Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations.

OBJECTIVES: To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers. METHODS: Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment. RESULTS: Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017). CONCLUSION: Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.

Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population.

BACKGROUND: p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population. METHODS: Surface expression, Gq and Gi coupled signalling as well as ß-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. RESULTS: p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect ß-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05). CONCLUSIONS: We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years.

Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 × 10-17]. This triglyceride-increasing effect of the wGRS interacted with changes in insulin resistance (Pinteraction = 1.5 × 10-6). This interaction indicated that the effect of the wGRS was stronger in individuals who became more insulin resistant over 5 years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger increase in fasting serum triglyceride levels in nondiabetic individuals during 5 years of follow-up. This effect of the wGRS is accentuated by increasing insulin resistance.

Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.

Pharmacogenetics and individual responses to treatment of hyperglycemia in type 2 diabetes.

The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression. Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines. Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes. Gene-gene, gene-environment, and gene-treatment interactions may explain some of the variation in disease progression. Several genetic variants have been suggested to be associated with response to antidiabetic drugs. Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9). Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify 'disease progressors' among patients with diabetes. Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made. Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.

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

BACKGROUND: Variations within the FOXA family have been studied for a putative contribution to the risk of type 2 diabetes (T2D), and recently the minor T-allele of FOXA2 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.Thus, the primary aim of this study was to investigate whether the minor T-allele of rs1205923 in FOXA2 associated with 1) decreased fasting plasma glucose and 2) a lower risk of developing T2D. Secondly, we investigated whether rs1205923 in FOXA2 associated with other glucose-related phenotypes. METHODS: The variant was genotyped in Danish individuals from four different study populations using KASPar(®) PCR SNP genotyping system. We examined for associations of the FOXA2 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. RESULTS: The FOXA2 rs1209523 was not associated with fasting plasma glucose (effect size (ß) = -0.03 mmol/l (95%CI: -0.07; 0.01), p = 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), p = 0.1) among Danish individuals. However, when we performed the analysis in a subset of 6,022 non-obese individuals (BMI < 30 kg/m(2)) an association with T2D was observed (OR = 0.68 (95%CI: 0.49-0.94), p = 0.02). Also, several indices of insulin release and ß-cell function were associated with the minor T-allele of FOXA2 rs1209523 in non-obese individuals. CONCLUSIONS: We failed to replicate association of the minor T-allele of FOXA2 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 FOXA2 in glucose homeostasis.

The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

Context: Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive. Objective: Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism. Methods: We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status. Results: A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels. Conclusion: Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Indirect comparison of efficacy of dupilumab versus mepolizumab and omalizumab for severe type 2 asthma.

This indirect comparison of dupilumab, mepolizumab and omalizumab for patients with severe type 2 asthma fulfilling start-up criteria for more than one drug shows no significant efficacy differences https://bit.ly/3pK9Nf9.

Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY).

BACKGROUND: Insulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood. METHODS: INS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study. RESULTS: One novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a approximately 30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin. CONCLUSION: Mutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.

Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma.

BACKGROUND: Omalizumab is approved for treating severe allergic asthma from age 6, but the definition of severe asthma including a systematic assessment to rule out difficult-to-treat asthma has changed since the drug was approved in 2003. METHODS: We conducted a systematic review and meta-analysis of two critical (exacerbation rate, oral corticosteroid (OCS) treatment) and eight important clinical outcomes in children, adolescents and adults, and specifically searched papers for systematic assessment of severe asthma. RESULTS: Adults: seven studies (n = 2159) ascertaining exacerbation rate showing a 37% (95% CI 21-50) reduction in favor of omalizumab, larger than the pre-specified minimal clinically important difference (MCID) of 25%. Only one open-label study (n = 82) was identified assessing the percentage of patients experiencing reduction of OCS-maintenance treatment showing a significantly greater decrease in the omalizumab group (- 45% vs. + 18.3%, p = 0.002). Children and adolescents: four studies (n = 1551) reported data on exacerbations (no meta-analysis conducted), showed overall improvements in exacerbation rate and some passed MCID. No OCS studies were identified. No included studies provided systematic assessment of severe asthma according to current guidelines. CONCLUSIONS: Omalizumab provides clinically relevant improvements in exacerbation rate among children, adolescents, and adults and in OCS-reduction among adults. New studies incorporating a guideline-approached definition of severe asthma are warranted.

Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis.

Background: New, complex, and expensive therapies targeting Interleukin-5 (IL-5) to treat severe eosinophilic asthma are emerging. Objective: To assess efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab for treating severe eosinophilic asthma. Design: A systematic review and meta-analysis on randomized, placebo-controlled, clinical trials elucidating two critical (exacerbation rate and oral corticosteroid (OCS) use) and six important clinical outcomes on the efficacy and safety of mepolizumab and reslizumab. Results: Five studies (N = 2197) contributed with data for exacerbation rate, showing a reduction of 53% (95% CI 46; 59) in favour of anti-IL-5, corresponding to -0.94 annual exacerbations (95% CI -1.08;-0.82), thus exceeding the predefined minimal clinical important difference (MCID) of 25% reduction of the estimated ≥2 annual exacerbations. Quality of evidence was considered moderate, with low heterogeneity in study findings (I2 = 0%). One study (N = 135) contributed with data on percentage of patients experiencing ≥50% reduction inoral corticosteroid treatment, showing an effect of 20% (95% CI 2.3;47) in favour of anti-IL-5 treatment (mepolizumab), thus exceeding the predefined MCID of 10%. Quality of evidence was considered low. Compared to placebo, anti-IL-5 showed significant improvements in lung function, asthma control, and asthma-related quality of life, but below the MCIDs. No differences were observed for serious adverse events and number of patients, who dropped out. No studies evaluating sickleave or head-to-head comparisons were identified. By indirect comparison, we found no significant difference between mepolizumab and reslizumab in any ofthe predefined clinical outcomes. OCS treatment reduction could not be compared due to lack of reslizumab studies investigating this outcome. Conclusions: Mepolizumab and reslizumab provide significant and clinically relevant improvements in exacerbation rate and OCS reduction. Indirect, inter-study comparisons revealed no differences between the anti-IL-5 drugs in efficacy or safety measures.

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

Publisher Correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.

In the originally published version of this Article, the affiliation details for Santi González, Jian'an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain', and Jian'an Luan and Claudia Langenberg should have been affiliated with 'MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK'. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.

High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus.

CONTEXT: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of ß-cell dysfunction. OBJECTIVES: We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up. DESIGN SETTING AND PATIENTS: We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow-up 10 years after the index pregnancy. MAIN OUTCOME MEASURES: The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured. RESULTS: At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS. CONCLUSIONS: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM.

1H-MRS Measured Ectopic Fat in Liver and Muscle in Danish Lean and Obese Children and Adolescents.

OBJECTIVES: This cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children. METHODS: Fasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8-18 years. RESULTS: In 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed. Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol. CONCLUSION: Hepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk.

Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased ß-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort.

CONTEXT: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. OBJECTIVE: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. DESIGN AND PARTICIPANTS: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. RESULTS: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 with T2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14 rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. CONCLUSIONS: BCAR1 rs7202877 may mediate its diabetogenic impact through impaired ß-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.

Genetic risk score of 46 type 2 diabetes risk variants associates with changes in plasma glucose and estimates of pancreatic ß-cell function over 5 years of follow-up.

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of ß-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and ß-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

The birth weight lowering C-allele of rs900400 near LEKR1 and CCNL1 associates with elevated insulin release following an oral glucose challenge.

BACKGROUND AND AIM: The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample. METHODS: For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses. RESULTS: The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([-41.3;-3.0], P = 0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (ß = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (ß = 1.76% [0.04; 3.49], P = 0.05). CONCLUSION: The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.

Do gene variants influencing adult adiposity affect birth weight? A population-based study of 24 loci in 4,744 Danish individuals.

BACKGROUND: Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn. METHODOLOGY/PRINCIPAL FINDINGS: Midwife records from the Danish State Archives provided information on mother's age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10(th) percentile), normal (10(th)-90(th) percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI. CONCLUSION: 24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life.