Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy.

BACKGROUND: Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated. METHODS: We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes. RESULTS: We observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy-associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms ε and ι) and protein tyrosine kinase 2. CONCLUSIONS: Our comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets.

Like me, like you - relative importance of peers and siblings on children's fast food consumption and screen time but not sports club participation depends on age.

BACKGROUND: Lifestyle interventions to prevent paediatric obesity often target family and peer settings; their success is likely to depend on the influence that peers and families exert on children's lifestyle behaviors at different developmental stages. OBJECTIVE: First, to determine whether children's lifestyle behavior more closely resembles their peers' or siblings' behaviors. Secondly, to investigate longitudinally whether children's behavioral change is predicted by that of their peers or their siblings as they grow older. METHODS: The European prospective IDEFICS/I.Family cohort (baseline survey: 2007/2008, first follow-up: 2009/2010, and second follow-up: 2013/2014) aims at investigating risk factors for overweight and related behaviors during childhood and adolescence. The present investigation includes 2694 observations of children and their siblings aged 2 to 18 years. Peers were defined as same-sex, same-age children in the same community and identified from the full cohort. The longitudinal analysis (mean follow-up time: 3.7 years) includes 525 sibling pairs. Children's lifestyle behaviors including fast food consumption (frequency/week), screen time (hours/week) and sports club participation (hours/week) were assessed by questionnaire. Data were analyzed using multilevel linear models. RESULTS: Children's lifestyle behavior was associated with the respective behavior of their peers and sibling for all 3 behaviors. For fast food consumption, the peer resemblance was more than 6-fold higher than the sibling resemblance and the peer resemblance surpassed the sibling resemblance by the age of 9-10 years. The similarities with peers for fast food consumption and screen time steadily increased, while the similarities with siblings steadily decreased with increasing age of the children (Pinteraction < 0.001). In contrast, the relative importance of peers and siblings on sports club duration did not vary by the age of the children. Longitudinal results showed that children's changes in fast food consumption were more strongly associated with those in their peer group than their sibling, in particular if the age gap between siblings was large. CONCLUSION: In conclusion, our results support the implementation of multi-setting interventions for improving lifestyle behaviors in children. Our findings might also guide future intervention studies in the choice of timing and setting in which interventions are likely to be most effective. From the ages of 9-10 years onwards, family- or home-based interventions targeting children's fast food intake and screen time behavior may become less effective than school- or community-based interventions aimed at peer groups.

Genotype frequency and use of single nucleotide polymorphisms for detection of informative allele by polymerase chain reaction.

OBJECTIVE: To determine genotype frequency of biallelic single nucleotide polymorphisms and its use in detection of informative allele in donor/recipient pairs (sibling pairs) having undergone haematopoietic stem cell transplantation with various haematological disorders using a PCR based method. METHODS: This descriptive study was conducted at GRC Lab Rawalpindi from Jan 2018- Oct 2019.A total of twenty donor/ recipient pairs (sibling pairs) were studied for genotype frequency and informativeness of single nucleotide polymorphisms. Genomic DNA was extracted from the peripheral blood and amplification of single nucleotide polymorphisms was done by PCR based method. The amplified DNA was seen by electrophoresis on 6% polyacrylamide gel. RESULTS: A sharp band of DNA on the polyacrylamide gel indicated a positive reaction. At least two or more informative SNP markers were found in every sibling pair. CONCLUSION: Our results demonstrate that PCR amplification of polyacrylamide gel electrophoresis using single nucleotide polymorphism has allowed the successful screening and detection of informative allele in all the donor/recipient pairs. (Sibling pairs). This PCR based assay using SNPs appears to be a quick, simple, reliable and technically feasible method for a use in a Pakistani setting.

A within-sibling pair analysis of lifestyle behaviours and BMI z-score in the multi-centre I.Family study.

BACKGROUND AND AIMS: By investigating differences in lifestyle behaviours and BMI in sibling pairs, family-level confounding is minimized and causal inference is improved, compared to cross-sectional studies of unrelated children. Thus, we aimed to investigate within-sibling pair differences in different lifestyle behaviours and differences in BMI z-scores in children and adolescents. METHODS AND RESULTS: We examined three groups of sibling pairs 1) all same-sex sibling pairs with maximum 4 years age difference (n = 1209 pairs from 1072 families in 8 countries, mean age 10.7 years, standard deviation 2.4 years), 2) sibling pairs discordant for overweight (n = 262) and 3) twin pairs (n = 85). Usual dietary intake was estimated by 24-h recalls and time spent in light (LPA) and moderate-to-vigorous physical activity (MVPA) was measured by accelerometers. Screen time, sleep and dieting for weight loss were assessed by questionnaires. Within all 3 groups of sibling pairs, more time in MVPA was associated with lower BMI z-score. Higher energy intake was associated with higher BMI z-score within twin pairs and within all sibling pairs who were not currently dieting for weight loss. Regarding LPA, screen time or sleep duration, no or inconsistent associations were observed for the three groups of sibling pairs. CONCLUSIONS: MVPA and energy intake were associated with BMI differences within sibling and twin pairs growing up in the same home, thus independent of family-level confounding factors. Future studies should explore whether genetic variants regulating appetite or energy expenditure behaviours account for weight differences in sibling pairs.

Variation in reproductive outcomes of women with histories of bulimia nervosa, anorexia nervosa, or eating disorder not otherwise specified relative to the general population and closest-aged sisters.

OBJECTIVE: This study seeks to examine the long-term reproductive consequences of eating disorders (ED), to assess variation in reproductive outcomes by ED type, and to examine reproductive differences between women with previous ED diagnosis and their discordant sisters. METHOD: Using a sample of women with previous ED diagnosis generated by the Utah Population Database, this study compares the fecundity (parity) and age at first birth of women by ED subtype (bulimia nervosa [BN], anorexia nervosa [AN], and ED not otherwise specified [EDNOS]) (n = 1,579). We also employed general population match case-control, and discordant sibling pair analyses, to estimate the magnitude of association between EDs and reproductive outcomes. RESULTS: Women previously diagnosed with AN or EDNOS experienced delayed first birth (HRR = 0.33, HRR = 0.34, respectively) and lower parity (IRR = 0.19, IRR = 0.22, respectively) relative to BN (p < .05), the general population (p < .05), and closest-aged sisters (p < .05). Women previously diagnosed with BN experienced more moderate reductions and delays to their reproduction, and had similar reproductive outcomes as their discordant sisters. DISCUSSION: Clinicians should consider ED type and family fertility histories when addressing the long-term reproductive health needs of women with prior AN, BN, or EDNOS diagnosis. Women previously diagnosed with AN or EDNOS likely experience the greatest reductions and delays in reproduction across their lifespan. Reproductive health screenings may be especially critical for the wellbeing of women with a history of AN or EDNOS.

The Early Determinants of Adult Health Study.

This issue of the Journal features collaborative follow-up studies of two unique pregnancy cohorts recruited during 1959-1966 in the United States. Here we introduce the Early Determinants of Adult Health (EDAH) study. EDAH was designed to compare health outcomes in midlife (age 40s) for same-sex siblings discordant on birthweight for gestational age. A sufficient sample of discordant siblings could only be obtained by combining these two cohorts in a single follow-up study. All of the subsequent six papers are either based upon the EDAH sample or are related to it in various ways. For example, three papers report results from studies that significantly extended the 'core' EDAH sample to address specific questions. We first present the overall design of and rationale for the EDAH study. Then we offer a synopsis of past work with the two cohorts to provide a context for both EDAH and the related studies. Next, we describe the recruitment and assessment procedures for the core EDAH sample. This includes the process of sampling and recruitment of potential participants; a comparison of those who were assessed and not assessed based on archived data; the methods used in the adult follow-up assessment; and the characteristics at follow-up of those who were assessed. We provide online supplementary tables with much further detail. Finally, we note further work in progress on EDAH and related studies, and draw attention to the broader implications of this endeavor.