Increased frequency of rare missense <i>PPP1R3B</i> variants among Danish patients with type 2 diabetes

<div><p>Background</p><p><i>PPP1R3B</i> has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.</p><p>Objectives</p><p>To study if rare missense variants in <i>PPP1R3B</i> increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.</p><p>Method</p><p>Targeted resequencing of <i>PPP1R3B</i> was performed in 8,710 samples; MODY patients with unknown etiology (<i>n</i> = 54), newly diagnosed patients with T2D (<i>n</i> = 2,930) and population-based control individuals (<i>n</i> = 5,726, of whom <i>n</i> = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test.</p><p>Results</p><p>Among <i>n</i> = 396 carriers, we identified twenty-three <i>PPP1R3B</i> missense mutations, none of which segregated with MODY. The burden of likely deleterious <i>PPP1R3B</i> variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36–0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20–0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14–5.79), <i>p</i> = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense <i>PPP1R3B</i> variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers.</p><p>Conclusion</p><p>Rare missense <i>PPP1R3B</i> variants may predispose to T2D.</p></div

Common variants in LEPR, IL6, AMD1, and NAMPT do not associate with risk of juvenile and childhood obesity in Danes:a case-control study

BACKGROUND: Childhood obesity is a highly heritable disorder, for which the underlying genetic architecture is largely unknown. Four common variants involved in inflammatory-adipokine triggering (IL6 rs2069845, LEPR rs1137100, NAMPT rs3801266, and AMD1 rs2796749) have recently been associated with obesity and related traits in Indian children. The current study aimed to examine the effect of these variants on risk of childhood/juvenile onset obesity and on obesity-related quantitative traits in two Danish cohorts. METHODS: Genotype information was obtained for 1461 young Caucasian men from the Genetics of Overweight Young Adults (GOYA) study (overweight/obese: 739 and normal weight: 722) and the Danish Childhood Obesity Biobank (TDCOB; overweight/obese: 1022 and normal weight: 650). Overweight/obesity was defined as having a body mass index (BMI) ≥25 kg/m(2); among children and youths, this cut-off was defined using age and sex-specific cut-offs corresponding to an adult body mass index ≥25 kg/m(2). Risk of obesity was assessed using a logistic regression model whereas obesity-related quantitative measures were analyzed using a general linear model (based on z-scores) stratifying on the case status and adjusting for age and gender. Meta-analyses were performed using the fixed effects model. RESULTS: No statistically significant association with childhood/juvenile obesity was found for any of the four gene variants among the individual or combined analyses (rs2069845 OR: 0.94 CI: 0.85–1.04; rs1137100 OR: 1.01 CI: 0.90–1.14; rs3801266: 0.96 CI: 0.84–1.10; rs2796749 OR: 1.02 CI: 0.90–1.15; p > 0.05). However, among normal weight children and juvenile men, the LEPR rs1137100 A-allele significantly associated with lower BMI (β = −0.12, p = 0.0026). CONCLUSIONS: The IL6, LEPR, NAMPT, and AMD1 gene variants previously found to associate among Indian children did not associate with risk of obesity or obesity-related quantitative measures among Caucasian children and juvenile men from Denmark

A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

<div><p>Background</p><p>Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.</p><p>Objective</p><p>This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.</p><p>Methods</p><p>Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5−24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2−22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.</p><p>Results</p><p>No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (<i>PDE10A</i> (rs2983511: <i>β</i> = 0.112<i>SD</i>, <i>p</i> = 4.8 ∙ 10⁻¹⁶), <i>FOXE1</i> (rs7847663: <i>β</i> = 0.223<i>SD</i>, <i>p</i> = 1.5 ∙ 10⁻²⁰), <i>NR3C2</i> (rs9968300: <i>β</i> = 0.194<i>SD</i>), <i>p</i> = 2.4 ∙ 10⁻¹¹), <i>VEGFA (</i>rs2396083: <i>β</i> = 0.088<i>SD</i>, <i>p</i> = 2.2 ∙ 10⁻¹⁰)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (<i>p</i><0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.</p><p>Conclusion</p><p>In a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.</p></div

The effect of FOXA2 rs1209523 on glucose-related phenotypes and risk of type 2 diabetes in Danish individuals

<p>Abstract</p> <p>Background</p> <p>Variations within the <it>FOXA </it>family have been studied for a putative contribution to the risk of type 2 diabetes (T2D), and recently the minor T-allele of <it>FOXA2 </it>rs1209523 was reported to associate with decreased fasting plasma glucose levels in a study using a weighted false discovery rate control procedure to enhance the statistical power of genome wide association studies in detecting associations between low-frequency variants and a given trait.</p> <p>Thus, the primary aim of this study was to investigate whether the minor T-allele of rs1205923 in <it>FOXA2 </it>associated with 1) decreased fasting plasma glucose and 2) a lower risk of developing T2D. Secondly, we investigated whether rs1205923 in <it>FOXA2 </it>associated with other glucose-related phenotypes.</p> <p>Methods</p> <p>The variant was genotyped in Danish individuals from four different study populations using KASPar^®PCR SNP genotyping system. We examined for associations of the <it>FOXA2 </it>genotype with fasting plasma glucose and estimates of insulin release and insulin sensitivity following an oral glucose tolerance test in 6,162 Danish individuals from the population-based Inter99 study while association with T2D risk was assessed in 10,196 Danish individuals including four different study populations.</p> <p>Results</p> <p>The <it>FOXA2 </it>rs1209523 was not associated with fasting plasma glucose (effect size (β) = -0.03 mmol/l (95%CI: -0.07; 0.01), <it>p </it>= 0.2) in glucose-tolerant individuals from the general Danish population. Furthermore, when employing a case-control setting the variant showed no association with T2D (odds ratio (OR) = 0.82 (95%CI: 0.62-1.07), <it>p </it>= 0.1) among Danish individuals. However, when we performed the analysis in a subset of 6,022 non-obese individuals (BMI < 30 kg/m²) an association with T2D was observed (OR = 0.68 (95%CI: 0.49-0.94), <it>p </it>= 0.02). Also, several indices of insulin release and β-cell function were associated with the minor T-allele of <it>FOXA2 </it>rs1209523 in non-obese individuals.</p> <p>Conclusions</p> <p>We failed to replicate association of the minor T-allele of <it>FOXA2 </it>rs1209523 with fasting plasma glucose in a population based sample of glucose tolerant individuals. More extensive studies are needed in order to fully elucidate the potential role of <it>FOXA2 </it>in glucose homeostasis.</p

Identification and Functional Characterization of <i>G6PC2</i> Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the <i>G6PC2-ABCB11</i> Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights