Harold O. Goodman

Genetic Predisposition to Formation of Calcium Oxalate Renal Calculi

Abstract Significantly higher frequencies of renal calculi were found among the 625 parents and sibs of 106 subjects prone to calcium oxalate stone formation as compared with 576 corresponding rela...

GENETIC FACTORS IN CALCIUM OXALATE STONE DISEASE

Idiopathic calcium oxalate nephrolithiasis is a complex, multifactorial disease resulting from an interaction between environmental and genetic factors. Urinary characteristics often associated with the disease include hypercalciuria, hyperoxaluria, hypocitraturia and hyperuricosuria. Roles have also been suggested for glycosaminoglycans, magnesium and several proteins in urine that may promote or inhibit stone formation. The relative contribution of these factors to stone disease is not known with any certainty. Furthermore, each of these components may be affected by environmental and genetic influences. Despite these complexities it is possible to dissect out genetic and environmental contributions. In particular, when the environmental factors are carefully controlled or assessed the genetic contribution may become evident. We will review evidence indicating that genetic factors may significantly affect the excretion of various analytes and suggest how these may influence the susceptibility of an individual to stone disease. The pattern of inheritance in the disease is polygenic and also suggests that only a limited number of genetic loci are involved. To support further the inference that only a limited number of loci are involved, we developed a computer model showing that with only 3 loci a pattern of inheritance is generated that simulates the observed inheritance of calcium oxalate nephrolithiasis in the population and among relatives of stone formers. The identification of the specific genes involved in calcium oxalate stone disease will not only lead to a greater understanding of how the disease develops but also assist in the evaluation of stone patients and in designing new therapeutic strategies.

Interactions Among Dietary Fat, Protein, and Cholesterol in Atherosclerosis-Susceptible Pigeons

Atherosclerosis-susceptible pigeons fed cholesterol developed coronary atherosclerosis much more frequently than pigeons maintained on a cholesterol-free diet. Fewer of the cholesterol-fed pigeons fed a low protein diet developed coronary atherosclerosis than did cholesterol-fed pigeons on a high protein diet. Corn oil decreased the frequency of coronary atherosclerosis in cholesterol-fed pigeons. Limited evidence suggests that the coronary arteries and aortae in noncholesterol-fed birds are independent of each other in their susceptibility to atherosclerosis.

Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides.

The present study has indicated that significant shifts in plasma, urinary, and tissue taurine and in non-taurine dialyzable amines occur in the STZ-induced diabetic rat, especially in the kidney. Taurine administration at relatively low dosage ameliorated only kidney taurine concentration. Anticipated alterations in plasma glucose and creatinine were observed but neither of these changes was affected by taurine administration. Similarly, urinary output of creatinine, glucose, and NAG increased significantly among diabetic rats, but none of these were detectably influenced by taurine. Increases in plasma triglycerides observed in STZ-induced diabetes appear to be attenuated by taurine administration, and although cholesterol concentrations were lower in taurine-treated rats, the differences were not statistically significant. These findings should encourage further studies of these effects in rats as a useful model for several complications of human diabetes including atherosclerosis, retinopathy, and nephropathy.

Genes in idiopathic calcium oxalate stone disease

An examination of the urinary excretions of 101 normal subjects indicated that the major genetic influence on calcium excretion is a codominant pair of alleles giving rise to three phenotypes, low, intermediate and high (hypercalciuric) excretors. This inference was based on variance, Hardy-Weinberg and segregation analyses. Similar independent gene pairs also appear to influence oxalate and citrate excretion, A 3-locus Hardy-einberg table using estimates of gene frequencies derived from the study of normals suggests that only 3 or 4 leading genes are involved in oxalate stone disease. Strong candidate genes identified from molecular and physiological studies cannot be proposed at present, but it is assumed that they influence the transport of these ions in either the intestine, kidney or both organs. The identification of the genes involved should be facilitated by the reduction of dietary influences on urinary excretions through the use of formula diets.

GENETIC AND DIETARY INFLUENCES ON URINARY OXALATE EXCRETION

Abstract Several genes contribute to the development of calcium oxalate nephrolithiasis as it is a polygenic disease. To explore the influence of genetic factors on oxalate excretion we have examined the distribution of oxalate excretions in 101 normal individuals who consumed self-selected diets. The distribution was apparently trimodal, consistent with the existence of three classes of oxalate excretors reflecting two allelic genes determining high and low oxalate excretion occurring with frequencies of 0.32 and 0.68 respectively. The pattern of inheritance in eight families was compatible with the expression of a pair of codominant alleles. A comparison of the distribution of excretory classes among the 101 normal individuals with that of 101 calcium oxalate stone formers suggests that high oxalate excretion may be associated with a 4-fold increased risk of stone disease and intermediate excretion with a 1.6-fold increase. Control of dietary factors influencing oxalate excretion apparently improved the discrimination between excretory classes in 17 individuals but the intra-individual variability in oxalate excretion was not reduced in four of nine individuals in whom this parameter was evaluated. More stringent dietary control than that applied in this study may be required before more extensive genotyping of individuals is attempted.

Heterozygous cystinuria and calcium oxalate urolithiasis.

Many variables are known to be associated with the formation of calcium oxalate urolithiasis but none is essential for the initiation or growth of stones. It is likely that the predisposition to stone formation is related to multiple factors. We herein describe still another metabolic state that seems to predispose to calcium oxalate stone disease, namely heterozygosity for cystinuria. Cystine screening tests were done on 24-hour urine specimens obtained from 126 patients in whom recurrent calcium oxalate stones form and 84 controls and quantitative amino acid determinations were done on all positive specimens. Of those studied 17 of 126 stone patients and 1 of 84 controls were heterozygous cystinurics. A test of the differences between the relative frequencies of cystinuria heterozygotes in the 2 groups with Fishers exact test revealed them to be highly significant (p less than 0.001). Our study indicates that carrier status for 1 of the cystinuria genes predisposes to calcium oxalate stone formation but, like other factors related to urolithiasis, it is not a necessary cause of stone disease.

Interactions Among Dietary Fat, Protein, and Cholesterol in Atherosclerosis-Susceptible Pigeons Effects on Serum Cholesterol and Aortic Atherosclerosis

In a 3× 2× 2 factorially designed experiment, White Carneau pigeons were kept nine months on diets containing three levels of protein (5 per cent, 15 per cent, and 30 per cent casein) and two types of dietary fat (10 per cent oil or 10 per cent hydrogenated coconut oil). Identical groups received, in addition, 0.25 per cent cholesterol. Analysis for serum cholesterol, and for cholesterol, total lipids, and phospholipids in the aorta, and measurements of atherosclerotic index were carried out. The data were subjected to statistical evaluation by analysis of variance. The addition of cholesterol to the diets elevated the level of cholesterol in the serum and the aorta and increased the severity of atherosclerosis. A significant interaction was found to exist between the type of fat in the diet and the presence or absence of cholesterol. Among cholesterol-fed birds only, corn oil exerted a significant cholesterol-lowering action. Suggestive evidence was obtained for the concept that the severity of atherosclerosis is influenced by the type of dietary fat, the level of protein, and the presence or absence of cholesterol in the diet, and that bio-logical interactions exist among these dietary variables.

Familial brain tumors: studies of two families and review of recent literature

We studied two families in each of which three or more individuals were affected by brain tumors. In the first family, which had no evidence of neurofibromatosis or tuberous sclerosis, a man, his sister, and her son developed histologically proven gliomas; the mans great uncle was historically reported to have died from a brain tumor, but the exact nature of the tumor was not known. In this family two of the tumors were low grade astrocytomas of the cerebrum, whereas the third was a mixed glioma of the cerebellum. Karyotypic analysis of this tumor showed no marker chromosomes. A second family had a history of an unusual concentration of brain tumors. In one patient the tumor was a histologically verified glioma. Four other patients had historically reported brain tumors, the descriptions of which suggested gliomas. Both families showed involvement of individuals in adjacent generations, although in both instances there were skipped generations. Twins, siblings, or parents and children are the kindred groups affected in most other reported families with multiple brain tumors. The mode of inheritance of brain tumors in these two families and recent literature on the conditions associated with familial brain tumors are discussed.

Interrelated effects of dietary fats and proteins on atherosclerosis in the pigeon.

Summary White Carneau pigeons were maintained for 15 months on diets in which 30 % of the calories came from either margarine, butter, corn oil or Crisco (30 mg of cholesterol was added to each 100 g of the latter two fats to equal the cholesterol content of butter). Dietary protein was supplied by either wheat gluten or a casein-lactalbumin mixture, each fed at two levels. At the end of the experiments the levels of serum triglycerides and cholesterol were measured, as were the prevalence andseverity of aortic atherosclerosis. The aortas were analyzed for their cholesterol content as an additional measure of degree of atherosclerosis. The data from the factorially-designed experiment were analyzed by analysis of variance. The results indicate that almost all of the dietary variables studied (type of fat, presence of cholesterol, type and feeding level of protein) can influence one or more of the parameters thought to be related to atherosclerosis, e.g. , serum cholesterol or triglyceride levels, or the extent of aortic atherosclerosis. Of more significance, however, was the detection of significant interactions, indicating that the effect of a single dietary ingredient is infiuenced by the other components of the diet, and that such influences may be in opposite directions.