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Diabetes Care 29:2295-2299, 2006
DOI: 10.2337/dc06-0344
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

Sylvia Schön, PHD1, Christian Prante, MS1, Claudia Bahr, MS1, Lise Tarnow, MD, DMSC2, Joachim Kuhn, PHD1, Knut Kleesiek, MD1 and Christian Götting, PHD1

1 Institut für Laboratoriums und Transfusionsmedizin, Herz und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany
2 Steno Diabetes Center, Gentofte, Denmark

Address correspondence and reprint requests to Christian Götting, Institut für Laboratoriums und Transfusionsmedizin, Herz und Diabeteszentrum Nordrhein-Westfalen, Georgstraße 11, 32545 Bad Oeynhausen, Germany. E-mail: cgoetting{at}hdz-nrw.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—Xylosyltransferase I (XT-I) is the chain-initiating enzyme in the biosynthesis of proteoglycans in basement membranes. It catalyzes the transfer of xylose to selected serine residues in the core protein. The XYLT-II gene codes for a protein highly homologous to XT-I. Proteoglycans are important components of basement membranes and are responsible for their permeability properties. Type 1 diabetic patients have an altered proteoglycan metabolism, which results in microvascular complications. Thus, genetic variations in the xylosyltransferase genes might be implicated in the initiation and progression of these complications.

RESEARCH DESIGN AND METHODS—Genotyping of four genetic variations in the genes XYLT-I and XYLT-II was performed in 912 type 1 diabetic patients (453 with and 459 without diabetic nephropathy) using restriction fragment–length polymorphism.

RESULTS—The distribution of the c.343G>T polymorphism in XYLT-I is significantly different between patients with and without diabetic nephropathy (P = 0.03). T-alleles were more frequent in patients with diabetic nephropathy (odds ratio 2.47 [95% CI 1.04–5.83]). The allelic frequencies of the other investigated XYLT-I and XYLT-II variations (XYLT-I: c.1989T>C in exon 9; XYLT-II: IVS6–9T>C and IVS6–14_IVS6–13insG in intron 5; and c.2402C>G: p.T801R in exon 11) were not different between patients with and without diabetic nephropathy.

CONCLUSIONS—The XYLT-I c.343G>T polymorphism contributes to the genetic susceptibility to development of diabetic nephropathy in type 1 diabetic patients.

Abbreviations: SNP, single nucleotide polymorphism


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Type 1 diabetic patients have a high risk of developing several micro- and macrovascular complications such as diabetic nephropathy, diabetic retinopathy, and cardiovascular disease (1). Diabetic nephropathy affects 23–40% of type 1 diabetic patients, and peak onset is within 10–20 years of duration of diabetes (2–4). The molecular mechanisms of this microvascular complication still remain unclear, and present studies suggest a multifactorial etiology with contributions from hemodynamic alterations, metabolic abnormalities, and various growth factors as modifiable risk factors acting on a genetic background (5,6). Consequently, multiple genetic factors are thought to affect susceptibility to the pathogenesis of diabetic nephropathy (5,7,8).

Factors associated with microangiopathy include the thickening of the capillary basement membrane, which represents the central hallmark of the disease (9). Thickening of the basement membrane results in an increased capillary permeability of the microcirculation and is correlated with the degree of vasodilatory impairment (10).

The capillary basement membrane contains heparan sulfate, chondroitin sulfate, and dermatan sulfate proteoglycans. The sulfate groups of these proteoglycans confer an anionic charge that contributes to the charge-dependent permeability of the vessels, especially in the glomerular basement membrane (11,12). Perlecan is the predominant heparan sulfate proteoglycan in the basement membrane (13), which is important for its structural integrity and appears to play a role in all diabetes complications (14). Diabetic patients have an altered proteoglycan metabolism leading to a decreased content of heparan sulfate proteoglycans in the capillary and glomerular basement membranes (12).

Proteoglycans are macromolecules composed of a protein core to which glycosaminoglycans are covalently attached. The biological function of proteoglycans is intimately related to these anionic glycosaminoglycan chains. The glycosylation of core proteins in heparan sulfate, chondroitin sulfate, and dermatan sulfate proteoglycans is initiated by xylosyltransferase I (XT-I; EC 2.4.2.26), which catalyzes the transfer of xylose from UDP-xylose to selected serine residues in the core protein. This is the first and rate-limiting step in the formation of the glycosaminoglycan chains. The XYLT-II gene codes for a protein highly homologous to the XT-I (15). Both are type II transmembrane proteins with a highly conserved COOH-terminal region, where the catalytic domain is located in glycosyltransferases. These findings led us to conclude that the XYLT-II gene encodes another xylosyltransferase, although the catalytic activity and the biological function of XT-II are not yet known in detail (15).

The impaired function of basement membranes is associated with the pathogenesis of hypertension and microvascular complications in type 1 diabetic patients. Therefore, we have now investigated variations in the XYLT genes to analyze the hitherto unknown impact of the xylosyltransferases, the initial and committing step enzymes in proteoglycan homeostasis, in diabetic nephropathy. This follow-up study was carried out to elucidate the importance of four recently described XYLT variations conferring genetic susceptibility to microvascular complications in type 1 diabetic patients (16).


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
We examined DNA samples from 912 type 1 diabetic patients, 453 with and 459 without diabetic nephropathy, from the Steno Diabetes Center (Gentofte, Denmark). All adult Danish Caucasian type 1 diabetic patients who were suffering from diabetic nephropathy and were attending the outpatient clinic at Steno Diabetes Center since 1993 were asked to participate in a study of genetic risk factors for development of diabetic nephropathy (17). Of these, >70% was accepted and a corresponding control group of patients with type 1 diabetes and persistent normal urinary albumin excretion rates was recruited from the outpatient clinic (17). The previously described 96 patients (16) were not considered in this study. The clinical characteristics of the investigated patients are summarized in Table 1. All type 1 diabetic patients included in this study had duration of diabetes of at least 11 years. The patients had been dependent on insulin treatment from the time of diagnosis and received multiple injections of insulin per day. The average daily insulin dosage is given in Table 1. Of the patients, 438 were suffering from diabetic nephropathy in the predialysis state (96.7%), 3 were on maintenance dialysis (0.7%), and 12 received a kidney transplant (2.6%). A total of 268 of the diabetic nephropathy patients with antihypertensive treatment and 56 of the corresponding patients without diabetic nephropathy received an antihypertensive treatment with blockade of the renin-angiotensin-aldosterone system (ACE inhibitors, ß-blockers, spironolactone, and {alpha}2 agonists).


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  		Table 1— Clinical characteristics of 912 Caucasian type 1 diabetic patients subdivided into patients with and without nephropathy

 
The clinical examination of the patients occurred at the Steno Diabetes Center since 1993 (17). The investigations were performed on the same day as the drawing of the blood samples without any required pretreatment or fasting. Diabetic nephropathy was manifested if the following criteria were fulfilled: persistent albuminuria of ≥300 mg/24 h in at least two of three consecutive 24-h urine collections, presence of retinopathy, and no clinical or laboratory evidence of kidney or renal tract disease other than diabetic glomerulosclerosis (18,19). If no signs of retinopathy were observed, a kidney biopsy was required for diabetic nephropathy diagnosis. Diabetic retinopathy was determined by fundus photography after papillary dilatation and graded: nihil, simplex, and proliferative diabetic retinopathy (17,20). Hypertension was defined as systolic blood pressure of >140 mmHg and/or diastolic blood pressure >90 mmHg and/or use of antihypertensive medication. Standard methods were used for clinical laboratory analysis as described previously (20). The experimental design was approved by the local ethics committee, and all patients gave their informed consent.

Genotyping
Genotyping of XYLT polymorphisms was performed by restriction fragment–length polymorphism. Therefore, we amplified the exons of interest from genomic DNA by PCR. PCR was performed in a 25-µl reaction volume, containing ~30 ng genomic DNA, 12.5 pmol of each primer (Invitrogen, Leek, the Netherlands), 0.125 mmol/l of each dNTP (Promega, Madison, WI), and 0.75 units HotStar-Taq-DNA-Polymerase (Qiagen, Hilden, Germany) in 1x PCR buffer. For the amplification of exon 1 (XYLT-I), the addition of betaine (Sigma, St. Louis, MO) was necessary. We generated a restriction site for the analysis of c.2402C>G with the described primer. The primer sequences, annealing temperatures, and sizes of the PCR products are summarized in Table 2. The PCR conditions were as follows: initial denaturation at 95°C for 15 min, followed by 35 cycles of denaturation at 94°C for 1 min, annealing at fragment-specific temperature (Table 2) for 1 min, extension at 72°C for 1 min, and a final extension at 72°C for 15 min. The PCR products were restricted with the enzymes listed in Table 2 obtained from MBI Fermentas (St. Leon-Rot, Germany) and New England BioLabs (Frankfurt, Germany), and digestions were performed for 12 h according to the manufacturer’s instructions. PCR products of restriction-positive probes for the IVS6–9T>C and IVS6–14_IVS6–13insG in intron 5 of XYLT-II were initially sequenced on an Applied Biosystems 310 capillary sequencer using the BigDye Terminator v1.1 cycle sequencing kit (Perkin Elmer, Applied Biosystems, Foster City, CA) to check for the state of both variations.


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  		Table 2— Primer sequences, PCR conditions, and restriction enzymes for the investigated xylosyltransferase variations

 
For the determination of the restriction fragment–length polymorphism assay characteristics, a set of 10 evaluation samples containing wild-type, homozygous mutant, and heterozygous mutant genotypes were analyzed over a period of 14 days. The intra- and interassay precision was 100% for all genotyping methods. All results were 100% in concordance with the genotypes determined by DNA sequencing. To ensure the accuracy of the used genotyping methods, 10% of the samples used in this study were amplified by PCR again and reinvestigated by the restriction fragment–length polymorphism method. Samples for reevaluation were selected by a random-access procedure. Furthermore, 10 samples of each genotype were independently amplified by PCR and double-stranded sequenced. No genotype discrepancies were observed in any case.

Statistical analysis
The distribution of the alleles of each single nucleotide polymorphism (SNP) was tested for the Hardy-Weinberg equilibrium. Fisher’s two-tailed exact P test was used to compare allele frequencies between patients with and without diabetic nephropathy. P values of <0.05 were considered statistically significant. In consideration of multiple testing, P values were corrected according to the Bonferroni or Sidák method, if appropriate. For normally distributed clinical characteristics, a comparison between the groups was performed using an unpaired Student’s t test. For nonnormally distributed variables, a Mann-Whitney U test was used. Multiple logistic regression analysis was performed to assess the independent role of the c.343G>T (p.A115S) SNP in XT-I and sex, age, HbA1c (A1C), duration of diabetes, and nephropathy, retinopathy, hypertension, and BMI. The sample size and the post hoc power of the study were determined with the software CATS power calculator for genetic studies (21) and POWER (22), respectively.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Allele frequencies in type 1 diabetic patients with and without diabetic nephropathy
The allele frequencies of the investigated XYLT-I and XYLT-II variations in DNA samples from type 1 diabetic patients with and without diabetic nephropathy are summarized in Table 3. The genotype distributions for these variations were all in Hardy-Weinberg equilibrium. The allele frequencies of the XYLT-I SNP c.343G>T are significantly different in patients with and without diabetic nephropathy (P = 0.03) (Table 3). The T-allele occurs with a higher frequency in diabetic nephropathy patients (2.4% in patients without diabetic nephropathy and 4.3% in patients with diabetic nephropathy). Therefore, the carriage of this variation is associated with the development of diabetic nephropathy in type 1 diabetic patients (odds ratio 1.83 [95% CI 1.08–3.12]). After adjustment for sex, age, duration of diabetes, and nephropathy, retinopathy, A1C, BMI, and hypertension, this SNP remained significant (2.47 [1.04–5.83], P = 0.03). Genotype distributions of the other three analyzed variations did not differ between patients with and without diabetic nephropathy (P > 0.1), indicating that they are not associated with the development of diabetic nephropathy in type 1 diabetic patients. Power estimations have shown that the present study had a sufficient sample size to confirm associations with a >85% power for a relative risk of ≥2.0 for the more frequent variants (minor allele frequency 30–45%; significance level {alpha} 5%) assuming a recessive, multiplicative, dominant, or additive model for diabetic nephropathy. For the less abundant polymorphisms (minor allele frequency 2–4%; significance level {alpha} 5%), our study had a power of >80% if the relative risk exceeds 2.0 for a dominant or additive disease model. However, assuming a recessive model for these less frequent polymorphisms, the power was <2%. The allelic frequencies of the XYLT-I SNPs c.343C>T and c.1989C>T and the XYLT-II SNPs IVS6–9T>C/IVS6–14_IVS6–13insG and c.2402C>G in a general nondiabetic Caucasian cohort were 3.7% (23/630), 33.6% (218/648), 1.9% (17/862), and 38.7% (313/808), respectively.


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  		Table 3— Allele frequencies of XYLT variations in type 1 diabetic patients with and without diabetic nephropathy

 
Genotype-phenotype associations
To analyze if the investigated variations are implicated in alterations of clinical characteristics, we compared the phenotypes of patients with and without diabetic nephropathy with the dependency of their genotype. This comparison showed associations for the c.1989T>C SNP in exon 9 of XYLT-I and patients’ blood pressure and serum creatinine values. Nephropathy patients with the detected SNP in the homo- or heterozygous state at position c.1989T>C in exon 9 of XYLT-I had significantly lower systolic and diastolic blood pressures (systolic blood pressure, 141 ± 1 mmHg; diastolic blood pressure, 80 ± 1 mmHg, n = 291; P = 0.03) compared with the wild-type allele carriers (systolic blood pressure, 146 ± 2 mmHg; diastolic blood pressure, 83 ± 1 mmHg, n = 162). No further relevant genotype-phenotype correlations were detected.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Hallmarks of microvascular complications in type 1 diabetic patients are alterations in the structure and function of basement membranes (10). It was shown that the decreased content of heparan sulfate proteoglycans in the capillary and glomerular basement membrane leads to impaired function (12). The altered proteoglycan content in the basement membrane is possibly caused by an impaired proteoglycan homeostasis. Changes in proteoglycan degradation and its resynthesis rates point to the enzymes involved in proteoglycan biosynthesis and to genetic variations in the corresponding genes. XT-I is the initial and apparently rate-limiting enzyme in the biosynthesis of heparan sulfate proteoglycans. Therefore, we investigated in a large cohort of type 1 diabetic patients with and without diabetic nephropathy the distribution of four previously described variations in the XYLT-I and XYLT-II genes (16). These variations included a combination of a nucleotide exchange and an insertion in intron 5 of XYLT-II (IVS6–9T>C and IVS6–14_IVS6–13insG) and three SNPs. Two of these SNPs were coding (c.343G>T; p.A115S in XYLT-I and c.2402C>G; p.T801R in XYLT-II) and one was synonymous (c.1989T>C in XYLT-I).

The T-allele of the nonsynonymous SNP c.343G>T (p.A115S) in exon 1 of XYLT-I occurs with a significantly higher frequency in diabetic nephropathy patients. This finding indicates that this polymorphism is associated with the development of diabetic nephropathy in type 1 diabetic patients. The amino acid exchange p.A115S is located in the stem region of XT-I, which contains the putative proteinase restriction site for the generation of the soluble form of XT-I (23). Furthermore, it was discussed that the stem region is an important part of the signal sequence required for the Golgi localization of the enzyme. The localization of XT-I in the Golgi compartment is crucial for the proper function of this enzyme, since the xylosylation of the core proteins occurs in the early Golgi apparatus (24). The importance of the alanine residue at position 115 is supported by a phylogenetic comparison of the xylosyltransferase sequences of mus musculus, pan troglodytes, canis familiaris, Xenopus laevis, and other species. The alignment reveals that the alanine residue at this position is highly conserved, although it is located in a region that is characterized by a minor degree of sequence homology. Consequently, this amino acid exchange is accused to effect the enzyme localization and to influence the proteoglycan re-synthesis rate. This impact on the proteoglycan homeostasis in the glomerular basement membrane gives a biochemical explanation of the statistical association of p.A115S with the more than twofold increased risk for developing diabetic nephropathy. Unfortunately, information on the heparan sulfate content in the glomerular basement membrane of the T-allele carriers who suffer from diabetic nephropathy was not available. However, the detailed elucidation of the effects of the alteration from the unpolar amino acid alanine to the more reactive and hydrophile amino acid serine on these processes is only possible after the successful identification of the signal sequence and the protease cleavage site. Furthermore, follow-up studies should investigate whether p.A115S is also a risk factor for diabetic nephropathy in type 2 diabetic patients and for other chronic kidney diseases.

The statistical associations of the SNPs c.2402C>G and IVS6–9T>C and IVS6–14_IVS6–13insG in the XYLT-II gene, which were detected in the pilot study comprising 48 patients with diabetic nephropathy and 48 patients without diabetic nephropathy (16), could not be approved in this follow-up study. This result shows that positive findings in a small group could be identified as false-positive associations when larger sample sets are studied.

However, the present study confirms the previously detected connection between the variation c.1989T>C in exon 9 of XYLT-I and a reduced blood pressure. Diabetic nephropathy patients carrying the C-allele had significantly lower systolic and diastolic blood pressures than diabetic nephropathy patients with the T-allele. We can only assume the way in which this synonymous variation could influence patients’ blood pressure. Probably, this SNP is only a marker SNP and may be associated with the described effects in combination with other, to date unknown, variations. The variations that are responsible for the detected effects could be located in the introns or in the promoter region of the XYLT-I gene. They could function as enhancers, silencers, or transcription factor binding sites and affect gene transcription or RNA splicing. However, we can exclude the linkage with exonic alterations because we screened all XYLT-I exons and the exon/intron junctions (16).

The power of our present study was adequate to reliably detect doubling effects of the diabetic nephropathy risk. However, it cannot be totally excluded that relationships of smaller magnitude may have been missed in our analysis. The power did not exceed 0.8, especially for the low abundant variants with a minor allele frequency of <4%, indicating the possibility that the results may be falsely negative. Furthermore, our cohort size was not large enough to detect small associations of these less frequent variants when assuming a recessive disease model.

In conclusion, this follow-up study pointed out an association between the c.343G>T-SNP in the XYLT-I gene and diabetic nephropathy. The identification of major and minor risk factors for the development of diabetic nephropathy in diabetic patients is of importance due to the high morbidity and mortality of this chronic progressive kidney disease. Numerous genes and corresponding sequence variations were shown to have an impact on the risk for developing diabetic renal diseases. The gene products are involved in different physiological and pathological pathways including glucose metabolism, hemodynamic regulation, or extracellular matrix production (7,8,24–26). The identification of these new risk factors for diabetic nephropathy together with an insistent treatment (27,28) is crucial to delay or prevent end-stage renal disease and improve survival. The higher appearance of the c.343T allele in diabetic nephropathy patients detected in this study should be evaluated as an early marker for risk assessment of developing diabetic nephropathy in type 1 diabetic patients in further investigations.


   Acknowledgments
 
The authors thank Alexandra Adam and Oliver Jungmann for excellent assistance and Sarah L. Kirkby for linguistic advice.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication February 10, 2006. Accepted for publication July 13, 2006.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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