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Biomedical subjects

A Hinney

Publications and source records attributed to A Hinney.

At least 37 records · Page 2Linked to original sources
PubMed2002

5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders.

Positive association between obsessive compulsive disorder (OCD) and the A-allele of the 5-HT(2A)-receptor promoter polymorphism -1438G/A has recently been reported in adults. We performed an association analysis of this polymorphism in 55 children and adolescents with OCD and in 223 controls consisting of unrelated students. We detected statistically significant differences in genotype (P < 0.05) and allele frequencies (P < 0.05) between individuals with OCD and controls. In this, to our knowledge, first association study based on children and adolescents with OCD, we confirm an association of the A-allele of the 5-HT2A receptor gene with OCD.

Adolescent↗
PubMed2001

Systematic screening for mutations in the human necdin gene (NDN): identification of two naturally occurring polymorphisms and association analysis in body weight regulation.

BACKGROUND: NDN, which codes for the human necdin protein, is a candidate gene for Prader-Willi syndrome (PWS). One feature of this neurogenetic disorder is hyperphagia resulting in extreme obesity observed later in development. OBJECTIVE AND DESIGN: In this study we have used single-strand conformation polymorphism (SSCP) analysis to identify sequence variants at the human necdin gene. Furthermore we tested whether these variants were associated with obesity in extremely obese German children and adolescents. RESULTS: Two gene variants could be identified: a g.1352T-->C polymorphism in the putative promotor region and a silent g.2311C-->T polymorphism in the coding region. Genotype and allele frequency distribution of both of the polymorphisms were not significantly different between lower and higher body mass index (BMI) subjects. CONCLUSIONS: Hence, it is unlikely that these polymorphisms play a major role in the emergence of juvenile onset human obesity.

Adolescent↗
PubMed2001

The genetics of obesity: practical implications.

Over the past years substantial progress has been made in the molecular elucidation of monogenic forms of obesity both in rodents and in humans. In addition, several quantitive trait loci have been mapped in mice. In humans, non-parametric linkage studies have led to the identification of relevant chromosomal regions, some of which have already been confirmed. In this review we focus on an interpretation of the heritability estimates obtained in twin, family and adoption studies. These estimates include both direct and indirect genetic effects. Non-additive genetic factors seemingly contribute even more than additive factors. The importance of the non-shared environment is stressed. Gene x gene interactions need to be considered when interpreting recent molecular genetic results pertaining to haplo-insufficiency mutations in the melanocortin-4 receptor gene. We conclude by discussing the implications of the recent molecular findings in humans for phenotypical assessment in ongoing family studies.

Age Factors↗
PubMed2001

Association between an agouti-related protein gene polymorphism and anorexia nervosa.

Anorexia nervosa (AN) is a life threatening disorder affecting mostly adolescent women. It is a dramatic psychiatric syndrome accompanied by severe weight loss, hyperactivity and neuroendocrine changes (reviewed in Refs 1 and 2). Several studies have shown a strong genetic component in AN (reviewed in Ref 3). Recent advances in unraveling the mechanisms of weight control point to a crucial role of the melanocortin-4 receptor (MC4-r) system in regulating body weight. The orexigenic neuropeptide agouti-related protein (AGRP), a MC4-r antagonist, plays a crucial role in maintaining body weight, by inducing food intake. The sequence of the coding region of the human AGRP gene (AGRP) was determined and the AGRP of 100 patients with AN was screened for variations. Three single nucleotide polymorphisms (SNPs) were identified and screened in a further 45 patients and 244 controls. Two alleles were in complete linkage disequilibrium and were significantly enriched in anorectic patients (11%; P = 0.015) compared to controls (4.5%). These data indicate that variations of AGRP are associated with susceptibility for AN. This is possibly caused by defective suppression of the MC4-r by the variant AGRP, leading to a decreased feeding signal, increasing the risk of developing AN. These results implicate that antagonism of the MC4-r might be considered as pharmacotherapy for patients with AN.

Adolescent↗
PubMed2001

No evidence for involvement of alleles of the 825-C/T polymorphism of the G-protein subunit beta 3 in body weight regulation.

The 825-C/T polymorphism of the beta 3 subunit of the heterotrimeric G protein gene (GNB3) has been shown to be associated with essential hypertension in humans. Recently, it was also reported that the 825-T allele has a higher frequency in obese than non-obese hypertensives suggesting that the primary effect of this allele is on body weight. The association to hypertension might merely be a secondary effect of the higher weight of the respective allele carriers. To investigate an involvement of the 825-T allele in body weight regulation in young individuals, we evaluated allele frequencies in 440 extremely obese children and adolescents (82.9% had a body mass index [BMI] > or = 99th percentile), 51 obese students (BMI > or = 90th percentile), 110 normal weight students (BMI between 40th and 60th percentile) and 144 underweight students (BMI < or = 15th percentile). The study groups were genotyped by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis (PCR-RFLP). The one-sided Yates-corrected chi(2)-test and the Cochran-Armitage trend test for association were performed. Tests for association were negative. The 825-T allele frequencies were similar in the four study groups belonging to different weight ranges (extreme early onset obesity: 0.29; obesity: 0.28; normal weight: 0.35; underweight: 0.32). Similarly, genotype frequencies did not differ between the groups. We concluded that the 825-T allele of the GNB3 does not play a major role in weight regulation in German children, adolescents and young adults.

Adolescent↗
PubMed2001

Identification of a deletion variant in the gene encoding the human alpha(2A)-adrenergic receptor.

OBJECTIVE: The alpha(2)-adrenergic receptors are involved in the effects of catecholamines on energy metabolism. Of three known subtypes with differential expression, alpha(2A)-adrenergic receptors are also localized in adipose tissue where they counteract the lipolytic activity of beta-adrenergic receptors. This study was undertaken to assess whether variants in the alpha(2A)-adrenergic receptor gene are associated with body weight. DESIGN AND METHODS: Single strand conformation polymorphism (SSCP) screening and subsequent sequencing were applied to determine genetic variants in DNA samples from individuals with obesity, those of normal weight and those underweight. RESULTS: Analysis of the coding region resulted in the identification of an 18 bp deletion, with no other mutation found. Of 429 genotyped subjects, 7 carried the deletion, with no significant differences between lean and obese subjects. A previously identified polymorphism in the promoter of the alpha(2A)-adrenergic receptor gene also did not show an association with any of the tested body weight categories. CONCLUSION: Our data suggest that variants in the alpha(2A)-adrenergic receptor gene are unlikely to contribute to the predisposition for the lean or obese state.

Adolescent↗
PubMed2000

Candidate gene polymorphisms in eating disorders.

Anorexia nervosa and bulimia nervosa are complex disorders characterized by disordered eating behaviour. Attitudes towards weight and shape as well as the perception of body shape are disturbed. A substantial genetic influence on these disorders has been suggested by formal genetic studies. Obsessive-compulsive behaviour, perfectionism and anxious personality traits seem to occur premorbidly in several patients. Disturbances of neurotransmitter, neuropeptide and neuroendocrine systems have been reported in acutely ill and followed-up patients. Hence, these systems might be involved in the etiology of these eating disorders.Genetic studies on candidate genes have mainly focussed on the serotonergic system and on genes involved in body weight regulation. Up to now, polymorphisms and variations in various genes (e.g. genes for 5-HT receptors, leptin gene, melanocortin MC(4) receptor gene) have been assessed for association and transmission disequilibrium pertaining to anorexia nervosa and/or bulimia nervosa. Most of the studies yielded negative results. Four studies of a polymorphism (-1438 G/A) within the promoter of the 5-HT(2A) gene (5-HT(2A)) revealed an association of the A-allele to anorexia nervosa. However, three studies could not confirm this result. Furthermore, a meta-analysis did not support the positive association. Currently, combined efforts within the European Union will answer the question of whether or not the A-allele is involved in the predisposition to anorexia nervosa. A transmission disequilibrium test is being performed in about 300 trios consisting of a patient with anorexia nervosa and both parents. As candidate gene approaches did not unequivocally identify susceptibility genes (alleles) for anorexia nervosa or bulimia nervosa, systematic model-free genome-wide screenings should also be performed in order to identify currently unknown genes involved in eating disorders. This kind of approach has already been initiated for anorexia nervosa. Genetic research on eating disorders will hopefully lead to new pharmacological treatment strategies.

Animals↗
PubMed2000

Significant association between a silent polymorphism in the neuromedin B gene and body weight in German children and adolescents.

Neuromedin B has been shown to exert an inhibiting effect on food consumption in rats. The corresponding gene NMB maps to chromosome 15q22.3-q23, a region expected to contain a gene for the Bardet-Biedl syndrome type 4 (BBS4). Based on its map position and the putative function of the encoded peptide, NMB can be considered as a candidate gene both for BBS4 and the development of human obesity. To examine its involvement in these phenotypes, we determined the genomic structure of human NMB, and performed a mutation screen in its coding region. In genomic DNA of six BBS4 patients and in a large population sample, two sequence variants were detected: a g.253C-->A transversion creating a P73T substitution and a g.401G-->A silent mutation changing the stop codon TGA into stop codon TAA. A case-control study with 92 extremely obese patients and 94 underweight students revealed a significant association between the g.401G-->A polymorphism and body weight (adjustedp = 0.03), which was confirmed in a validation sample consisting of 95 extremely obese patients, and 95 normal weight and 48 underweight individuals (Mann-Whitney p = 0.02). These results suggest a contribution of NMB or a gene in its close vicinity to genetic weight control in humans.

Adolescent↗
PubMed2000

Epidemic obesity: are genetic factors involved via increased rates of assortative mating?

OBJECTIVE: Prevalence rates of obesity have been increasing in several countries over the past two decades. Mainly secular changes in energy intake and expenditure have been invoked to underly the increasing rates; genetic factors have not been considered because of the very recency of this phenomenon. We hypothesize that genetic factors might very well be involved via an increased rate of assortative mating between obese individuals. We speculate that the recent upsurge in social stigmatization of obese individuals underlies the hypothesized increase in assortative mating. DESIGN: To accumulate evidence for our hypothesis we analysed deduced rates of assortative mating among parents of extremely obese children and adolescents, who belonged to two different large study groups (n = 201 and n = 270). For this purpose we calculated parental body mass indices (BMIs) based on (a) measured current heights and weights, (b) self-reported current heights and weights, and finally (c) measured current heights and recalled weights at ages 20 and 30, respectively. BMI centiles were determined which in turn were attributed to the respective BMI decile. Deduced rates of assortative mating were evaluated in bivariate histograms of the paternal and maternal BMI deciles. RESULTS: High rates of assortative mating were observed as deduced from the bivariate histograms, which revealed a fairly consistent pattern. Thus, in the first study group almost 35% of the parental pairs had a BMI in the tenth decile; over 50% of the mothers and fathers had a BMI in this top decile. Recalled parental BMIs at ages 20 and 30 also clustered in the upper decile. These results were basically replicated in the second study group. In addition, parental loading on the tenth decile was shown to be higher for the subgroup of children and adolescents who had a BMI equal to or exceeding the highest BMI of the population-based age and gender matched control group. CONCLUSIONS: Our results indicate that assortative mating is common among parents of extremely obese children and adolescents, ascertained between 1995 and 1997. In addition, the parental loading on the tenth decile is most prominent for the most obese children. Whereas we are unable to document an increased rate of assortative mating, we interpret our results as being consistent with the hypothesis that an increased rate of assortative mating has contributed to the recent rise in obesity rates in several countries. Thus, assortative mating warrants further studies to assess its impact on obesity prevalence rates through both genetic and non-genetic mechanisms. Our results suggest that assortative mating might especially increase the rates for extreme obesity.

Adolescent↗
PubMed2000

Independent confirmation of a major locus for obesity on chromosome 10.

Linkage results obtained in genome-wide scans for complex phenotypes require confirmation in independent samples. Recently, linkage of obesity to chromosome 10p12 with a maximal multipoint LOD score of 4.85 was reported upon use of an affected sib-pair approach including nuclear families in which the adult index case had a BMI > or = 40 kg/m2 and at least one further sibling had a BMI > or = 27 kg/m2 (Hager et al., 1998, Nat Genet 20:304-8). To attempt to replicate this linkage finding we genotyped 11 markers spanning approximately 23 cM from 10p13 to 10ql1 in a total of 386 individuals stemming from 93 nuclear families with two or more young obese offspring with a BMI > or = 90th age percentile. The highest multipoint maximum likelihood binomial (MLB) LOD score using the extreme concordant sib-pair approach in which one sib had a BMI > or = 95th percentile, and other sibs a BMI > or = 90th percentile was 2.32. Six markers yielded nominal p-values < 0.05, the highest two point MLB-LOD score of 2.45 (nominal p = 0.0004) was obtained for the marker TCF8. Transmission disequilibrium tests for the most frequent parental allele yielded no nominal p-value < 0.05. The linkage results confirm the presence of a major susceptibility locus for obesity in a region near the centromere on chromosome 10.

Adult↗
PubMed1999

No evidence for involvement of polymorphisms of the dopamine D4 receptor gene in anorexia nervosa, underweight, and obesity.

Family and twin studies suggest a genetic contribution to the etiology of anorexia nervosa (AN) and obesity. Genes involved in weight regulation can be considered as candidate genes for AN. The dopaminergic system has been implicated in weight regulation; previous results had suggested a possible involvement of the dopamine D4 receptor gene (DRD4). We screened for alleles of two different polymorphisms (13-bp deletion, 48-bp repeat) in the DRD4. For association tests, allele frequencies were compared between 109 inpatients with AN, 82 underweight students, and 327 extremely obese children and adolescents. For application of transmission disequlibrium tests (TDT) we additionally genotyped 57 and 137 trios comprising a patient with AN or an extremely obese child or adolescent, respectively, and both parents. All genotyping was performed with polymerase chain reaction fragment length polymorphism analyses. None of the association tests or TDT rendered nominal P values below 0.1. An influence of alleles of the DRD4 on the development of AN, underweight, or extreme early onset obesity was not detected. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:594-597, 1999.

Adolescent↗
PubMed1999

[Body weight regulation in anorexia nervosa with special attention to leptin secretion].

Underweight is a key symptom in anorexia nervosa. In this review we summarize recent findings pertaining to weight regulation in this eating disorder. The observation that a body mass index below 13 kg/m2 upon admission for inpatient treatment is associated with a high mortality rate and chronic persistence of underweight is of obvious clinical relevance. A lowered leptin secretion, which results from the weight loss, is presumably of major importance for the development of amenorrhea. We discuss findings pertaining to a reduced body weight in other psychiatric disorders during adolescence in the light of Kretschmer's findings related to body frame and psychopathology.

Animals↗
PubMed1999

No evidence for an involvement of alleles of polymorphisms in the serotonin1Dbeta and 7 receptor genes in obesity, underweight or anorexia nervosa.

The serotonergic (5-hydroxytryptamine, 5-HT) system has been implicated in body weight regulation and in the etiology of anorexia nervosa (AN). Here we describe the screening of the known Phe-124-Cys polymorphism in the 5-HT1Dbeta receptor gene and of the known Pro-279-Leu polymorphism in the 5-HT7 receptor gene. For association tests allele frequencies were compared between up to 393 extremely obese children and adolescents, 142 underweight students and 84 patients with AN. None of the association tests revealed nominal P-values below 0.3. We conclude that a major role of the investigated polymorphisms in body weight regulation or AN appears unlikely.

Adolescent↗
PubMed1999

Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene.

Recently, haploinsufficiency mutations in the melanocortin-4 receptor gene (MC4-R) were detected which were assumed to lead to the phenotype of extreme obesity. Previously, we detected three obese carriers among 306 index patients. Here we describe the detection of one haploinsufficiency carrier in an additional study group of 186 obese individuals. We subsequently genotyped and phenotyped 43 family members of these four index patients, two of whom were second-degree cousins. A total of 19 carriers were identified. Extreme obesity was the predominating phenotype. However, moderate obesity occurred in three of the carriers. No other specific phenotypic abnormalities were detected. Female haploinsufficiency carriers were heavier than male carriers in the respective families, a finding similar to findings in MC4-R-knockout mice. In conclusion, our data fully support the etiologic role of MC4-R haploinsufficiency mutations in obesity.

Adolescent↗
PubMed1999

Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.

The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.

Adolescent↗