BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a... Show moreBACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 x 10(-6) ) and a candidate threshold (1.6 x 10(-4) ).RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLAB*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99).CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes. Show less
Johnsen, G.M.; Storvold, G.L.; Drabbels, J.J.M.; Haasnoot, G.W.; Eikmans, M.; Spruyt-Gerritse, M.J.; ... ; Stafr, A.C. 2018
Acute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral... Show moreAcute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral arteries in the decidua basalis layer of the pregnant uterus. This layer forms the fetal-maternal immunological interface, where fetal extravillous trophoblasts interact with maternal immune cells to promote decidual spiral artery remodeling and maternal immune tolerance towards the fetus. Of the classical polymorphic class I HLAs, extravillous trophoblasts express only HLA-C. HLA-C is a ligand for killer immunoglobulin-like receptors (KIR) on NK- and T-cells. Genetic combinations of fetal HLA-C and maternal KIRs affect pregnancy outcome. However, the role of HLA and KIR genes in acute atherosis is unknown.We hypothesized that specific genetic combinations of fetal HLA and maternal KIR are associated with the presence of acute atherosis lesions in the decidua basalis. We genotyped HLA class-I and II loci in paired fetal and maternal DNA samples from 166 pregnancies (83 preeclamptics, 83 controls). Acute atherosis was identified in 38 of these. Maternal KIR-loci were also genotyped.We found that the combination of maternal KIR-B haplotype and fetal HLA-C2 was significantly associated with acute atherosis in preeclampsia. In preeclamptic pregnancies with acute atherosis, 60% had this combination, compared to 24.5% in those without acute atherosis (p = 0.001). We suggest that interactions between fetal HLA-C2 and activating KIRs on maternal decidual NK-cells or T-cells may contribute to the formation of acute atherosis by promoting local decidual vascular inflammation. Show less
Several years ago we embarked on a journey, aiming to identify the molecular mechanisms of candidate risk genes for type 1 diabetes (T1D), focusing on their role in disease pathogenesis. In this... Show moreSeveral years ago we embarked on a journey, aiming to identify the molecular mechanisms of candidate risk genes for type 1 diabetes (T1D), focusing on their role in disease pathogenesis. In this context, we studied phenomena of T1D with clinical relevance in great detail and aimed to find genetic correlates of these. This thesis can be considered the clinical chapter of this journey providing validation and extension of several clinically relevant gene polymorphisms with functional consequences in relation to growth (INS-VNTR, IGF1, disease progression and remission (IFN-_, IL-10,), islet autoimmunity (INS-VNTR), and environment (Lewis). We found: Increased early growth, rather than birth weight, to be a risk factor for T1D; Accelerated growth preceding T1D is limited to early life i.e. to the 1st year of life ; Early in life and in contrast to the INS-VNTR, an IGF-1 variant is associated with T1D via accelerated growth ; Remission or disease progression is at least partially immune-mediated ; IFN-_ levels, along with their corresponding genotypes, could be valuable in predicting (partial) clinical remission at clinical onset of diabetes ; T1D disease mechanisms appear to overrule genetic influences in disease progression. Show less
