Distinct and shared genetic architectures of Gestational diabetes mellitus and Type 2 Diabetes Mellitus.

Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 diabetes (T2D). The diseases are hypothesized to share a genetic predisposition, but there are few GWAS studies of GDM and none of them is sufficiently powered to assess whether any variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen Study and identified 13 GDM-associated loci including 8 novel loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into two distinct categories - one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis, and placental expression. These results pave the way for an improved biological understanding of GDM pathophysiology and its role in the development and course of T2D.

Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Usefulness of internet in adolescent mental health outpatient care.

Internet has become increasingly common in adolescents' daily lives and also in health care. However, there is still need to explore how nurses perceive its use as a part of adolescents' treatment. This explorative qualitative study aim was to explore how nurses perceive the usefulness of Internet in adolescents' outpatient care in mental health. The data were collected among nurses (n=12) working in two psychiatric adolescent outpatient clinics in university central hospitals in Finland. The data were collected in focus group interviews and analysed using inductive content analysis. The analysis showed that Internet use could promote the care process of adolescents with depression by supporting their self-reflection and self-management, enhancing nurses' understanding of adolescents' daily lives and facilitating nurse-adolescent interaction. Disadvantages identified among nurses were fear of role changes in the nurse-adolescent interaction, changes in the intervention, when Internet might be a third party in the face-to-face interaction and negative effects of Internet on adolescents. Facilitators in the use of Internet were nurses' positive attitude to Internet, knowledge and experiences of Internet usage. Nurses' negative attitude to Internet and lack of training and instructions were seen as barriers in promoting the successful utilization of Internet among adolescents with depression in outpatient care.

Serum highly sensitive C-reactive protein in preterm premature rupture of membranes.

OBJECTIVE: Low-grade inflammation may raise serum C-reactive protein (CRP) concentrations. We studied whether serum CRP is altered in preterm premature rupture of membranes (PPROM), which is frequently associated with an asymptomatic intrauterine infection. STUDY DESIGN: CRP was quantitated with highly sensitive immunofluorometric (IFMA) and immunoenzymometric (IEMA) assays in 32 women with PPROM at 30.7+/-0.4 gestational weeks (mean+/-standard error of the mean) and in 27 gestational age-matched healthy women. The results were compared to those obtained by the conventional immunoturbidimetric method. RESULTS: Twenty-three PPROM patients had a normal CRP value (

Waterborne outbreak of Campylobacter enteritis after outdoors infantry drill in Utti, Finland.

Diarrhoea, abdominal pain, malaise and fever affected 75 of the 88 conscript soldiers in Utti, Finland after an outdoors infantry drill. Campylobacter jejuni, heat-stable serotype 3/43/59, was isolated from 37 out of 63 men investigated. A clear serological response was evident in the risk group and negligible in the control group. The entire population at risk was interviewed. The outbreak was associated with the consumption of untreated surface water. C. jejuni, heat-stable serotype 3/43/59, was isolated on two occasions from the water source.