A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference.

METHODS: We analyzed data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R and K656N) of LEPR with body mass index (BMI; kg/m(2)) and waist circumference (WC). A total of 3263 related and unrelated subjects from diverse ethnic backgrounds including African-American, Caucasian, Danish, Finnish, French Canadian and Nigerian were studied. We tested effects of individual alleles, joint effects of alleles at multiple loci, epistatic effects among alleles at different loci, effect modification by age, sex, diabetes and ethnicity, and pleiotropic genotype effects on BMI and WC. RESULTS: We found that none of the effects were significant at the 0.05 level. Heterogeneity tests showed that the variations of the non-significant effects are within the range of sampling variation. CONCLUSIONS: We conclude that, although certain genotypic effects could be population-specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or WC in the overall population.

Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity.

Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises important statistical issues. In the process of analyzing data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R, and K656N) of LEPR with body mass index (BMI; kilograms divided by the square of the height in meters) and waist circumference (WC), we encountered the following methodological challenges: data on relatives, missing data, multivariate analysis, multiallele analysis at multiple loci, heterogeneity, and epistasis. We propose herein statistical methods and procedures to deal with such issues. With a total of 3263 related and unrelated subjects from diverse ethnic backgrounds such as African-American, Caucasian, Danish, Finnish, French-Canadian, and Nigerian, we tested effects of individual alleles; joint effects of alleles at multiple loci; epistatic effects among alleles at different loci; effect modification by age, sex, diabetes, and ethnicity; and pleiotropic genotype effects on BMI and WC. The statistical methodologies were applied, before and after multiple imputation of missing observations, to pooled data as well as to individual data sets for estimates from each study, the latter leading to a metaanalysis. The results from the metaanalysis and the pooling analysis showed that none of the effects were significant at the 0.05 level of significance. Heterogeneity tests showed that the variations of the nonsignificant effects are within the range of sampling variation. Although certain genotypic effects could be population specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or waist circumference in the general population.

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families.

Family studies have shown that in some populations up to 75% of the variation of body mass index can be explained by genetic factors. However, in humans, no major obesity gene has been identified to date. In contrast, there are a number of genetically well defined animal models for obesity. In two of those models (ob/ob and db/db), defects in the same pathway are responsible for obesity. Recently, some evidence has been found for the OB gene also being involved in human obesity. In this study we investigated the potential role of the OB receptor (OBR) in the etiology of massive obesity in humans using familial linkage analyses and case-control association studies. The typing of two microsatellite markers (D1S198 and D1S209), flanking the OBR gene, in 256 sib pairs showed no evidence for linkage with obesity. In order to be able to detect small gene effects, association studies with a 3'-UTR insertion/deletion polymorphism were carried out. The results of these analyses remained non-significant (chi 2 = 3.442, P = 0.18). However, subjects heterozygous for the insertion/deletion polymorphism showed a slight trend towards lower insulin values 30 min after an oral glucose load compared to homozygous individuals (P = 0.02). In summary, our results do not support a major role of the human OBR gene in the development of morbid obesity in our population.

Mitochondrial glycerol-3-phosphate dehydrogenase. Cloning of an alternatively spliced human islet-cell cDNA, tissue distribution, physical mapping, and identification of a polymorphic genetic marker.

Pancreatic beta-cell mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) plays a major role in glucose-induced insulin secretion. Decreased activity of this enzyme has thus been proposed to play a role in the pathogenesis of NIDDM. Cloning of human insulinoma mGPDH cDNAs disclosed the existence of two variant transcripts with different 5' ends. Reverse transcription polymerase chain reaction (PCR) confirmed the presence of both mGPDH mRNAs in purified native human pancreatic islets and other tissues. A major 6.5-Kb mGPDH transcript was detected by Northern blot analysis in RNA from human and rat pancreatic islets, with distinctly lower levels in other human tissues, indicating that previously reported high mGPDH enzymatic activity in beta-cells is determined by high transcript levels. The mGPDH gene was mapped to chromosome 2 by PCR analysis of genomic DNA from human/rodent somatic cell hybrids, and five independent overlapping yeast artificial chromosome (YAC) clones containing the mGPDH sequence were identified from the Centre d'Etude du Polymorphisme Humain YAC library. Analysis of these YAC clones identified a highly polymorphic chromosome 2q21-q33 dinucleotide repeat genetic marker (D2S141) physically linked to the mGPDH gene. These studies provide the means to investigate the role of the human mGPDH gene in the pathogenesis of NIDDM and illustrate the value of a novel strategy to identify genetic markers for diabetes candidate genes.

[Quality and value of expert assessment of disability with reference to evaluation of cardiovascular diseases]. / Zur Qualität und Aussagekraft von Invaliditätsgutachten hinsichtlich der Beurteilung von Herz-Kreislauf-Krankheiten.

Because of the high frequency of diseases of heart and circulation a great number of physicians is concerned with experts opinions of them. There were 273 experts opinions from the rural and city district of Leipzig analysed in order to estimate quality and assertions force of experts opinions of invalidity with regard to estimation of diseases of heart and circulation. There was often found that data of anamnesis and documents extracts did not satisfy. But the parts about findings and estimates of experts opinions were in most cases well. Often complaints of patients and possibilities of therapy and rehabilitation were considered too less. The code of diagnosis did not always correspond to the International Statistical Classification of Diseases and Death Causes. There was often no sufficient evidence of diagnosis and degree of heaviness in the text of the experts opinions. But clinical findings with function checks were very well documented in many experts opinions.

[The behavior of heart rate and blood pressure during loading in stage-I and -II hypertensives--a criterion for the differential therapy of arterial hypertension]. / Das Verhalten von Herzfrequenz und Blutdruck unter Belastung bei Hypertonikern der Stadien I und II--ein Kriterium für die Differentialtherapie der arteriellen Hypertonie.

84 hypertensives and 40 normotensives were examined on a bicycle ergometer. In the hypertensives different reaction patterns of blood pressure and heart rate were found, which could be subdivided into 5 groups. From this subdivision conclusions to the developmental mechanism of the hypertension may be derived: hyperkinetic dysregulation or resistance high blood pressure. Furthermore, a conditioned by situation "consulting hours hypertension" may be demarcated from the disease accompanied by hypertension. A haemodynamically oriented differential therapy and a following control ergometry were performed. Previously increased values of blood pressure and heart rate were significantly lower. Finally the indications for ergometry of patients with hypertension are demonstrated.

[Which anamnestic data and which findings are meaningful in assessing coronary circulatory function in disability evaluation?]. / Welche anamnestischen Angaben und welche Befunde sind für die Beurteilung der Herz-Kreislauf-Funktion bei der Begutachtung bedeutsam?

For the judgement of the function of heart and circulation in the expert's opinion concerning invalidity are significant; anamnestic data (dyspnoea, angina pectoris, giddiness, disturbances of consciousness); clinical findings (cyanosis, dyspnoea, stasis of the jugular vein, pulse, heart sounds and extrasounds, enlargement of the liver, oedemata); paraclinical findings (thorax-x-ray, ECG, ergometry). Already by a critically made anamnesis a classification according to clinical degrees of severity (NYHA) can be done. By synopsis of anamnesis, clinical and paraclinical findings apart from the establishment of a diagnosis an objective estimation of the disease-related restriction of the working capacity is possible. All data necessary for the judgement must be in the expert's opinion.

[Response of the heart rate and blood pressure to exertion - criterion for the differential therapy of hypertension]. / Verhalten von Herzfrequenz und Blutdruck unter Belastung - ein Kriterium für die Differentialtherapie der Hypertonie?

In 37 patients with essential hypertension (WHO-stage I and II) ergometric examinations with submaximum stress were performed in sitting position for the judgement of the behaviour of heart rate and blood pressure (control group 20 clinically healthy persons). On account of the different behaviour of the heart rate the patients could be subdivided into 4 groups: A: normal heart rate in rest and under stress. B: heart rate increased only under stress. C: heart rate increased already in rest. Group D consisted of patients with hypertensive disturbance of the regulation (normal blood pressure immediately before ergometry). In 12 of the patients were also performed ergometric examinations under therapy: in group A the combined use of beta-receptor blocker and saluretic was necessary, in the groups B, C and D monotherapy with beta-receptor blocker was sufficient. The opinion is uttered that an abundant increase of blood pressure under stress in anamnestically known increased values of blood pressure in rest is also an indication to therapy as the appearance of very varying and on an average occasionally increased blood pressure values. In group A (normal regulation of frequency) by the beta-receptor blocker alone as a rule no sufficient effect is expected, the combination with a saluretic is necessary. In the other groups apart from the regulation of the blood pressure also the regulation of the heart rate is disturbed (among others reduction of the vagal inhibition of the heart, lack of training) and apart from the medicamentous therapy with beta-receptor blockers also a physical training is to be recommended. The different patterns of reaction which were to be proved by means of ergometry in patients with hypertension may in most cases be supposed already by the observation of the course and thus be included in the consideration concerning the differential therapy.

[Overturned left type - manifestation of impaired intraventricular stimulus conduction or position dependent?]. / Uberdrehter Linkstyp - Ausdruck einer intraventrikuären Erregungsleitungsstörung oder lagebedingt?

When an overturned left type is present special criteria render possible the diagnosis of the left-anterior fascicular block. Among 7,687 ECG in 698 cases (9.1%) an overturned left type was to be seen. In accidental random test of 300 ECG with overturned left type in 183 cases (61%) a left-anterior fascicular block, in 111 cases (37%) an overturned QRS-left position were found. In 6 cases (2%) a decision was not possible. The left-anterior fascicular block increasedly appears with growing age beyond the 50th year of life. Hypertension (67%), chronic ischaemic heart disease (46%) clearly prevail in patients with left-anterior fascicular block, on the other and non-cardiovascular diseases with 58% more frequently appeared in the group of patients with overturned QRS-left-position. In this group hypertension occurred only in 33%, chronic ischaemic heart disease only in 14%.

[Aortic stenosis in old age - a diagnostic problem]. / Aortenstenose im höheren Lebensalter - ein diagnostisches Problem.

From 1973 to 1978 in the dissection material of the Medical Clinic in 78 deceased a stenosis of the aortic valve was diagnosed. Clinically diagnosed was the failure of the aortic valve, however, only in 33 cases. The retrospective analysis of the dissection material showed from the clinical point of view that the old age of the patients at admission (x = 70 years), the short stay in the ward and the reduced general condition were factors which rendered difficult the diagnosis of a stenosis of the aortic valve. On the basis of our results we are of the opinion that when a systolic murmur is present above the basis in connection with signs of the load of the left heart in the ECG in every case the diagnosis of the stenosis of the aortic valve is to be included into the diagnostic considerations also when a picture of heart complaints is not present in older persons.

[Methods and evaluation of clinical ergometer tests]. / Zur Methodik und Auswertung von klinischen Ergometeruntersuchungen.

Taking into consideration biological calibration of ergometers the authors suggest load steps to be related to oxygen uptake. A pedalling rate of 45 rev/min should be used. At each stage of load an almost steady state should be reached, at which there is no further increase of the pulse rate. Thus, one load period will extend over 3--6 minutes. Intermittent rest pauses are required only for special reasons of method. The parameters to be measured depend on required data. In evaluating test results it should be considered that poor performance in an exercise test cannot only be caused by heart or lung diseases, but also by functional disturbances.

[Improvement of drug therapy for essential hypertension]. / Zur Optimierung der medikamentösen Therapie der essentiellen Hypertonie.

Only 20-30% out of all the patients suffering from hypertension have sufficient treatment. In spite of full treatment a small part of the patients (about 5%) shows an insatisfactory result. Subjective factors are more important: on the part of physicians doubtfulness about choice of medicaments and imperfect consistency to long-term treatment, on the part of patients inadequate co-operation. The use of 9 selected antihypertensive medicaments is suggested in a decided order under rational aspects (mode of action, side effects, expense for controls, cost). In 1975-1978 development of consumption of antihypertensives and diuretics in the district of Leipzig corresponded to this conception. The respective medicaments placed at disposal in the district of Leipzig were sufficient to treatment of 30% out of all persons suffering from hypertension in 1975 and of 40% in 1978.

[Optimization of therapy using cardiac glycosides]. / Zur Optimierung der Therapie mit Herzglykosiden.

By the estimation of the serum glycoside concentration during the last years numerous new recognitions have been got, particularly concerning the pharmacokinetics of the heart glycosides, which increasingly will be reflected in the clinical practice. Apart from thoughts on pharmacokinetics the author adopts a definite attitude to glycoside tolerance, to the influence of age and bodyweight as well as to the importance of disturbances of the renal function. Moreover it is referred to new aspects in the dosage of heart glycosides, in which case the revision of the central therapy recommendations seems to be necessary.

[Results of stationary management of patients with hypertension with reference to previous ambulatory care]. / Ergebnisse stationärer Behandlung von Patienten mit Hypertonie unter Berücksichtigung der ambulanten Vorbehandlung.

The case histories of 100 patients who were hospitalised in the Department of Internal Medicine of St. George's Hospital in the period from January 1975 to March 1976 are analysed mainly to study their treatment as outpatients (information of the patient, previous diagnoses and treatment, and diagnosis at the time of hospitalisation) and the results of their in-hospital treatment. Most of the patients were admitted to hospital at an advanced stage, usually when out-patient treatment had failed to produce results, but in 80% of the cases the result of in-hospital treatment was satisfactory or good. Besides improvement in drug combination and treatment of cardiac insufficiency, the most frequent complication, observation of general therapeutic principles under conditions of in-hospital treatment was found to be of special importance. Over and above this, we regard close cooperation of hospital and out-patient clinic as essential in the optimisation of the treatment of hypertension.