43 research outputs found
Functional ENTPD1 Polymorphisms in African Americans With Diabetes and End-Stage Renal Disease
Objective: The vascular ectonucleotidase ENTPD1 protects against renal injury and modulates glucose homeostasis in mouse models. We sought to determine whether human variation in ENTPD1 influences predisposition to diabetes or diabetic nephropathy. Research Design and Methods: We analyzed ENTPD1 single nucleotide polymorphisms (SNPs) in 363 African American control subjects, 380 subjects with type 2 diabetes and end-stage renal disease (DM-ESRD), and 326 subjects with ESRD unrelated to diabetes (nonâDM-ESRD). Using human cell lines, we correlated disease-associated ENTPD1 haplotypes with ENTPD1 gene expression. Finally, we studied consequences of ENTPD1 deletion in a mouse model of type 2 diabetes (db/db). Results: A common ENTPD1 two-SNP haplotype was associated with increased risk for DM-ESRD (P = 0.0027), and an uncommon four-SNP haplotype was associated with protection against DM-ESRD (P = 0.004). These haplotypes correlated with ENTPD1 gene expression levels in human cell lines in vitro. Subjects with high ENTPD1-expressing haplotypes were enriched in the DM-ESRD group. By crossing ENTPD1-null mice with db mice, we show that ENTPD1 deletion has prominent effects on metabolic syndrome traits. Specifically, deletion of ENTPD1 lowered glucose levels in control (db/â) mice with one functional leptin receptor and dramatically lowered weights in db/db mice with no functional leptin receptors. Similar effects were seen in aged ENTPD1-null mice with normal leptin receptors. Conclusions: ENTPD1 polymorphisms appear to influence susceptibility to type 2 diabetes and/or diabetic nephropathy in African Americans. Studies in human cell lines and in vivo mouse data support a potential role for ENTPD1 genetic variation in susceptibility to type 2 diabetes
ZwiÄ zek miÄdzy polimorfizmem insercyjno-delecyjnym genu enzymu konwertazy angiotensyny I i obecnoĆciÄ zmian miaĆŒdĆŒycowych w tÄtnicach wieĆcowych u pacjentĂłw ze zwÄĆŒeniem zastawki aortalnej
WstÄp: Celem pracy byĆa ocena zaleĆŒnoĆci miÄdzy polimorfizmem insercyjno-delecyjnym genu
konwertazy angiotensyny (ACE) a czÄstoĆciÄ
wystÄpowania istotnych zmian miaĆŒdĆŒycowych
w tÄtnicach wieĆcowych u pacjentĂłw z istotnym zwÄĆŒeniem zastawki aortalnej.
MateriaĆ i metody: Badano 392 pacjentĂłw (159 kobiet i 233 mÄĆŒczyzn) w Ćrednim wieku
61 ± 10 lat z izolowanym zwÄĆŒeniem zastawki aortalnej.
U wszystkich pacjentĂłw przed operacjÄ
wymiany zastawki aortalnej wykonano koronarografiÄ
oraz oznaczono warianty polimorfizmu genu ACE. Za istotne przyjÄto zwÄĆŒenie tÄtnicy wieĆcowej
> 70% (lub > 50-procentowÄ
zmianÄ w pniu lewej tÄtnicy wieĆcowej).
Wyniki: Istotne zmiany miaĆŒdĆŒycowe w tÄtnicach wieĆcowych stwierdzono u 95 badanych
- u 30 kobiet (19%) i 65 mÄĆŒczyzn (28%). Istotne zwÄĆŒenia odnotowano u 14% kobiet
z genotypem II, u 20% z genotypem DI i u 21% pacjentek z genotypem DD. U mÄĆŒczyzn istotne
zwÄĆŒenia obserwowano u 38% pacjentĂłw z genotypem II, u 25% z genotypem DI i u 22%
badanych z genotypem DD. Znamiennie czÄstsze istotne zwÄĆŒenia stwierdzono wĆrĂłd mÄĆŒczyzn
z genotypem II (p < 0,05). W grupie kobiet rĂłĆŒnice nie byĆy istotne statystycznie.
Wnioski: U pacjentĂłw ze zwÄĆŒeniem zastawki aortalnej zaleĆŒnoĆÄ miÄdzy polimorfizmem I/D
genu ACE a wystÄpowaniem istotnych zmian miaĆŒdĆŒycowych tÄtnic wieĆcowych jest rĂłĆŒna
u kobiet i mÄĆŒczyzn. U kobiet zaobserwowano tendencjÄ do czÄstszego wystÄpowania istotnych
zmian miaĆŒdĆŒycowych w tÄtnicach wieĆcowych u pacjentek z allelem D, natomiast u mÄĆŒczyzn
zmiany takie zanotowano istotnie czÄĆciej u homozygot II. (Folia Cardiol. 2003; 10: 161–168
ZwiÄ zek miÄdzy polimorfizmem insercyjno-delecyjnym genu enzymu konwertazy angiotensyny I i obecnoĆciÄ zmian miaĆŒdĆŒycowych w tÄtnicach wieĆcowych u pacjentĂłw ze zwÄĆŒeniem zastawki aortalnej
WstÄp: Celem pracy byĆa ocena zaleĆŒnoĆci miÄdzy polimorfizmem insercyjno-delecyjnym genu
konwertazy angiotensyny (ACE) a czÄstoĆciÄ
wystÄpowania istotnych zmian miaĆŒdĆŒycowych
w tÄtnicach wieĆcowych u pacjentĂłw z istotnym zwÄĆŒeniem zastawki aortalnej.
MateriaĆ i metody: Badano 392 pacjentĂłw (159 kobiet i 233 mÄĆŒczyzn) w Ćrednim wieku
61 ± 10 lat z izolowanym zwÄĆŒeniem zastawki aortalnej.
U wszystkich pacjentĂłw przed operacjÄ
wymiany zastawki aortalnej wykonano koronarografiÄ
oraz oznaczono warianty polimorfizmu genu ACE. Za istotne przyjÄto zwÄĆŒenie tÄtnicy wieĆcowej
> 70% (lub > 50-procentowÄ
zmianÄ w pniu lewej tÄtnicy wieĆcowej).
Wyniki: Istotne zmiany miaĆŒdĆŒycowe w tÄtnicach wieĆcowych stwierdzono u 95 badanych
- u 30 kobiet (19%) i 65 mÄĆŒczyzn (28%). Istotne zwÄĆŒenia odnotowano u 14% kobiet
z genotypem II, u 20% z genotypem DI i u 21% pacjentek z genotypem DD. U mÄĆŒczyzn istotne
zwÄĆŒenia obserwowano u 38% pacjentĂłw z genotypem II, u 25% z genotypem DI i u 22%
badanych z genotypem DD. Znamiennie czÄstsze istotne zwÄĆŒenia stwierdzono wĆrĂłd mÄĆŒczyzn
z genotypem II (p < 0,05). W grupie kobiet rĂłĆŒnice nie byĆy istotne statystycznie.
Wnioski: U pacjentĂłw ze zwÄĆŒeniem zastawki aortalnej zaleĆŒnoĆÄ miÄdzy polimorfizmem I/D
genu ACE a wystÄpowaniem istotnych zmian miaĆŒdĆŒycowych tÄtnic wieĆcowych jest rĂłĆŒna
u kobiet i mÄĆŒczyzn. U kobiet zaobserwowano tendencjÄ do czÄstszego wystÄpowania istotnych
zmian miaĆŒdĆŒycowych w tÄtnicach wieĆcowych u pacjentek z allelem D, natomiast u mÄĆŒczyzn
zmiany takie zanotowano istotnie czÄĆciej u homozygot II. (Folia Cardiol. 2003; 10: 161–168
Genetic associations in diabetic nephropathy: a meta-analysis
Diabetes mellitus: pathophysiological changes and therap
Predicting Diabetic Nephropathy Using a Multifactorial Genetic Model
AIMS: The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. METHODS: Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random "training" (75%) and "test" (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. RESULTS: The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statisticâ=â0.672) better than a model based on conventional variables only (Câ=â0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (Ï(2)â=â17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (Ï(2)â=â3.2673, pâ=â0.07). CONCLUSION: In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for use across multiple ethnic groups or if population-specific models are required
A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level
<p>Abstract</p> <p>Background</p> <p>Serum creatinine (S<sub>CR</sub>) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S<sub>CR </sub>level is explicable by genetic factors.</p> <p>Methods</p> <p>We performed a meta-analysis of genome-wide association studies of S<sub>CR </sub>undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with S<sub>CR </sub>(candidate loci) were replicated in two additional population-based samples ('replication cohorts').</p> <p>Results</p> <p>After the discovery meta-analysis, 29 loci were selected for replication. Association between S<sub>CR </sub>level and polymorphisms in the collagen type XXII alpha 1 (<it>COL22A1</it>) gene, on chromosome 8, and in the synaptotagmin-1 (<it>SYT1</it>) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 Ă 10<sup>-6 </sup>and 1.7 Ă 10<sup>-4</sup>, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (<it>GABRR2</it>) gene and the ubiquitin-conjugating enzyme E2-J1 (<it>UBE2J1</it>) gene (replication p value = 3.6 Ă 10<sup>-3</sup>). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (<it>UMOD</it>) gene and in the schroom family member 3 (<it>SCHROOM3</it>) gene were also replicated.</p> <p>Conclusions</p> <p>While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes <it>SYT1 </it>and <it>GABRR2 </it>corroborate previous findings that highlighted a possible role of the neurotransmitters GABA<sub>A </sub>receptors in the regulation of the glomerular basement membrane and a possible interaction between GABA<sub>A</sub>receptors and synaptotagmin-I at the podocyte level.</p