Search PubMed⌕ Search

Biomedical subjects

Andrzej S Krolewski

Publications and source records attributed to Andrzej S Krolewski.

At least 19 recordsLinked to original sources
PubMed2006

Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes.

The Genetics of Kidneys in Diabetes (GoKinD) study is an initiative that aims to identify genes that are involved in diabetic nephropathy. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents also were enrolled to form family trios. As of November 2005, GoKinD included 3075 participants who comprise 671 case singletons, 623 control singletons, 272 case trios, and 323 control trios. Interested investigators may request the DNA collection and corresponding clinical data for GoKinD participants using the instructions and application form that are available at http://www.gokind.org/access. Participating scientists will have access to three data sets, each with distinct advantages. The set of 1294 singletons has adequate power to detect a wide range of genetic effects, even those of modest size. The set of case trios, which has adequate power to detect effects of moderate size, is not susceptible to false-positive results because of population substructure. The set of control trios is critical for excluding certain false-positive results that can occur in case trios and may be particularly useful for testing gene-environment interactions. Integration of the evidence from these three components into a single, unified analysis presents a challenge. This overview of the GoKinD study examines in detail the power of each study component and discusses analytic challenges that investigators will face in using this resource.

Adult↗
PubMed2006

New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals.

The K121Q polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is associated with type 2 diabetes and obesity. The possibility of other ENPP1 polymorphisms influencing these phenotypes has received little attention. Our aim was to examine the associations of tagging single nucleotide polymorphisms (SNPs) and haplotypes of the linkage disequilibrium (LD) block containing K121Q polymorphism with type 2 diabetes in a Polish population, controlling for any effect of obesity. We genotyped 426 type 2 diabetic case and 370 control subjects for seven SNPs in ENPP1. In the total group, neither type 2 diabetes nor obesity was significantly associated with any SNP. However, in obese subjects, two SNPs were significantly associated with type 2 diabetes: the Q allele of K121Q (odds ratio 1.6 [95% CI 1.003-2.6]) and T allele of rs997509 (4.7 [1.6-13.9]). In the LD block, four SNPs plus the K121Q polymorphism distinguished six haplotypes, three of which carried the Q allele. Interestingly, the T allele of rs997509 sufficed to distinguish a 121Q-carrying haplotype that was significantly more associated with type 2 diabetes than the other two (4.2 [1.3-13.5]). These other two 121Q-carrying haplotypes were not associated with type 2 diabetes. In conclusion, we found a new SNP, rs997509, in intron 1 that is strongly associated with risk of type 2 diabetes in obese individuals. The molecular mechanisms underlying this association are unknown.

Adult↗
PubMed2006

A disease haplotype for advanced nephropathy in type 2 diabetes at the ACE locus.

Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for disease haplotype associations. A case-control study design was used where case subjects were type 2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >6 years of diabetes. None of the individual markers showed significant disease association when considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of the A.T.D risk haplotype in case subjects (0.136) compared with control subjects (0.075) (P = 0.009), thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE locus.

Adult↗
PubMed2006

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes.

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h(2)) in diabetic (h(2) = 0.45, P < 1 x 10(-5)) and nondiabetic (h(2) = 0.36, P < 1 x 10(-3)) relatives. Genetic correlation (r(G) = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.

Adult↗
PubMed2005

A novel framework for sib pair linkage analysis.

Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.

Algorithms↗
PubMed2005

Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study.

Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.

Adult↗
PubMed2005

Early nephropathy in type 1 diabetes: a new perspective on who will and who will not progress.

Impaired renal function and end-stage renal disease (ESRD) affect up to a third of patients with type 1 diabetes. Thus, strategies for early detection and for preventative interventions are of critical importance. A model of diabetic nephropathy was developed in the 1980s that placed paramount importance on the finding of microalbuminuria as an early marker of a committed process of progressive kidney disease in diabetes. However, recent studies have provided evidence that microalbuminuria is a marker of dynamic, rather than fixed, kidney injury. Preliminary studies into early renal function decline, a process measured in early nephropathy using a simple assay for cystatin C to calculate the slope of glomerular filtration rate change over time, suggest that it is a more proximal marker than microalbuminuria of a person's trajectory toward impaired renal function and ESRD. Therefore, early renal function decline, rather than microalbuminuria, may be considered as the early marker of the committed process underlying progressive diabetic nephropathy.

Albuminuria↗
PubMed2005

Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes.

Proteinuria and impaired kidney function are 2 major traits of diabetic nephropathy that aggregate (are heritable) in families of diabetic individuals. Although both traits are heritable, they are not genetically correlated. These findings not only support the hypothesis that the development of diabetic nephropathy consists of 2 distinct disease processes (ie, increasing proteinuria and declining kidney function) but also strongly justify searches for the putative genes that separately determine variation in these processes. These searches have used both genome-wide scans and candidate-gene approaches. By use of genome-scan approaches, several research groups have identified genetic regions on chromosomes 7q, 18q, and 22q that harbor genes that determine either variation in urinary albumin excretion or susceptibility to proteinuria in families who have type 2 diabetes. The evidence for linkage in these 3 genetic regions was suggestive or strong, but, except for 7q, the regions did not overlap across studies. Two genome scans performed in families who have type 2 diabetes identified genetic regions on chromosome 3q, 6q, 7p, and 18q that harbor susceptibility genes that determine variation in glomerular filtration rate or susceptibility to the development of end-stage renal disease (ESRD). The region on 7p overlapped in both studies. Optimism is growing that a positional cloning approach applied to these putative genetic regions will lead to the isolation of the susceptibility genes for proteinuria and ESRD. Meanwhile, significant efforts that make use of the candidate-gene approach have been directed to the search for susceptibility genes for diabetic nephropathy. Unfortunately, positive findings have not been consistent.

Diabetes Mellitus, Type 2↗
PubMed2005

Epidemic of end-stage renal disease in people with diabetes in the United States population: do we know the cause?

BACKGROUND: The number of individuals initiating renal replacement therapy in the United States population grew exponentially over the past two decades. Cases of end-stage renal diseae (ESRD) attributed to diabetes accounted for most of this increase. In this report we examined factors that may account for the increase to determine whether it truly represents an epidemic of ESRD due to diabetes. METHODS: We reviewed time trends in data of the United States Renal Data system, the Diabetes Surveillance Program of the Centers for Disease Control and Prevention, and diabetes literature. RESULTS: Recent growth of the number of individuals with diabetes accounted for less than 10% of the increase in the number of diabetes-related ESRD. Instead, most of it was due to a threefold increase in risk of ESRD in people with diabetes and, therefore, qualifies as an epidemic. Curiously, this epidemic occurred despite widening implementation of effective renoprotective therapies. Individuals with type 2 diabetes, regardless of gender, age, or race, experienced the greatest increase in risk. There is no evidence that diabetic patients have been surviving longer, so the increased risk was not attributable to the high risk associated with long duration diabetes. CONCLUSION: We hypothesize that an epidemic of ESRD has occurred in people with diabetes in the United States population over the last two decades. The nature of the factor responsible for the epidemic and the reasons it affects patients with type 2 diabetes particularly are unknown. Research efforts to identify the putative factor deserve high priority, as does a commitment of resources to provide care for the burgeoning number of patients with ESRD and type 2 diabetes.

Adult↗
PubMed2005

The fatty acid-binding protein-2 A54T polymorphism is associated with renal disease in patients with type 2 diabetes.

The intestinal fatty-acid binding protein-2 (FABP2) gene codes a protein responsible for the absorption of long-chain fatty acids. To test whether FABP2 is a candidate gene for renal disease in patients with type 2 diabetes, a functional A54T polymorphism was genotyped in 1,042 Brazilians with type 2 diabetes. Patients were classified as having normoalbuminuria (urinary albumin excretion [UAE] <20 microg/min; n = 529), microalbuminuria (UAE 20-199 microg/min; n = 217), or proteinuria (UAE >199 microg/min; n = 160). Patients with end-stage renal disease (ESRD) (n = 136) were also included. The prevalence of the TT genotype was higher in patients with renal involvement compared with those with normoalbuminuria (odds ratio [95% CI] 2.4 [1.1-5.4]) following adjustment for type 2 diabetes duration, BMI, hypertension, A1C, and cholesterol levels. The risk was similar considering different stages of renal involvement. In a second independent patient sample (483 type 2 diabetic Caucasians residing in Massachusetts), a significant association was also observed between the TT genotype and proteinuria or ESRD (2.7 [1.0-7.3]; P = 0.048). This study thus provides evidence that FABP2 confers susceptibility to renal disease in type 2 diabetic patients.

Brazil↗
PubMed2005

Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect.

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.

Adult↗
PubMed2004

Examination of candidate chromosomal regions for type 2 diabetes reveals a susceptibility locus on human chromosome 8p23.1.

In a panel of large Caucasian pedigrees, we genotyped markers in eight chromosomal regions previously reported as supporting linkage with type 2 diabetes. We previously reported significant linkage on chromosome 20q (maximum logarithm of odds score [MLS] = 2.79) in this panel. In the present analysis, candidate regions on 1q, 2q, 3q, 5q, 9q, and 10q yielded little evidence for linkage; a region on 2p (MLS = 1.64, P = 0.01 at position 9.0 cM) gave suggestive evidence of linkage; and a region on 8p (MLS = 3.67, P = 2.8 x 10(-5), at position 7.6 cM) gave significant evidence of linkage. Conditional analyses were performed for both 2p and 8p regions and the region reported on 20q. The MLS for 2p increased from 1.64 to 1.79 (empirical P = 0.142) when conditioned for heterogeneity on 20q. The case was similar for 8p, where the MLS increased from 3.67 to 4.51 (empirical P = 0.023) when conditioned on families without evidence of linkage at 20q. In conclusion, our data support a type 2 diabetes susceptibility locus on chromosome 8p that appears to be independent from other susceptibility loci. Although we were able to replicate linkage in our pedigrees on chromosome 2p, we did not find evidence of linkage for regions on 1q, 2q, 3q, 5q, 9q, or 10q.

Age of Onset↗
PubMed2004

Scrutiny of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) locus reveals conserved haplotype block structure not associated with diabetic nephropathy.

Glutamine-fructose-6-phosphate transaminase 1 (GFAT) is the rate-limiting enzyme of the hexosamine pathway that has been implicated in the pathogenesis of diabetic nephropathy. As such, we hypothesized that GFPT1, which encodes for GFAT, may confer genetic susceptibility to this complication among Caucasians. Screening of all known functional regions of GFPT1 revealed six single nucleotide polymorphisms (SNPs) that were located in the promoter, introns, and 3' untranslated region. The approximately 60 kb GFPT1 locus was encompassed in a single conserved haplotype block, and two tagging SNPs were sufficient to capture >90% of the haplotype diversity. Analysis of these SNPs in a case-control study made up of type 1 diabetic subjects (324 case subjects with diabetic nephropathy and 289 control subjects with normoalbuminuria despite >15 years of diabetes) revealed no significant association even after stratification by sex, diabetes duration, glucose control, and blood pressure. Similar results were obtained among type 2 diabetic subjects (202 case and 114 control subjects). Genetic variation in GFPT1 is thus unlikely to have a major impact on susceptibility to diabetic nephropathy.

3' Untranslated Regions↗
PubMed2004

Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23.

Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal dominant inheritance and a young onset. Six MODY genes have been discovered to date. To identify additional MODY loci, we conducted a genome scan in 21 extended U.S. families (15 white and 6 from minorities, for a total of 237 individuals) in which MODY was not caused by known MODY genes. Seven chromosomal regions (1q42, 2q24, 2q37, 4p13, 8p23, 11p15, and 19q12) had a parametric heterogeneity logarithm of odds (HLOD) > or =1.00 or a nonparametric logarithm of odds (LOD) > or =0.59 (P < or = 0.05) in the initial screen. After typing additional markers at these loci to reduce the spacing to 2-3 cM, significant linkage was detected on 8p23 (HLOD = 3.37 at D8S1130 and nonparametric LOD = 3.66; P = 2 x 10(-5) at D8S265), where a 4.7-Mb inversion polymorphism is located. Thirty percent of the families (6 of 21) were linked with this region. Another linkage peak on chromosome 2q37 with an HLOD of 1.96 at D2S345/D2S2968 accounted for diabetes in an additional 25% of families (5 of 21). All 6 minority families were among the 11 families linked to these loci. None of the other loci followed up had an HLOD exceeding 1.50. In summary, we have identified a MODY locus on 8p23 that accounts for diabetes in a substantial proportion of MODY cases unlinked to known MODY genes. Another novel MODY locus may be present on 2q37. Cloning these new MODY genes may offer insights to disease pathways that are relevant to the cause of common type 2 diabetes.

Adolescent↗
PubMed2003

Regression of microalbuminuria in type 1 diabetes.

BACKGROUND: In the present study, we aimed to determine the frequency of a significant reduction in urinary albumin excretion and factors affecting such reduction in patients with type 1 diabetes and microalbuminuria. METHODS: The study included 386 patients with persistent microalbuminuria, indicated by repeated measurements of urinary albumin excretion (estimated on the basis of albumin-to-creatinine ratios) in the range of 30 to 299 microg per minute during an initial two-year evaluation period. Subsequent measurements during the next six years were grouped into two-year periods, averaged, and analyzed for regression of microalbuminuria, which was defined as a 50 percent reduction in urinary albumin excretion from one two-year period to the next. RESULTS: Regression of microalbuminuria was frequent, with a six-year cumulative incidence of 58 percent (95 percent confidence interval, 52 to 64 percent). The use of angiotensin-converting-enzyme inhibitors was not associated with the regression of microalbuminuria. However, microalbuminuria of short duration, salutary levels of glycosylated hemoglobin (less than 8 percent), low systolic blood pressure (less than 115 mm Hg), and low levels of both cholesterol and triglycerides (less than 198 mg per deciliter [5.12 mmol per liter] and 145 mg per deciliter [1.64 mmol per liter], respectively) were independently associated with the regression of microalbuminuria. Patients with salutary levels of all modifiable factors had a hazard ratio for regression of 3.0 (95 percent confidence interval, 1.5 to 6.0), as compared with patients with no salutary levels of any modifiable factor. CONCLUSIONS: Frequent regression of microalbuminuria in patients with type 1 diabetes indicates that elevated urinary albumin excretion does not imply inexorably progressive nephropathy. Identification of the multiple determinants of the regression of microalbuminuria has implications for current theories about the mechanisms of early diabetic nephropathy.

Adolescent↗
PubMed2003

Methylenetetrahydrofolate reductase gene polymorphism and susceptibility to diabetic nephropathy in type 1 diabetes.

BACKGROUND: The T allele of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated plasma homocysteine levels, and it has been postulated to be a risk factor for the development of diabetic nephropathy. We examined this hypothesis in both a case-control and a follow-up study in individuals with type 1 diabetes. METHODS: In the case-control study, the control group included 310 subjects with normoalbuminuria and diabetes duration of 15 years or greater, and the case group included 88 prevalent cases with end-stage renal disease (ESRD). The follow-up study included 235 subjects with overt proteinuria followed up for 6 years (on average), during which time ESRD developed in 69 subjects. DNA from each individual was genotyped for the C677T MTHFR polymorphism. RESULTS: The frequency of TT homozygotes did not vary significantly among the four groups: 10% in controls, 15% in prevalent cases of ESRD, 13% in cases with new-onset ESRD, and 11% in those who remained proteinuric during follow-up (P = 0.9, 6 df). Similarly, frequency of the T allele varied little among the same groups (range, 33% to 36%; P = 0.9, 3 df) During follow-up, 52 of 323 individuals with diabetic nephropathy died. Total mortality rates were 4.3/100 person-years in TT homozygotes, 2.4/100 person-years in CT heterozygotes, and 3.0/100 person-years in CC homozygotes (P = 0.55, 2 df). CONCLUSION: Using both a large case-control and a follow-up study, we found no evidence that the C677T MTHFR polymorphism has a significant role in the development of diabetic nephropathy in type 1 diabetes.

Adult↗
PubMed2003

TGF-beta 1 as a genetic susceptibility locus for advanced diabetic nephropathy in type 1 diabetes mellitus: an investigation of multiple known DNA sequence variants.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine suspected to be a crucial factor underlying glomerulosclerosis in advanced diabetic nephropathy. However, its potential role as a susceptibility gene for the development of this microvascular complication is unresolved. METHODS: We examined whether DNA sequence variants in the TGF-beta1 gene are associated with advanced diabetic nephropathy among Caucasians with type 1 diabetes mellitus. These variants included three coding (Leu10Pro, Arg25Pro, and Thr263Ile) and two noncoding single-nucleotide polymorphisms (-800 and -509), as well as an insertion/deletion of a cytosine residue in intron 4. A large case-control study design was used in which cases were patients with type 1 diabetes with advanced diabetic nephropathy (presence of persistent proteinuria or end-stage renal disease [ESRD]; n = 298) and controls were patients who remained normoalbuminuric despite greater than 15 years of type 1 diabetes (n = 263). RESULTS: Genotype frequencies for all polymorphisms were in Hardy-Weinberg equilibrium. Genotype distributions of all six DNA sequence variants were very similar between cases and controls (P = not significant). There was no significant difference in genotype distributions among cases regardless of whether these individuals with diabetes were proteinuric at the time of examination or had already developed ESRD secondary to diabetic nephropathy. Stratified analyses according to diabetes duration and glycemic control likewise did not detect an association between DNA sequence variants and advanced diabetic nephropathy. CONCLUSION: Genetic variation at the TGF-beta1 locus is unlikely to confer significant susceptibility to advanced diabetic nephropathy in patients with type 1 diabetes mellitus.

Adolescent↗