The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes

A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.We confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).Studies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained

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

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

BACKGROUND:The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS:1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS:Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS:Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research

Meta-analysis of the effect of the C-allele of <i>TMEM154</i>-rs6813195 on insulinogenic index in 6,486 individuals from the Inter99 study (n = 5,181), Health 2008 study (n = 592), ADIGEN controls (n = 246), ADIGEN obese cases (n = 165) and Danish Family study (n = 302).

<p>Gray diamond represents combined change per risk allele and the 95% confidence interval. Gray squares represent effects size estimates (beta coefficients) in single studies sized according to their weight in the meta-analyses. The horizontal lines through the gray squares represent the 95% confidence interval. ob, obese. <i>p</i>, <i>P</i>-value. CI, confidence interval. W(fixed), study weight in the fixed effect meta-analysis.</p

Meta-analysis of the effect of the G-allele of <i>FAF1</i>-rs17106184 on 2-hour serum insulin in 6,260 individuals from the Inter99 study (n = 5,547), ADIGEN controls (n = 246), ADIGEN obese cases (n = 165) and Danish Family study (n = 302).

<p>Gray diamond represents combined change per risk allele and the 95% confidence interval. Gray squares represent effects size estimates (beta coefficients) in single studies sized according to their weight in the meta-analyses. The horizontal lines through the gray squares represent the 95% confidence interval. ob, obese. <i>p</i>, <i>P</i>-value. CI, confidence interval. W(fixed), study weight in the fixed effect meta-analysis.</p

Associations between the seven T2D risk variants and quantitative traits in up to 5,744 Danish individuals naive to glucose-lowering medication.

<p>Raw data are mean±SD or median (interquartile range) and are stratified according to genotype. Values of serum insulin and derived indexes of insulinogenic index, ISI_Matsuda, disposition index and BIGTT-AIR were natural logarithmical (ln) transformed before analysis. Effects represent beta coefficients and are shown for the T2D risk allele. <i>P</i>-values (<i>P</i>) are adjusted for age (BIGTT-AIR and BIGTT-SI) or sex and age (all other traits). <i>P</i>_adjBMI are <i>P</i>-values adjusted for age, sex and BMI. All analyses assume an additive genetic model. SE, standard error.</p><p>Associations between the seven T2D risk variants and quantitative traits in up to 5,744 Danish individuals naive to glucose-lowering medication.</p

T2D case-control analyses of up to 5,777 patients from Inter99 (n = 320), Health 2006 (n = 166), Health 2008 (n = 18), Steno Diabetes Center (n = 1,424), ADDITION (n = 1,870) and Vejle Biobank (n = 1,979) and up to 7,956 individuals with normal fasting glucose from Inter99 (n = 4,590), Health 2006 (n = 2,412), Health 2008 (n = 528) and Vejle Biobank (n = 426).

<p>Number of cases vs. number of controls is shown as 0/1/2 risk alleles. Odds ratios (OR) and <i>P</i>-values (<i>P</i>) are adjusted for age and sex. OR_adjBMI and <i>P</i>_adjBMI are adjusted for age, sex and BMI. SNP, single nucleotide polymorphism. RA, risk allele. RAF, risk allele frequency. CI, confidence interval.</p><p>T2D case-control analyses of up to 5,777 patients from Inter99 (n = 320), Health 2006 (n = 166), Health 2008 (n = 18), Steno Diabetes Center (n = 1,424), ADDITION (n = 1,870) and Vejle Biobank (n = 1,979) and up to 7,956 individuals with normal fasting glucose from Inter99 (n = 4,590), Health 2006 (n = 2,412), Health 2008 (n = 528) and Vejle Biobank (n = 426).</p

Meta-analysis of the effect of the C-allele of <i>TMEM154</i>-rs6813195 on disposition index in 6,486 individuals from the Inter99 study (n = 5,181), Health 2008 study (n = 592), ADIGEN controls (n = 246), ADIGEN obese cases (n = 165) and Danish Family study (n = 302).

<p>Gray diamond represents combined change per risk allele and the 95% confidence interval. Gray squares represent effects size estimates (beta coefficients) in single studies sized according to their weight in the meta-analyses. The horizontal lines through the gray squares represent the 95% confidence interval. ob, obese. <i>p</i>, <i>P</i>-value. CI, confidence interval. W(fixed), study weight in the fixed effect meta-analysis.</p

Association of genome-wide variants with plasma fT4 concentrations.

<p>SNPs that passed QC are plotted on the x-axis according to their chromosomal position against their–log10(<i>p</i>-value). The results were considered genome-wide significant with a <i>p</i><5·10⁻⁸ and a replication threshold was set at <i>p</i><1·10⁻⁶.</p