Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of ...genome-wide association data in 67,093 Caucasian individuals from 20 population-based studies to identify new susceptibility loci for reduced renal function, estimated by serum creatinine (eGFRcrea), cystatin C (eGFRcys), and CKD (eGFRcrea <60 ml/min/1.73m
2
; n = 5,807 CKD cases). Follow-up of the 23 genome-wide significant loci (p<5×10
−8
) in 22,982 replication samples identified 13 novel loci for renal function and CKD (in or near
LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2
, and
SLC7A9
) and 7 creatinine production and secretion loci (
CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72, BCAS3
). These results further our understanding of biologic mechanisms of kidney function by identifying loci potentially influencing nephrogenesis, podocyte function, angiogenesis, solute transport, and metabolic functions of the kidney.
Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible ...for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.
We observed the Joubert syndrome (JS) associated with bilateral morning glory disk anomaly and cystic dysplastic kidneys in three patients from a consanguineous kindred. Homozygosity mapping excluded ...three JS candidate loci as sites harboring the disease gene. We thus delineate an autosomal recessive disorder, distinct from JS and related conditions.
Influence of hematocrit on the measurement of lipoproteins demonstrated by the example of lipoprotein(a).
The measurement of many parameters of human blood is usually performed in plasma or serum. ...Since lipoproteins or apolipoproteins, for example, are found almost exclusively in the plasma fraction after low-speed centrifugation, these parameters can be expected to be distributed in a different plasma volume depending on the hematocrit value. Therefore, the measured plasma levels might be relatively too low or too high in comparison to the whole blood concentrations in the case of abnormal hematocrit levels. The aim of our experiments was to evaluate the extent of differences between whole blood and plasma concentrations, taking as an example lipoprotein(a) Lp(a) in hemodialysis patients with documented decreased hematocrit values.
Lp(a) was measured in plasma as well as whole blood of 15 hemodialysis patients with low hematocrit values (0.29 ± 0.02) in comparison to 11 control subjects (0.45 ± 0.04).
Plasma concentrations were 27% higher in patients than in controls (19.7 vs. 15.5mg/dl). The relative difference was twice as high (59%) when measured in whole blood (13.5 vs. 8.5mg/dl). Similar relative differences were observed when whole blood concentrations of 125 hemodialysis patients and 256 controls were calculated with the formulaLp(a)pasma*(1−hematocrit).
Our findings clearly demonstrate that hematocrit is a strong confounding variable of lipoprotein measurement in epidemiological studies when concentrations are measured in plasma, especially in cases of abnormal hematocrit values. Furthermore, studies investigating the longitudinal changes of lipoproteins should consider potential hematocrit changes.
OBJECTIVE:--In response to hyperglycemia, {szligbeta}-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful ...pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all {szligbeta}-cell hormones. RESEARCH DESIGN AND METHODS--Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, {szligbeta}-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 ± 1 kg/m², 47 ± 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 ± 1 kg/m², 50 ± 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 ± 1 kg/m², 47 ± 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS:--PKT patients had higher fasting amylin (19 ± 3 vs. control subjects: 7 ± 1 pmol/l) and insulin (20 ± 2 vs. control subjects: 10 ± 1 microU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. {szligbeta}-Cell sensitivity to glucose was reduced in PKT patients (-64%, P < 0.009). Fasting plasma amylin was inversely associated with {szligbeta}-cell sensitivity to glucose (r = -0.543, P < 0.004). CONCLUSIONS:--After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired {szligbeta}-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired {szligbeta}-cell function in type 1 diabetic patients after PKT.
The atherogenic lipoprotein(a) (Lp(a)) is significantly increased in patients with kidney disease. Some studies in hemodialysis patients described this increase to be dependent on the genetic ...apolipoprotein(a) (apo(a)) isoforms. Only patients who express high molecular weight (HMW) apo(a) isoforms but not those with low molecular weight (LMW) isoforms show a relative increase of Lp(a) when compared to healthy controls matched for apo(a) isoforms. However, this was not confirmed by all studies. We therefore prospectively investigated the changes of Lp(a) deriving from each apo(a) isoform in heterozygotes following kidney transplantation. Lp(a) concentrations were measured by ELISA. To calculate the isoform-specific concentrations and the changes of Lp(a) deriving from each isoform, we densitometrically scanned the apo(a) bands from immunoblots before and after transplantation in 20 patients expressing two apo(a) isoforms. Of these, 10 patients expressed both an LMW and an HMW apo(a) isoform. The other 10 patients expressed only HMW isoforms. Densitometric scanning of apo(a) bands and calculation of isoform-derived Lp(a) concentrations clearly demonstrated that the decrease of Lp(a) following kidney transplantation is caused by changes in the expression of HMW apo(a) isoforms. In some patients, we observed an almost complete disappearance of the HMW apo(a) isoform after transplantation. This study clearly demonstrates that the changes of Lp(a) plasma concentrations in kidney disease depend on the genetically determined size of apo(a). This provides evidence for an interaction of apo(a) genetic variability and kidney function on Lp(a) concentrations.
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