ADPKD: practical implications of population genetics.
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Humans↗
Biomedical subjects
J C Bear
Publications and source records attributed to J C Bear.
Autosomal dominant polycystic kidney disease: new information for genetic counselling.
We evaluated the accuracy of ultrasonographic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) and factors influencing its prognosis in members of 17 Newfoundland families originally described in 1984. In 10 families showing genetic linkage between ADPKD and markers for the PKD1 locus, rates of false negative ultrasonographic diagnosis are estimated as 36% below the age of 10 years and 8% or less thereafter, comparable with findings of genetic linkage studies of a subset of family members. At ages above 30 years, false negative ultrasonographic diagnosis of PKD1 disease is unlikely. In 2 families in which ADPKD is not co-inherited with PKD1 markers, only 11% of members aged less than 30 years had kidney cysts. The mean (SE) age of onset of ESRD is 56.3 (1.8) years for persons with the PKD1 form of ADPKD, and 68.7 (1.7) years for affected members of families in which ADPKD is not co-inherited with PKD1 markers (P = 0.01). In the PKD1 families, age of onset of end stage renal disease (ESRD) was unrelated to the sex of the affected individual but was earlier in persons inheriting the disease from their mothers than from their fathers (50.5 vs. 64.8 years, P = 0.004), consistent with an influence of genetic imprinting on disease progression. In females with a PKD1 mutation, onset of ESRD was not influenced by parity. In PKD1 families, resemblance in age of onset of ESRD was apparent; variation was less within than between families (F = 13.0, P less than 0.0001), and risk of false negative ultrasonographic diagnosis appears largely restricted to families in which ESRD occurs relatively late.
Adolescent↗
The diagnosis and prognosis of autosomal dominant polycystic kidney disease.
BACKGROUND: Autosomal dominant polycystic kidney disease is usually caused by a mutant gene at the PKD1 locus on the short arm of chromosome 16, but in about 4 percent of families with the disorder it is caused by unknown mutations elsewhere in the genome. The natural course of the disease in both genetic forms is not well characterized. METHODS: We studied 17 families with autosomal dominant polycystic kidney disease to compare presymptomatic diagnosis by ultrasonography with diagnosis by genetic-linkage studies and to relate clinical variation of the disease to whether the PKD1 mutation was implicated. RESULTS: In 10 families the disorder was found to cosegregate with polymorphic DNA markers flanking the PKD1 locus, in 2 families it did not, and in 5 families linkage could not be determined. In the 10 families with the PKD1 mutation, 46 percent of the members less than 30 years old who had a 50 percent risk of inheriting a mutation had renal cysts, as compared with 11 percent of the members of the two families without linkage (P less than 0.001). In the PKD1 families, all 67 diagnoses made by ultrasonography were confirmed by determination of the genotype as inferred from linkage. Forty of 48 members (83 percent) less than 30 years old who inherited the PKD1 mutation had renal cysts. All 27 members 30 years old or older who inherited the mutation had renal cysts, suggesting that the probability of a false negative diagnosis did not exceed 0.13 in this age group (P less than 0.05). The mean (+/- SE) age at the onset of end-stage renal disease among members of the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/- 1.7 years among members with cysts in the families without linkage (P = 0.0025). Hypertension and renal impairment were less frequent and occurred later in the families without the PKD1 mutation. CONCLUSIONS: At present, in most persons with a 50 percent risk of autosomal dominant polycystic kidney disease, imaging techniques are the only mode of reaching a diagnosis before symptoms appear. In such persons a negative ultrasonographic study during early adult life indicates that the likelihood of inheriting a PKD1 mutation is small. In the few who inherit a non-PKD1 mutation for polycystic kidney disease, renal failure is likely to occur relatively late in life.
Adult↗
Inbreeding in outport Newfoundland.
We investigated inbreeding in 3 outport Newfoundland study areas in which persistent genetic isolation was demonstrated previously. The inbreeding coefficient of every person born in each area was calculated from reconstructed pedigree data. The average inbreeding coefficient for persons born between 1960 and 1979 is 0.0032 in Trepassey Parish (southern Avalon Peninsula), 0.0171 for a group of communities on the west coast of the Great Northern Peninsula, and 0.0007 for southeastern Labrador. Average inbreeding of these populations was higher earlier in this century. Averages are high compared to those reported for other populations, consistent with genetic isolation. Coefficients of kinship were calculated for large samples of pairs of births in each study area, and frequency distributions of inbreeding coefficients compared with frequency distributions of kinship coefficients, to evaluate random and nonrandom mating with respect to consanguinity. These comparisons show that matings between unrelated individuals are more frequent than expected, that matings between first cousins are not strongly avoided in 2 of the 3 study areas, that matings between first cousins once removed are favored, and that matings between distantly related individuals are becoming more frequent. To gain an impression of the potential contribution of inbreeding to the prevalence of recessive disease, we calculated indirect estimates of the expected excess of prereproductive mortality due to inbreeding. These estimates are 15% for Trepassey Parish, 49% for the West Coast study area, and 2% for southeastern Labrador. It is unlikely that genetic isolation of outport Newfoundland populations will decrease. Elevated prevalences of recessive disease, due primarily to matings between persons unaware of their distant consanguinity, therefore require consideration in health care planning in Newfoundland.
Consanguinity↗
Regional localization of the autosomal dominant polycystic kidney disease locus.
The localization of the autosomal dominant polycystic kidney disease locus (PKD1) within an array of anonymous polymorphic DNA sequences on chromosome 16 band p13 was determined by multipoint mapping. Nine polymorphic DNA markers, including two hypervariable sequences, were used to study 19 PKD1 and 21 reference families. PKD1 was found to lie proximal to the 3' and 5' hypervariable regions of alpha-globin and distal to the anonymous sequence CRI-0327. Somatic cell hybrid mapping places PKD1 within the region 16p13.11-16pter. The availability of an array of linked markers which bracket the PKD1 locus provides a framework for further attempts to identify the PKD1 gene and offers an improved method of presymptomatic diagnosis of the disease.
Animals↗
Persistent genetic isolation in outport Newfoundland.
The historical development of genetic isolation has been evaluated for three outport Newfoundland study areas. An attempt was made to ascertain all livebirths in each study area, and determine the parentage of each. Data from records of baptism and marriage were used for this, supplemented with other historical and ethnographic information. Parent-offspring migration was used as a measure of genetic exchange between subpopulations within study areas, and gene flow into the study areas. Currently, 1-8% of parents originate outside the study areas; these rates are low compared to earlier periods, and compared to present-day rates for European isolate populations. Average kinship was estimated, to measure genetic relatedness within and between subpopulations of each area and the potential for random inbreeding; these values, which are minimum estimates, are now at historically high levels. Increased migration into the study areas, which would decrease average kinship, is not likely. Thus, any regionally or locally elevated frequencies of deleterious alleles will persist, and must be taken into account in providing genetic counseling and evaluating the utility of local screening programs.
Consanguinity↗
How the method used to measure refractive error is expected to affect statistical results.
Values of refractive error (RE) observed for subjects and groups depend on the degree to which the measurement method used relaxes accommodation. This affects statistics calculated on RE measurements in predictable ways. Comparing noncycloplegic (NC) with cycloplegic (C) methods, myopia is expected to be more frequent, differences between group means should be less, and correlations and regressions relating RE to other variables may be reduced slightly. Tests based on the categorization of RE will show weaker associations with putative influencing variables. The implications of this are discussed for comparing published studies and choosing measurement methods in epidemiological and genetic studies.
Humans↗
Heterogeneity of systemic lupus erythematosus elucidated by cluster analysis. The influence of HLA.
For 75 patients with systemic lupus erythematosus (SLE), 39 laboratory and clinical characteristics, including HLA-A, B, C and DR typing, were analysed using a cluster analysis technique. Three groups were identified. Group I (46 patients) was characterized by infrequently severe disease, good response to therapy and infrequent multisystem involvement. Group II (24 patients) was characterized by a severe course of disease (although the tendency to remit after therapy was not unusual), and frequently, renal involvement and pericarditis. Group III (5 patients) was characterized by more severe renal disease. Of the 75 patients studied, 38.7% possessed HLA-DR3, compared to 17.4% of controls. Group I patients did not differ from controls but 80% of Group II patients and 4/5 Group III patients had DR3. Cluster analysis identifies subsets of SLE patients who show marked differences in disease course and severity, correlated with possession of the HLA B8, DR3 phenotype.
HLA Antigens↗
The burden of genetically determined eye disease.
We determined the underlying aetiology of blindness for the registered blind population of the Province of Newfoundland and Labrador. In both 1981 and 1984 single-gene disorders accounted for 30% of total blindness and congenital defects for another 10-11%. Genetically determined conditions, diabetes, and senile macular degeneration (SMD) were the three leading causes of registration in each year, 1980-4. We calculated mean ages of registration and mean ages of death over the last four years for five major aetiological groups. Patients with genetic conditions were registered at a much younger age and had a correspondingly longer duration of blindness (21 years as compared with 5 years for either diabetes or SMD). Total 'person-years of blindness' was then calculated from the product of this duration of blindness and the total numbers registered in each group. This index shows that the overall individual and population impact of monogenic blindness is overwhelmingly greater than that of other causes (6849 person-years compared with 270 for diabetes and 430 for SMD). In view of this frequency and duration of monogenic blindness, and also of the substantial hereditary liability to relatively common causes of blindness such as glaucoma, diabetic retinopathy, and high myopia, we suggest that more attention needs to be paid to elucidating the genetic contribution to blindness.
Adult↗
The major histocompatibility complex and autoimmune thyroid disease.
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Autoimmune Diseases↗
The role of HLA antigens in the manifestation and course of Graves' disease.
Graves' disease is associated with HLA-DR3 in Caucasoids. We have now demonstrated, on the basis of disease-associated MHC haplotypes (A1, Cw3, B8, DR3 and fragments thereof) from 38 families in which more than one member had Graves' disease compared with MHC haplotypes from 56 healthy families, that the risk was highest with the DR locus (relative risk for A1, B8, DR3 = 2.3, for B8, DR3 = 5.3, and for DR3 = 6.8). We further used the sib-pair method to explore linkage of Graves' disease liability to the MHC in 67 affected sib-pairs. The data were consistent with an MHC-linked recessive gene with a frequency of 0.2 to 0.3 and a penetrance of 7.2%; the data, however, accommodated penetrance of up to 16.3%. A recessive model was also consistent with the HLA-B8 genotype distribution in 286 unrelated patients. As the effect of the marker alleles on the course of the disease had been debated several times, we applied a cluster analysis method using 49 clinical and laboratory characteristics, including the HLA-A and HLA-B antigens of 196 patients. Three groups were identified, corresponding to patients with mild disease, Hashitoxicosis and severe (relapsing) disease. The prevalence of HLA-B8 was 8.9%, 21% and 87%, respectively (compared to 18.8% in 380 controls). This suggests the existence of an underlying continuum of genetic liability, apparently related to that for Graves' disease severity, associated with the MHC and mediated through immunoregulatory disturbances.
Adolescent↗
The genetic epidemiology of type I diabetes mellitus and autoimmune thyroid disease. Molecular interactions at the population level.
Liability to type I diabetes and autoimmune thyroid disease is familial but not monogenic. Associations of each disorder with several genetic polymorphisms suggest complex interactions in genetic liability, as do associations with aberrant immune function in patients and their unaffected relatives. Each disorder may be genetically heterogeneous, and epidemiological studies suggest that environmental influences on liability to type I diabetes are complex. Familial aggregation of these and other autoimmune endocrine disorders is observed. Genetic analyses have not taken full account of these complexities, due to limitations in data, analytical methods, or both. Evaluating interactions of influences on liability to these disorders will require comprehensive investigations in which all relevant immunological and genetic indicators of liability are assessed for patients, affected and unaffected relatives, and healthy controls. These should aim to determine the influence of allelic variation of participating molecules on normal and aberrant immune function, liability to autoimmunity, and liability to individual diseases. Such efforts would facilitate rational immunological manipulation of liability to these disorders.
Alleles↗
Variant multiple endocrine neoplasia I (MEN IBurin): further studies and non-linkage to HLA.
We have extended our study of an incomplete variant of multiple endocrine neoplasia Type I (MEN IBurin). In this syndrome, primary hyperparathyroidism and prolactin-secreting adenoma are common, with hormone-secreting pancreatic tumors being rarely seen. The recent localization of the prolactin structural gene to chromosome 6 made further investigation of linkage to HLA of particular interest. Results in 2 multigeneration families exclude close linkage to HLA. We cannot at this time draw any inference regarding linkage of MEN IBurin to the prolactin structural gene.
Adenoma↗
The genetics of Graves' disease: HLA and disease susceptibility.
To relate genetic variation in Graves' disease (GD) susceptibility to polymorphism at MHC loci, clinical and family studies were undertaken in eastern Hungary. Among 1980 relatives of 534 index patients, 2.9% of siblings, 2.7% of offspring, and 3.0% of parents had GD. HLA haplotype combinations in affected sibling pairs were determined in the present data and combined with data in the literature (12 sibling pairs from Farid 1981, 12 from Chan et al. 1980, and 15 from Sasazuki et al. 1983); 43, 23, and 1 affected sibling pairs shared, respectively, 2, 1, and 0 HLA haplotypes. This distribution is inconsistent with simple dominant inheritance, but is consistent with simple recessive inheritance of HLA-related susceptibility over a range of gene frequencies (0.2-0.4). A frequency of 0.3 gives the best fit and is consistent with penetrance of 7.1% for the recessive susceptibility genotype; the data, however, can accommodate penetrance values up to 16%. The distribution of HLA haplotypes in 33 families related disease susceptibility more strongly to DR than to other loci. The distribution of HLA-B8 genotypes in 256 patients was in close agreement with Hardy-Weinberg equilibrium proportions, also favoring recessive inheritance of MHC-related susceptibility. The probability that an individual will be affected with GD can be predicted, based on sex, HLA genotype, and family history. For example, 14.9% of DR3-positive women with an affected first degree relative are likely to be affected. These predictions can be tested as family data accumulate.
Adolescent↗
Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling.
Few reports are available on the age-related risk of relatives of affected persons to manifest adult polycystic kidney disease (APKD). For 371 persons in 17 kindreds, at risk for APKD by virtue of having an affected first degree relative, we calculated the estimated probability of clinical diagnosis of APKD to be 0.011 by age 20, 0.041 by age 30, 0.115 by age 40, 0.299 by age 50, and 0.404 by age 60 years (expected = 0.50). Ultrasonographic examination of 172 asymptomatic persons at risk showed definite APKD in 60. The probability of ultrasonographic detection of asymptomatic APKD is estimated as 0.222, 0.657, and 0.855 at age 5, 15, and 25 years, respectively. The probability of having APKD following normal ultrasonogram results (conservatively assuming 90% specificity) is estimated as 0.46, 0.28, and 0.14 for persons at 50% risk in their first, second, or third decade. The marginal benefit of ultrasound as a diagnostic test for APKD for persons in the second or third decade is estimated as 0.37 and 0.41, respectively for a "positive" test and 0.22 and 0.37 for a "negative" test.
Adolescent↗
Prognosis of adult onset polycystic kidney disease re-evaluated.
To appraise the prognosis of adult onset polycystic kidney disease (APKD), an inception cohort containing 140 subjects from 17 kindreds was assembled. Multiple renal cysts, demonstrable by ultrasonography, or clinical APKD, or both were present in 100 subjects. APKD was predicted in 32 subjects unavailable for ultrasonography and could not be excluded in eight deceased subjects. All had been at risk for endstage renal disease (ESRD) since birth. The probability of either developing ESRD, requiring dialysis or transplantation, or dying was estimated using a time-to-event analysis. The earliest age at which ESRD occurred was 36 years. For those with APKD, the probability of being alive and not having ESRD was 77% by age 50, 57% by age 58, and 52% by age 73 years. Excluding those predicted to have APKD changes these probabilities to 75, 53, and 47%, respectively. The serum creatinine values were less than 1.5 mg/dl for most subjects who had not developed ESRD. The prognosis for subjects with APKD is much better than most reports suggest and can be estimated from the time-to-event data presented.
Adult↗
HLA and urolithiasis.
Frequencies of persons having particular HLA-A, -B, and -C antigens were compared for 113 urolithiasis clinic patients, a subset of 24 patients who had hypercalcuria , and 225 controls. The frequency of HLA- A30 was significantly elevated among the patients. A suggestion (S afwenberg et al. 1978) that HLA-B27 frequency is elevated among hypercalcuric patients with recurrent kidney stones was not confirmed.
Adult↗
Graves' disease--the thyroid stimulating antibody and immunological networks.
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Antibody Formation↗