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At least 361 records · Page 20Linked to original sources
PubMed2003

Irinotecan pathway genotype analysis to predict pharmacokinetics.

PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2024

Chromosome-scale assembly with improved annotation provides insights into breed-wide genomic structure and diversity in domestic cats.

INTRODUCTION: Comprehensive genomic resources offer insights into biological features, including traits/disease-related genetic loci. The current reference genome assembly for the domestic cat (Felis catus), Felis_Catus_9.0 (felCat9), derived from sequences of the Abyssinian cat, may inadequately represent the general cat population, limiting the extent of deducible genetic variations. OBJECTIVES: The goal was to develop Anicom American Shorthair 1.0 (AnAms1.0), a reference-grade chromosome-scale cat genome assembly. METHODS: In contrast to prior assemblies relying on Abyssinian cat sequences, AnAms1.0 was constructed from the sequences of more popular American Shorthair breed, which is related to more breeds than the Abyssinian cat. By combining advanced genomics technologies, including PacBio long-read sequencing and Hi-C- and optical mapping data-based sequence scaffolding, we compared AnAms1.0 to existing Felidae genome assemblies (20 scaffolds, scaffolds N50 > 150 Mbp). Homology-based and ab initio gene annotation through Iso-Seq and RNA-Seq was used to identify new coding genes and splice variants. RESULTS: AnAms1.0 demonstrated superior contiguity and accuracy than existing Felidae genome assemblies. Using AnAms1.0, we identified over 1.5 thousand structural variants and 29 million repetitions compared to felCat9. Additionally, we identified > 1,600 novel protein-coding genes. Notably, olfactory receptor structural variants and cardiomyopathy-related variants were identified. CONCLUSION: AnAms1.0 facilitates the discovery of novel genes related to normal and disease phenotypes in domestic cats. The analyzed data are publicly accessible on Cats-I (https://cat.annotation.jp/), which we established as a platform for accumulating and sharing genomic resources to discover novel genetic traits and advance veterinary medicine.

Animals↗
PubMed1998

Systematic search for mutations in the 14-3-3 eta chain gene on chromosome 22 in schizophrenics.

The brain-rich 14-3-3 protein regulates synthesis and excretion of bioamine by activating tyrosine and tryptophan hydroxylases, and by exocytosis of catecholamines and serotonin. In humans, at least eight subunits of the 14-3-3 protein family have been isolated. The 14-3-3 eta chain gene is located at 22q12.1 to q13.1, one of the chromosome regions identified as possibly linked to schizophrenia. We systematically searched for nucleotide variants in the coding region, 5' and 3' untranslated region, and in the exon-intron boundaries of the genomic 14-3-3 eta gene in 24 schizophrenics and 24 controls. Two polymorphic sites were found: one in the 5' untranslated region and one in the 3' untranslated region. However, no variants predicting amino-acid alterations were observed. Similar allelic and genotypic distributions for both polymorphisms were found in 308 schizophrenics and 135 controls.

14-3-3 Proteins↗
PubMed2025

In silico prediction of the impact of genomic variations in the small conductance calcium activated potassium channel SK3 structure and function.

The small-conductance calcium-activated potassium channel SK3, encoded by the KCNN3 gene, plays a critical role in regulating dopaminergic neuron (DN) firing patterns by modulating after hyperpolarization currents. SK3 dysfunction has been implicated in neuropsychiatric and neurodegenerative disorders. We analyzed structural and functional consequences of KCNN3 splicing and genetic variation. Alternative splicing variants of the KCNN3 gene were retrieved from the Ensembl database and aligned using T-Coffee, manually inspected and curated. Protein domains were identified with Pfam 35.0, SMART 9.0, and InterPro 98.0, and visualized. An AlphaFold2 model of SK3 full-length protein (UniProt: Q9UGI6) used as reference and structural models of its splicing variants were predicted with ColabFold. Functional domains (S1-S6 transmembrane helices, H5 pore loop, and calmodulin-binding) were defined and superimposed onto the AlphaFold2 reference. Domain integrity was assessed based on completeness of all expected residue indices within each functional region. SNPs and CNVs across all coding KCNN3 splicing variants were analyzed, classified, and filtered to isolate pathogenic variants prioritizing non-synonymous amino acid substitutions. Differential variant impacts across splicing isoforms were assessed by mapping variant positions to individual transcript protein sequences and used to predict functional consequences. Two long and two short splicing variants are known. Short variants lack the motif required for potassium channels. Pathogenic variants result from missense mutations resulting in amino acid substitutions. In all cases, the consequential effects depend on the specific location and role of the amino acid being changed.

SK3 channels↗
PubMed2002

A distinct 5' flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria.

The Plasmodium falciparum multigene var family codes for approximately 50 variant adhesive proteins expressed in a mutually exclusive manner at the surface of infected red blood cells (iRBCs). Switching expression of var genes can lead to fundamental changes in the adhesive and antigenic properties of iRBCs. For example, a specific phenotypic switch in adhesion from CD36 to chondroitin sulphate A (CSA) is associated with malaria pathogenesis in pregnant women. The factors and DNA elements that control the expression of a particular member of the var gene family during gestational malaria remains enigmatic. Here, we report that the subtelomeric FCR3 varCSA is expressed under the control of a unique DNA element of 1.8 kb, whereas the other members of the var multigene family are flanked by common regulatory elements. The 5' varCSA-type element is conserved as a single copy in laboratory strains and clinical isolates from Brazil and West Africa and contains two distinct repetitive elements of 150 bp and 60 bp respectively. The 5' varCSA-type sequence tags a var gene in the 3D7 genome that is homologous to the FCR3 varCSA gene. A recombinant DBL gamma domain of this var gene showed specific binding to CSA. This subtelomeric varCSA gene is transcribed in the opposite sense when compared with the usual orientation of telomere-adjacent var genes. This unique arrangement might explain why the varCSA gene is relatively conserved in genetically distinct parasites despite being located in a highly recombinogenic chromosome compartment. The 5' untranslated region (UTR) of the varCSA-type sequence is also transcribed in placental isolates that bind to CSA, illustrating an important role for the unique 5' varCSA-type sequence in the regulation of var genes involved in malaria pathogenesis in pregnant women. However, this promoter is not always found to be transcribing var genes selected for expression of products that bind to CSA in vitro. Our work identifies a sequence tag for the identification of varCSA genes in placental isolates for the first time.

5' Untranslated Regions↗
PubMed1995

Identification of proximal sequence element nucleotides contributing to the differential expression of variant U4 small nuclear RNA genes.

The two U4 genes in the chicken genome code for distinct sequence variants of U4 small nuclear RNA that are differentially expressed during development. Whereas U4B RNA is constitutively expressed, U4X RNA is specifically down-regulated relative to U4B in a tissue-specific manner during development. To investigate mechanisms controlling the differential expression of the U4B and U4X genes, chimeric U4 genes were constructed and their transcriptional activities assayed by injection into Xenopus oocytes or by transfection of CV-1 cells. The proximal regulatory region of the U4B gene and the enhancers of both the U4B and U4X genes functioned efficiently in each expression system. However, the proximal region of the U4X gene was inactive. To localize and identify the responsible nucleotides, reciprocal point mutations were introduced into the U4X and U4B proximal regulatory regions. The results indicate that the U4X gene contains a suboptimal proximal sequence element, and that this results primarily from the identities of the nucleotides at positions -61 and -57 relative to the transcription start site.

Animals↗
PubMed1994

Insulin receptor substrate-1 variants in non-insulin-dependent diabetes.

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.

Aged↗
PubMed1995

Differential alternative splicing of PACAP receptor in pituitary cell subpopulations.

The capability of rat pituitary cells to express receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and VIP was evaluated by binding studies and measurement of adenylate cyclase activity on whole gland preparations and by reverse transcriptase-polymerase chain reaction (TR-PCR) using specific primers on preparations from isolated cell populations enriched in PRL- and GH-producing cells. Data obtained on whole gland preparations indicated that selective PACAP receptors (PACAP Type I) predominated. The mRNA coding for PACAP Type I and for the non-selective PACAP receptors Type II VIP2 (but not VIP1) were identified. The mRNA coding for four different spliced variants of the PACAP Type I receptor were detected. In PRL producing cells, three variants and the VIP2 mRNA were detected, whereas in GH-producing cells the mRNA coding for the variant having a 28-amino acid insert (termed HOP) in the third intracellular loop was the only present.

Adenylyl Cyclases↗
PubMed2025

Rare pathogenic NR2F2 (COUP-TFII) variants as potential etiological causes in pediatric patients with congenital heart diseases (CHDs).

OBJECTIVES: Congenital heart diseases (CHDs) are complex genetic disorders, and their genetic basis is not yet fully understood. Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TFII) encodes a transcription factor which is expressed at high levels during mammalian development. Few studies have identified heterozygous and rare variants in the NR2F2 gene in individuals with CHD. This study aimed to evaluate the association between pathogenic genetic alterations in NR2F2 with CHD risk. METHODS: A case-control study was conducted on a group of 135 patients (83 boys and 52 girls) with various types of non-hereditary, isolated CHD who were undergoing open-heart surgery. Additionally, 95 matched healthy children without syndromic or isolated heart abnormalities were selected. RESULTS: Using Sanger sequencing, we identified 5 heterozygous single nucleotide variants in exons 2 and 3 of the NR2F2 gene. These variations were novel and not present in any genomic variation databases. Four of the variations were missense mutations (p.Pro159Arg, p.Ser329Phe, p.Qln338Pro, and p.Tyr348Ser) and one was a synonymous variant (p.G361 = ) in the coding region. Importantly, in silico results indicated that the missense variants had pathogenic effects on protein function. Additionally, the missense variants substantially altered the predicted structure of COUP-TFII. CONCLUSION: The results we obtained not only validate the correlation between NR2F2 mutations and CHDs but also have significant potential for guiding new preventive and therapeutic strategies. This could contribute to the advancement of medical interventions in the fields of cardiology and genetics.

Humans↗
PubMed2003

Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Genetic variants in the coding regions of the mismatch repair genes MLH1 (Ile-219Val) and MSH3 (Arg-940Glu and Thr-1036Ala) could contribute to an individual's susceptibility as modifiers in leukaemogenesis. To investigate this possibility, we conducted a case-control study on 287 children with ALL and 320 healthy controls both of French-Canadian origin. MLH1 and MSH3 variants, when taken independently, seemed to play little or no role in the aetiology of childhood ALL. However, when the MLH1 genotypes were combined with genotypes previously shown to influence ALL susceptibility, we found that the MLH1 variant Val-219 further increases the risk of GSTM1 null and CYP1A1*2A genotypes [combined odds ratio (OR) = 6.0, P = 0.002] as well as that of CYP2E1*5 (OR = 15.8, P = 0.001). No association was found with MSH3 variants. This study suggests an association of leukaemogenesis in children with both xenobiotic metabolism and DNA repair, and thus points to the effect of environmental exposure.

Adaptor Proteins, Signal Transducing↗
PubMed1997

[The topological structure of the genetic code].

On the basis of the topological concept of the vicinity of the point, graphs of connectedness for four nitrous bases (L and D tetrahedra) and the topological patterns of doublet and triplet genetic codes were constructed. These topological patterns were isomorphic to Boolean hypercubes B4 and B6, respectively. The resultant structures of the genetic code resembled those obtained earlier in terms of the rhombic variant of the genetic code table, which was constructed on the basis of complementarity of the coding doublets. Specifically, both models assumed the following: (1) when two groups of doublets and quartets of triplets that coded for one amino acid or two amino acids each were transformed into each other according to Rumer's rule (C <--> A, G <--> U), they retained C2 symmetry, and (2) single transitions of nitrous bases changed the structures of the encoded amino acids to the minimum possible extent. A possible mechanism for the origin of the genetic code and the possibility of using the characteristics of the obtained structures to develop the algorithm of prediction of the supermolecular protein structure, read genetic "texts", and refine the functions of amino acids as molecular modules are discussed in terms of the results obtained.

Algorithms↗
PubMed1995

Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene.

The most common mycobacterial disease in humans is tuberculosis, and there is evidence for genetic factors in susceptibility to tuberculosis. In the mouse, the Bcg gene controls macrophage priming for activation and is a major gene for susceptibility to infection with mycobacteria. A candidate gene for Bcg was identified by positional cloning and was designated "natural resistance-associated macrophage protein gene" (Nramp1), and the human homologue (NRAMP1) has recently been cloned. Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1. Of the four variants in the coding region, there were two missense mutations and two silent substitutions. The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein. A microsatellite was located in the immediate 5' region of the gene, three variants were in introns, and one variant was located in the 3' UTR. The allele frequencies of each of the nine variants were determined in DNA samples of 60 Caucasians and 20 Asians. In addition, we have physically linked two highly polymorphic microsatellite markers, D2S104 and D2S173, to NRAMP1 on a 1.5-Mb YAC contig. These molecular markers will be useful to assess the role of NRAMP1 is susceptibility to tuberculosis and other macrophage-mediated diseases.

Alleles↗
PubMed1993

A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family.

A transthyretin (TTR) mutation is described in a 44 year old French woman from Caen who presented at the age of 40 with neuropathy in all four extremities, diarrhoea, and orthostatic hypotension. Her father died with a similar syndrome including vitreous opacities. A nerve biopsy from the proband showed amyloid deposits which stained with anti-transthyretin. Direct genomic DNA sequencing of TTR exon 3 showed both thymine and cytosine in the position corresponding to the second base of codon 71. This codes for a variant alanine (GCG) as well as the normal valine (GTG), indicating that the proband is heterozygous for the substitution. Since this substitution does not result in the creation or abolition of a restriction endonuclease recognition site, a new technique (PCR-IMRA) was used to create an RFLP. Using a 24 bp nucleotide mutagenesis primer in the PCR reaction, a new NspBII site is created on amplification of the variant allele. With this method a 170 bp TTR exon 3 PCR product was generated for both the normal and the variant allele. On digestion of the PCR product with NspBII, DNA from a heterozygous subject showed both the 170 bp undigested product from the normal allele and a 146 bp digestion product from the variant allele. By PCR-IMRA, two of five children of the proband were positive for the variant allele. This non-radioactive technique gives a rapid method for testing subjects at risk for this mutation.

Adult↗
PubMed1983

Cloning and sequence analysis of a rat liver cDNA coding for a phenobarbital-inducible microheterogenous cytochrome P-450 variant: regulation of its messenger level by xenobiotics.

A rat liver cDNA library was prepared from total polyribosomal poly(A)+ RNA extracted from phenobarbital-treated animals. A cDNA clone coding for a phenobarbital-inducible cytochrome P-450 (PB P-450) was identified by differential colony hybridization to cDNAs synthesized from liver poly(A)+RNAs isolated from phenobarbital-treated rats for positive selection and cDNAs from either untreated rats or beta-naphthoflavone-treated rats as negative controls, followed by hybrid-selected translation and analysis of the translation products by immunoprecipitation. As the cloning and screening strategies involve no prior enrichment for specific mRNAs, they also permit the identification of sequences coding for phenobarbital-induced proteins other than cytochromes P-450. This relatively straightforward approach is generally applicable to the molecular cloning of sequences coding for other inducible cytochromes P-450. Nucleic acid sequencing data indicated that the cloned PB P-450 cDNA codes for a cytochrome P-450 variant [designated P-450e(U.C.)] that is very similar, but not identical, to P-450e. Sequence analysis of the section of cDNA specifying the 3'-non-coding region of the mRNA revealed that it lacked the usual poly(A) addition site signal sequence but contained three inverted repeat structures. Solution hybridization analysis demonstrated that PB P-450 mRNA is increased 20-fold by phenobarbital treatment and decreased 3-fold by beta-naphthoflavone treatment.

Animals↗
PubMed2000

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).

The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3'-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder.

Amino Acid Substitution↗
PubMed2001

Polymorphism of Immune Response Genes as a Factor for Predisposition to Development of Diseases.

The association of particular allelic variants of genes coding proteins, such as transporter associated with processing (TAP) and heat shock protein (HSP), involved in endocellular processing of endogenous antigens, with synovium pathology accompanied with urogenital infection was observed. The particular alleles of TAP1 and TAP2 genes appeared to be the factor of predisposition or resistance for Chlamidia trachomatis but not for Mycoplasma hominis. At the same time, the relative risk for C. trachomatis and M. hominis infection development was increased among persons with HSP70-2*A/B phenotype. Some TAP2 gene allelic variants were determined as the factor of an increased relative risk to develop synovium pathology, especially accompanied with urogenital infection. The preliminary data concerning gene polymorphism of some proinflammatory cytokines in human immunodeficiency virus (HIV) infected patients are presented. We observed an increased frequency of C/T allele of IL-4 gene among HIV patients. None of patients showed A/A homozygous variant of IL-10 and TNF-alpha genes. Our obtained results may be used as informative criteria for prognosis of resistance or predisposition to different diseases.

Journal Article↗
PubMed2002

Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.

BACKGROUND: Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. METHODS: We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. RESULTS: Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. CONCLUSION: We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.

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↗