Neonatal screening in Sweden and disease-causing variants in phenylketonuria, galactosaemia and biotinidase deficiency

Phenylketonuria, galactosaemia and biotinidase deficiency were the first three inborn errors of metabolism to be included in the Swedish programme. This thesis describes these conditions with an emphasis on screening performance and disease-causing genetic variants in the patients. Classical galactosaemia (GALT deficiency) is caused by a defect in the conversion of galactose-1-phosphate and UDP-glucose to glucose-1-phosphate and UDP-galactose, resulting in accumulation of toxic levels of galactose-1-phosphate and a deficiency of UDP-galactose. Early treatment prevents severe sequelae and life-threatening infections. The incidence of GALT deficiency in Sweden is 1/100 000, which is lower than the reported incidences for other European countries. The Swedish NBS programme has high sensitivity and specificity, with a positive predictive value (PPV) of approximately 0.5. The increase in PPV was achieved after the decision to adjust the recall level in order to avoid detection of milder variants, which probably do not require treatment. The genetic studies revealed pathogenic variants on both alleles in all patients with GALT deficiency. Only a few variants were found in more than one patient, with the most cited variant, p.Gln188Arg, occurring most frequently. A high proportion of the variants have not been described before. Women with GALT deficiency who have been fortunate enough to become mothers have been recommended not to breast-feed because of the increase in toxic galactose metabolites seen at the end of pregnancy and after delivery. We observed the same increase, but the levels returned to normal within three weeks after birth in two consecutive pregnancies, in a woman who chose to breast-feed her babies. Our findings have been confirmed by other groups and women with GALT-deficiency are no longer discouraged to breast-feed. Phenylketonuria (PKU) is caused by a defect in the conversion of the amino acid phenylalanine (Phe) to tyrosine (Tyr). Without treatment, patients develop mental retardation. Inclusion of the Phe/Tyr ratio has decreased the number of false positive screening outcomes to the present PPV of 0.92 without any known missed cases. The recall levels have been lowered several times since the start of screening. An increase in the incidence of patients with milder disease has been observed with time. We were able to show that the impact of the adjusted recall levels was low. Instead, milder genetic variants, which are more common in Southern Europe, are found more often, which is an effect of the large number of non-Nordic immigrants who have come to Sweden during the last 25 years. The immigration has widened the spectrum of detected pathogenic variants. Biotinidase deficiency (BD) is a rare disorder affecting the recycling of the vitamin biotin. The most common symptoms are unspecific and progressive with eczema, hair loss and delayed psychomotor development. The majority of patients remained unrecognised before the introduction of screening. With NBS, the incidence of BD in Sweden is the same as in other Western countries (1/60 000). With adjustments of initial recall levels, virtually only infants with profound BD are detected in the screening programme. Disease-causing variants were detected in all alleles, with p.Thr532Met occurring most frequently. In conclusion, the Swedish screening programme for PKU, galactosaemia and BD is well-functioning with an internationally comparatively low rate of false positive outcomes. Future research will tell if attenuated forms of the disorders, that are not targets in the Swedish programme, may benefit from early detection and ought to be included in the programme

Heterogeneity of disease-causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants

The aim was to determine disease-causing variants in the GALT gene which codes for the enzyme galactose-1-phosphate uridylyltransferase. Loss of activity of this enzyme causes classical galactosemia-a life threatening, treatable disorder, included in the Swedish newborn screening program since 1967. A total of 66 patients with the disease are known in Sweden and 56 index patients were investigated. An additional two patients with Duarte galactosemia were included. The disease-causing variants were identified in all patients. As reported from other countries only a few variants frequently recur in severe disease. The two variants p.(Gln188Arg) (c.563A\u3eG) and p.(Met142Lys) (c.425T\u3eA) are present in several index patients whereas the remaining are found in one to three patients each. The most common variant, p.(Gln188Arg), has an allele frequency of 51% in the cohort. A total of 16 novel variants were found among the 33 different variants in the cohort. Two of these are synonymous variants affecting splicing, demonstrating the importance of the evaluation of synonymous variants at the cDNA level. Concise sentence: Galactosemia is a rare disease in Sweden and the disease-causing variants are heterogenous including two synonymous variants

Konsumenters påverkan av lojalitetsprogrammens framväxt

Course: FEKH29 Business Administration: Bachelor thesis in Marketing, Undergraduate Level, 15 ECTS Authors: Sophie Jensen, Annika Klaus, Fredrik Ohlsson Advisor: Clara Gustafsson Key words: Loyalty, Loyalty program, consumer behavior, impact & customer club Purpose: The purpose of this study is to improve the understanding of how a younger target group respectively an older target group influences of a membership in a loyalty program and if there are any differ-ences between these target groups. Methodology: The research strategy for this study is a quantitative approach and a deductive process to formulate hypotheses. The collection of data was made through a survey where the respondents were about to answer questions regarding the theories on a seven-grade likertscale. Theoretical Perspectives: The theoretical framework is taking point from the four theories; instrumental learning, perception and status, Word-of-Mouth and the self. These theories were later on put against the empirical foundations. Empirical foundations: The empirical data is based on a survey and was answered by 147 respondents, both men and women in the two chosen target groups. Conclusion: The conclusion we found in the study is that the younger target group, as well as the older target group, do not see social status as something important, and are not being influenced by it, regarding to loyalty programs. Consuming in a way to strengthen the self is neither something that is influencing the target groups. On the oth-er hand, the both target groups are being influenced of Word-of-Mouth, since both can imagine recommending a loyalty program to other consumers. The learning process of a loyalty program do also influence both target groups if companies are offering reward systems. No differences is seen between these two target groups

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions