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O Pedersen

Publications and source records attributed to O Pedersen.

At least 19 recordsLinked to original sources
PubMed2007

Studies of the associations between functional beta2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects.

AIMS/HYPOTHESIS: Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the beta2-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results. MATERIALS AND METHODS: We investigated both of these variants in 7,808 unrelated, middle-aged white people for their association with obesity in a case-control study, quantitative trait analysis and meta-analysis. Moreover, both variants were investigated for their potential influence on measures of hypertension and type 2 diabetes by case-control and quantitative trait analyses. RESULTS: The present study did not find consistent evidence for an association of these beta2-adrenergic receptor variants with obesity or hypertension; neither did the quantitative trait analyses show any effect of the variants on obesity-related traits. However, both the Gly allele of the Arg16Gly variant and the Glu allele of the Gln27Glu variant showed nominal association with systolic blood pressure. Furthermore, there was a nominal association of the Arg16 allele frequency and genotype distribution with type 2 diabetes; however, no influence on quantitative biochemical phenotypes related to type 2 diabetes was found. A nominal association of the Arg/Gly genotype with the metabolic syndrome was also observed (p=0.003). Logistic regression analyses provided no evidence of a synergistic or an additive effect of these variants on obesity, hypertension or diabetes. CONCLUSIONS/INTERPRETATION: After studying 7,808 middle-aged white subjects, we were unable to demonstrate any consistent associations between two common amino acid polymorphisms of the beta2-adrenergic receptor and obesity, hypertension or type 2 diabetes.

Adult↗
PubMed2007

Long-term effects of leisure time physical activity on risk of insulin resistance and impaired glucose tolerance, allowing for body weight history, in Danish men.

AIMS: To determine if the level of leisure time physical activity (LTPA) in young adulthood in obese and non-obese men reduces the risk of insulin resistance (IR) and impaired glucose tolerance (IGT) in middle age, and if such an effect is explained by the current level of LTPA, or by the body mass index (BMI) history preceding and subsequent to the assessment of LTPA. METHODS: Longitudinal study of groups of obese and randomly selected non-obese men identified at around age 19, and re-examined at mean ages of 32, 44 and 51. BMI was measured at all four examinations. LTPA was assessed by self-administrated questionnaires at the last three examinations. IR and the presence of IGT was determined by an oral glucose tolerance test at the last examination. RESULTS: LTPA in young adulthood reduced the risk of IR and IGT in middle age throughout the range of BMI. Adjustment for the BMI history preceding and subsequent to the assessment of LTPA attenuated the association with IR and IGT, but active men remained at low risk of IR and IGT. Adjustment for subsequent and current levels of LTPA, smoking habits, alcohol intake, educational level and family history of diabetes had no notable influence on the results. CONCLUSION: LTPA appears to reduce the risk of IR and IGT, an effect which is not explained by the current level of physical activity, and only partially explained by the BMI history preceding and subsequent to the assessment of LTPA.

Adult↗
PubMed2006

Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects.

AIMS/HYPOTHESIS: The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity. METHODS: The coding region of NPY2R was analysed for mutations in 48 obese Danish white subjects and two silent substitutions were identified: SNPs 1 and 2 (rs1047214 and rs2880415). SNP1 and additional reported variants (SNPs 3-6 [rs11099992, rs12649641, rs2342676 and rs6857530]) located in the 5' region were examined in 5,971 Danish white subjects. Since SNPs 1-2 and 4-6, respectively, were in tight linkage disequilibrium large-scale analyses of genetic epidemiology were restricted to SNPs 1, 3 and 4. RESULTS: Homozygous carriers of the minor A allele of SNP4 were more common among obese subjects; the AA frequency was 15.9 (95% CI 15.2-16.6) among 4,837 non-obese subjects (BMI <30 kg/m(2)) vs 19.0 (95% CI 17.2-20.8) among 960 obese subjects (BMI > or =30 kg/m(2)), odds ratio 1.24 (95% CI 1.04-1.48), p=0.02. SNPs 1-3 were not associated with obesity. CONCLUSIONS/INTERPRETATION: Common variants rs12649641, rs2342676 and rs6857530 in the 5' region of NPY2R are associated with obesity in Danish white subjects.

5' Untranslated Regions↗
PubMed2006

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects.

AIMS/HYPOTHESIS: Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor alpha subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes. SUBJECTS AND METHODS: The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites. RESULTS: No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10-1.25], p=1x10(-6)). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m(2); odds ratio 1.63 [95% CI 1.09-2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait. CONCLUSIONS/INTERPRETATION: In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.

Adult↗
PubMed2006

Genetic analysis of the estrogen-related receptor alpha and studies of association with obesity and type 2 diabetes.

BACKGROUND: The estrogen-related receptor alpha (ERRalpha or NR3B1) is a transcription factor from the nuclear receptor super-family, group III. The gene encoding ERRalpha (ESRRA) is located on chromosome 11q13, a region showing genetic linkage to body mass index and fat percentage. Through interaction with the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), ERRalpha regulates key enzymes involved in the beta-oxidation of fatty acids. RESULTS: By screening 48 overweight or obese subjects for variants in the exons, exon-intron boundaries and 1000 base pairs (bp) of the promoter region of ESRRA using bi-directional nucleotide sequencing, we identified seven variants. Four rare variants had minor allele frequencies (MAF) below 1%: Pro369Pro, Gly406Asp, 3'UTR+418G>A, 3'UTR+505C>A. Two single-nucleotide polymorphisms, Pro116Pro and IVS6+65C>T (MAF 15%), were in complete linkage disequilibrium (LD) (r (2)=1). We also confirmed the presence of a reported 23 bp microsatellite repeat (ESRRA23). The Pro116Pro and ESRRA23 variants were not associated with obesity, type 2 diabetes or related phenotypes in a large population-based study of 6365 Danish whites. The two variants were examined for interactions with variants in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta; however, no evidence of epistatic effects between the variants was demonstrated. CONCLUSION: The ESRRA23 and Pro116Pro variants of the gene encoding ERRalpha are not associated with obesity, type 2 diabetes or related quantitative traits in the examined Danish whites.

Aged↗
PubMed2006

Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance.

Type II diabetes is caused by a failure of the pancreatic beta-cells to compensate for insulin resistance leading to hyperglycaemia. There is evidence for an essential role of an increased beta-cell apoptosis in type II diabetes. High glucose concentrations induce IL-1beta production in human beta-cells, Fas expression and concomitant apoptosis owing to a constitutive expression of FasL. FASL and FAS map to loci linked to type II diabetes and estimates of insulin resistance, respectively. We have tested two functional promoter polymorphisms, FAS-670 G>A and FASL-844C>T as well as a microsatellite in the 3' UTR of FASL for association to type II diabetes in 549 type II diabetic patients and 525 normal-glucose-tolerant (NGT) control subjects. Furthermore, we have tested these polymorphisms for association to estimates of beta-cell function and insulin resistance in NGT subjects. We found significant association to type II diabetes for the allele distribution of the FASL microsatellite (P-value 0.02, Bonferroni corrected). The FAS-670G>A was associated with homeostasis model assessment insulin resistance index and body mass index (P-values 0.02 and 0.02). We conclude that polymorphisms of FASL and FAS associate with type II diabetes and estimates of insulin resistance in Danish white subjects.

3' Untranslated Regions↗
PubMed2006

Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents.

INTRODUCTION: Randomly estimated fasting hyperglycaemia in an asymptomatic individual may represent the first sign of pancreatic beta-cell dysfunction. OBJECTIVE: We aimed at specifying the genetic aetiology of asymptomatic hyperglycaemia in a cohort of children and adolescents. SUBJECTS AND METHODS: We analysed the aetiological diagnosis in 82 non-obese paediatric subjects (38 males) aged 0.2-18.5 years (median: 13.1) who were referred for elucidation of a randomly found blood glucose level above 5.5 mmol/l. In addition to fasting glycaemia and circulating levels of insulin and C-peptide, the subjects were tested by an oral glucose tolerance test and an intravenous glucose tolerance test and screened for mutations in the genes encoding glucokinase (GCK), HNF-1alpha (TCF1), Kir6.2 (KCNJ11) (if aged <2 years) and HNF-4alpha (HNF4A) (those with a positive family history of diabetes). RESULTS AND DISCUSSION: We identified 35 carriers of GCK mutations causing MODY2, two carriers of TCF1 mutations causing MODY3, one carrier of a HNF4A mutation causing MODY1 and one carrier of a KCNJ11 mutation causing permanent neonatal diabetes mellitus. Of the remaining patients, 11 progressed to type 1 diabetes mellitus (T1DM) and 9 had impaired glucose tolerance or diabetes mellitus of unknown origin. In 23 subjects, an impairment of blood glucose levels was not confirmed. We conclude that 39 of 82 paediatric patients (48%) with randomly found fasting hyperglycaemia suffered from single gene defect conditions, MODY2 being the most prevalent. An additional 11 patients (13%) progressed to overt T1DM. The aetiological diagnosis in asymptomatic hyperglycaemic children and adolescents is a clue to introducing an early and effective therapy or, in MODY2, to preventing any future extensive re-investigations.

Adolescent↗
PubMed2006

Possible role of adiponectin and insulin sensitivity in mediating the favorable effects of lower body fat mass on blood lipids.

AIMS: The objective of this study was to investigate the role of insulin sensitivity and serum adiponectin concentration as determinants, in middle-aged men, of the relationship between lower body fat and blood lipids after truncal fat has been accounted for. METHODS: Men (443) aged 39-65 yr, body mass index 18-43 kg/m(2), participated in the study. The following variables were measured: regional body fat distribution as assessed by dual-energy x-ray absorptiometry, maximal oxygen uptake, physical activity, fasting levels of serum adiponectin, triglycerides, and high-density lipoprotein- and total cholesterol. Plasma glucose and serum insulin were measured in the fasting state and after an oral glucose load. RESULTS: Lower body fat mass was inversely associated with serum triglycerides and total cholesterol and positively with serum high-density lipoprotein-cholesterol after adjustment for age, lean tissue mass, truncal fat mass, weight history, maximal oxygen uptake, and the level of physical activity (P < 0.0005). Serum adiponectin level and Matsudas insulin sensitivity index were positively intercorrelated, and both were positively correlated to lower body fat mass. When including adiponectin and insulin sensitivity in the analyses, the relationships between lower body fat mass and serum lipids were partly explained. CONCLUSION: For a given level of truncal fat mass, a large lower body fat mass is associated with an advantageous blood lipid profile, which may be partially mediated by the relationships to both insulin sensitivity and serum adiponectin level.

Absorptiometry, Photon↗
PubMed2006

Randomized, multi-center trial of two hypo-energetic diets in obese subjects: high- versus low-fat content.

OBJECTIVE: To investigate whether a hypo-energetic low-fat diet is superior to a hypo-energetic high-fat diet for the treatment of obesity. DESIGN: Open-label, 10-week dietary intervention comparing two hypo-energetic (-600 kcal/day) diets with a fat energy percent of 20-25 or 40-45. SUBJECTS: Obese (BMI >or=30 kg/m(2)) adult subjects (n = 771), from eight European centers. MEASUREMENTS: Body weight loss, dropout rates, proportion of subjects who lost more than 10% of initial body weight, blood lipid profile, insulin and glucose. RESULTS: The dietary fat energy percent was 25% in the low-fat group and 40% in the high-fat group (mean difference: 16 (95% confidence interval (CI) 15-17)%). Average weight loss was 6.9 kg in the low-fat group and 6.6 kg in the high-fat group (mean difference: 0.3 (95% CI -0.2 to 0.8) kg). Dropout was 13.6% (n = 53) in the low-fat group and 18.3% (n = 70) in the high-fat group (P=0.001). Among completers, more subjects lost >10% in the low-fat group than in the high-fat group ((20.8%, n = 70) versus (14.7%, n = 46), P = 0.02). Fasting plasma total, low-density lipoprotein- and high-density lipoprotein-cholesterol decreased in both groups, but more so in the low-fat group than in the high-fat group. Fasting plasma insulin and glucose were lowered equally by both diets. CONCLUSIONS: The low-fat diet produced similar mean weight loss as the high-fat diet, but resulted in more subjects losing >10% of initial body weight and fewer dropouts. Both diets produced favorable changes in fasting blood lipids, insulin and glucose.

Adult↗
PubMed2006

Oxygen dynamics during submergence in the halophytic stem succulent Halosarcia pergranulata.

This study elucidated O2 dynamics in shoots and roots of submerged Halosarcia pergranulata (Salicornioideae), a perennial halophytic stem succulent that grows on floodprone mudflats of salt lakes. Oxygen within shoots and roots was measured using microelectrodes, for plants when waterlogged or completely submerged, with shoots in light or in darkness, in a controlled environment. Net photosynthesis (PN) when underwater, at a range of dissolved CO2 concentrations, was measured by monitoring O2 production rates by excised stems. The bulky nature and apparently low volume of gas-filled spaces of the succulent stems resulted in relatively high radial resistance to gas diffusion. At ambient CO2, quasi-steady state rates of PN by excised succulent stems were estimated to be close to zero; nevertheless, in intact plants, underwater photosynthesis provided O2 to tissues and led to radial O2 loss (ROL) from the roots, at least during the first several hours (the time period measured) after submergence or when light periods followed darkness. The influence of light on tissue O2 dynamics was confirmed in an experiment on a submerged plant in a salt lake in south-western Australia. In the late afternoon, partial pressure of O2 (pO2) in the succulent stem was 23.2 kPa (i.e. approximately 10% above that in the air), while in the roots, it was 6.2-9.8 kPa. Upon sunset, the pO2 in the succulent stems declined within 1 h to below detection, but then showed some fluctuations with the pO2 increasing to at most 2.5 kPa during the night. At night, pO2 in the roots remained higher than in the succulent stems, especially for a root with the basal portion in the floodwater. At sunrise, the pO2 increased in the succulent stems within minutes. In the roots, changes in the pO2 lagged behind those in the succulent stems. In summary, photosynthesis in stems of submerged plants increased the pO2 in the shoots and roots so that tissues experience diurnal changes in the pO2, but O2 from the H2O column also entered submerged plants.

Amaranthaceae↗
PubMed2006

IRS1, KCNJ11, PPARgamma2 and HNF-1alpha: do amino acid polymorphisms in these candidate genes support a shared aetiology between type 1 and type 2 diabetes?

AIMS: Type 1 diabetes mellitus (T1DM) is a chronic disorder primarily triggered by environmental and immunological factors in genetically susceptible individuals. Despite the fact that there are indications of common aetiological features of T1DM and type 2 diabetes (T2DM), variation in genes involved in insulin secretion and insulin signalling has to a large extent been ignored as potential modifiers in the pathogenesis of T1DM. Recent studies suggest, however, that proven T2DM susceptibility gene variants may be involved in the pathogenesis of T1DM. The objective of this study was to estimate the impact of four selected amino acid polymorphisms -IRS-1 Gly972Arg, Kir6.2 Glu23Lys, HNF-1alpha Ala98Val and PPARgamma2 Pro12Ala in a Danish population of T1DM families. METHODS: All variants were genotyped in 490 simplex- and multiplex-T1DM families applying polymerase chain reaction-restriction fragment length polymorphism, and results were evaluated by means of a transmission disequilibrium test (TDT) analysis. RESULTS: TDT analysis revealed that the Arg972 IRS-1, the Lys23 Kir6.2 and the Val98 HNF-1alpha variants were transmitted from heterozygous parents to affected probands at frequencies of 49.1%, 47.0% and 54.1%, respectively (p > 0.05 for all). This was similar to the rate of transmission to unaffected siblings. The transmission rate of the Ala12 PPARgamma2 variant to affected probands was 46.5% (p > 0.05) which differed significantly from the transmission to unaffected offspring (p = 0.024). A combined analysis of the present and published pertinent data of 1691 transmissions showed a significantly decreased transmission of the PPARgamma2 Ala12 allele to affected probands (p = 0.0045). CONCLUSIONS: The Pro12Ala variant of PPARgamma2 is associated with T1DM, the minor Ala allele conferring a reduced risk. This same finding has been reported in patients with T2DM.

Adolescent↗
PubMed2006

Large-scale study of the -232C > G polymorphism of PCK1 in Type 2 diabetes.

AIMS: Phosphoenolpyruvate carboxykinase (PEPCK) is a catalyst of the rate-limiting step in the gluconeogenic pathway and is regulated at the transcriptional level predominantly by insulin, glucocorticoids, glucagon, and cAMP. The -232C > G polymorphism in the gene encoding PEPCK (PCK1) is reported to associate with Type 2 diabetes in Canadian Caucasians and Oji-Cree populations. We have estimated the impact of the PCK1-232C > G polymorphism in a relatively large-scale case-control study of Type 2 diabetes and in association studies of common metabolic phenotypes. Interaction studies of the PCK1-232C > G polymorphism with variants in the genes encoding peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1alpha and hepatic nuclear factor (HNF)-4alpha were also performed. METHODS: PCK1-232C > G was genotyped in a total of 7467 Danish white subjects using TaqMan allelic discrimination. A case-control study of Type 2 diabetes was performed using 6057 of the participants, and quantitative trait studies of metabolic variables were carried out in a subgroup of 5718 non-diabetic subjects. Additionally, variants in PGC-1alpha (Gly482Ser) and HNF-4alpha (Thr130Ile, Val255Met, and rs1884614) were investigated for epistatic interaction with the PCK1-232C > G polymorphism. RESULTS: In the case-control study of Type 2 diabetes of 1377 Type 2 diabetic patients and 4680 normoglycaemic and normal glucose-tolerant subjects we found no association of the PCK1-232C > G polymorphism with diabetes. In addition, the variant was not associated with age of clinical onset of Type 2 diabetes. In the study of 5718 non-diabetic subjects, we found no relationships of quantitative metabolic traits with the PCK1-232C > G polymorphism. We failed to demonstrate any convincing epistatic effects of the variants in the genes encoding PGC-1alpha and HNF-4alpha with the PCK1-232C > G polymorphism. CONCLUSIONS: The PCK1-232C > G polymorphism is not a major contributor to the pathogenesis of Type 2 diabetes in the Danish population.

Case-Control Studies↗
PubMed2006

Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.

Adult↗
PubMed2005

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes.

AIMS/HYPOTHESIS: The 825C>T polymorphism in the gene encoding the G protein beta3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. MATERIALS AND METHODS: The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case-control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. RESULTS: We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels-a finding in contrast with most previous studies-but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. CONCLUSIONS/INTERPRETATION: The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.

Adult↗
PubMed2005

Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1.

AIMS/HYPOTHESIS: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by an autosomal dominant inheritance, an early clinical onset, and a primary defect in beta-cell function. The aims of the present study were to examine the prevalence and nature of mutations in the three common MODY genes, HNF4A, GCK, and TCF1, in Danish patients with a clinical diagnosis of MODY and to describe metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. METHODS: Seventy-eight unrelated subjects of Danish Caucasian origin (29 men, 49 women) and their 351 family members were examined. The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing. RESULTS: We identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Our findings suggest a relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. CONCLUSIONS: Forty-nine percent of the families carried mutations in the three examined MODY genes. Our findings highlight that unidentified MODY genes may play a central role for diabetes characterized by autosomal dominant transmission. Furthermore, baseline measurements of various anthropometric and biochemical variables are not appropriate markers of MODYX.

Adolescent↗
PubMed2005

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection. METHODS: HNF-4alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1alpha MODY but negative for HNF-1alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. RESULTS: Mutations in HNF-4alpha were found in 14/48 (29%) probands negative for HNF-1alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4alpha mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal. CONCLUSIONS/INTERPRETATION: HNF-4alpha mutations are common when no HNF-1alpha mutation is found in strictly defined MODY families. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4alpha should be performed in patients with clinical characteristics of HNF-1alpha MODY in whom mutations in HNF-1alpha are not found.

Adolescent↗
PubMed2005

Variation near the hepatocyte nuclear factor (HNF)-4alpha gene associates with type 2 diabetes in the Danish population.

AIMS/HYPOTHESIS: The hepatocyte nuclear factor (HNF)-4alpha is an orphan nuclear receptor, which plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The gene encoding HNF-4alpha (HNF4A) is located on chromosome 20q12-q13 in a region that in several studies has shown linkage with type 2 diabetes. Recently, two independent studies identified single nucleotide polymorphisms (SNPs) in a 90-kb region spanning HNF4A, which showed strong association with type 2 diabetes in the Finnish and Ashkenazi Jewish populations. In an attempt to replicate and extend these findings, we selected four SNPs in the same HNF4A region, which in the Finnish and Ashkenazi Jewish populations were associated with type 2 diabetes, and examined their relationships with type 2 diabetes and prediabetic phenotypes in the Danish Caucasian population. METHODS: The rs1884614, rs2425637, rs1885088 and rs3818247 were analysed in case-control studies of 1387, 1429, 1417 and 1371 type 2 diabetic patients and 4766, 4727, 4665 and 4748 glucose-tolerant subjects respectively. Genotype-quantitative trait analyses comprised 4430, 4394, 4336 and 4413 middle-aged glucose-tolerant subjects from the population-based Inter99 cohort for the rs1884614, rs2425637, rs1885088 and rs3818247 respectively. RESULTS: The risk allele of the rs1884614, which is located 4 kb upstream of the HNF4A P2 promoter, was associated with type 2 diabetes (odds ratio [OR]=1.14, p=0.02) and with a subtle increase in post-OGTT plasma glucose levels in glucose-tolerant subjects (additive model, p=0.05). CONCLUSIONS/INTERPRETATION: Consistent with results from studies of Finnish and Ashkenazi Jewish subjects, variation near the P2 region of HNF4A is associated with type 2 diabetes in the Danish population.

Cohort Studies↗