITA influences susceptibility to SLE or specific secondary SLE phenotypes (Chapter 4); (4) common genetic variation in CIITA influences susceptibility to MS (Chapter 5); (5) common genetic variation in CLEC16A influences susceptibility to RA (Chapter 6); (6) the HLA class II DRB1 locus influences susceptibility to SLE through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 7); and (7) the HLA classical loci influence susceptibility to T1D through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 8).

This dissertation includes the first study to fully characterize common genetic variation in CIITA and CLEC16A, including assesment of haplotypes, sex-specific effects, secondary clinical phenotypes and HLA risk alleles. Results do not provide evidence for association between CIITA and RA or SLE or for association between CLEC16A and RA. Interestingly, this study revealed evidence for an association between the CIITA missense mutation rs4774 and increased risk for MS in the presence of the HLA-DRB1*1501 risk allele. There was no linkage disequilibrium between CIITA and CLEC16A, and the observed association between CIITA and MS in the presence of HLA-DRB1*1501 was independent of the association between CLEC16A and MS.

The first studies to examine maternal-offspring HLA compatibility in T1D and HLA-DRB1 parent-of-origin and NIMA effects in SLE, and the largest study to examine maternal-offspring HLA compatibility in SLE and HLA parent-of-origin and NIMA effects in T1D were also performed. No evidence that the HLA-DRB1 locus influences risk for SLE or that the classical HLA loci influence risk for T1D through these novel biological phenomena was revealed.

Introduction: The purpose of the study was to measure national prescribing patterns for hydrocodone/acetaminophen among veterans seeking emergency medical care, and to see if patterns have changed since this medication became a Schedule II controlled substance.

Methods: We conducted a retrospective cohort study of emergency department (ED) visits within the Veterans Health Administration (VA) between January 2009 and June 2015. We looked at demographics, comorbidities, utilization measures, diagnoses, and prescriptions.

Results: During the study period, 1,709,545 individuals participated in 6,270,742 ED visits and received 471,221 prescriptions for hydrocodone/acetaminophen (7.5% of all visits). The most common diagnosis associated with a prescription was back pain. Prescriptions peaked at 80,776 in 2011 (8.7% of visits), and declined to 35,031 (5.6%) during the first half of 2015 (r=‒0.99, p<0.001). The percentage of hydrocodone/acetaminophen prescriptions limited to 12 pills increased from 22% (13,949) in 2009 to 31% (11,026) in the first half of 2015. A prescription was more likely written for patients with a painscore≥7 (OR 3.199, CI [3.192‒3.205]), a musculoskeletal (OR 1.622, CI [1.615‒1.630]) or soft tissue(OR 1.656, CI [1.649‒1.664]) diagnosis, and those below the first quartile for total ED visits (OR 1.282, CI [1.271‒1.293]) and total outpatient ICD 9 codes (OR 1.843, CI [1.833‒1.853]).

Conclusion: Hydrocodone/acetaminophen is the most frequently prescribed ED medication in the VA. The rate of prescribing has decreased since 2011, with the rate of decline remaining unchanged after it was classified as a Schedule II controlled substance. The proportion of prescriptions falling within designated guidelines has increased but is not at goal.

The epikarst crustacean fauna from four Sicilian caves (Conza, Entella, Molara, and Zubbia del Cavallo caves) and four caves in the Lessinian Massif in the Venetian Prealps (Covolo della Croce, Ponte di Veja, Roverè Mille, Buso della Rana caves) was recently investigated. The two groups of caves differ in their environmental conditions: the Sicilian caves are fossil except one which has an active branch; they are all fed by strongly intermittent and scarce rainfall peaking in the fall. The Lessinian caves are fed by more abundant rainfall, with two yearly peaks (May-June and October-November); two of them are active, one has a temporary stream, one is fossil. The crustacean fauna found in the epikarst drip of each of the studied caves is characterized by interesting endemic harpacticoid and cyclopoid copepods, and one bathynellacean syncarid, often collected in only one cave. Higher diversity of stygobiotic taxa was recorded for the Lessinian caves (9 species of copepods in the Lessinian, and 6 species of copepods and one bathynellacean in Sicily); most of the taxa collected in Sicily are endemic to one cave. Spatial analysis showed very different distributions over short spatial scales (tens of kilometers) and, within each cave, the distribution also varied over distances of a few meters. Our data correspond with other studies where many epikarst crustaceans showed a distribution with a linear extent of only a few hundred meters: the epikarst fauna is not uniformly distributed but rather divided in “blocks” probably characterized by different environmental conditions and, as a consequence, by different taxocoenoses. The data highlight the epikarst as a source of “hidden” biodiversity, and the importance of management protection plans which include not only the caves, but also the epikarst overlying layer and the water sources that feed it.