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From the Clinical Research Centers |
Departments of Biochemistry (V.O.S., J.K.G., D.L.V.J.), Internal Medicine (V.O.S., Y.S., R.I.D., M.Y., R.P.E., P.G.Z.), and Family and Community Medicine (C.S.), University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131; Dialysis Clinic, Inc. (J.N.), Nashville, Tennessee 37203; and the Department of Medicine, Istituto Scientifico H San Raffaele (M.S., S.V.), 20132 Milan, Italy
Address all correspondence and requests for reprints to: Philip G. Zager, M.D., Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. E-mail: pzag{at}unm.edu
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Abstract |
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We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells.
At UNMHSC we identified 10 alleles ranging from Z-10 to Z+8. The prevalence of the Z-2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z-2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z-2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z-2, and 69% and 32%, respectively, had 1 copy or more of Z-2. Among diabetics, homozygosity for the Z-2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71–17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 ± 0.050) than in group I (0.068 ± 0.025), group II (0.042 ± 0.020), or group IV (0.015 ± 0.011; P < 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z-2 homozygotes (0.098 ± 0.06) and Z-2 heterozygotes (0.080 ± 0.04) than in patients with no Z-2 allele (0.043 ± 0.02; P < 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z-2 homozygotes (0.034 ± 0.04) and Z-2 heterozygotes (0.038 ± 0.03) were similar to levels in patients without a Z-2 allele (0.047 ± 0.03; P = NS).
At HSR we identified eight alleles ranging from Z-12 to Z+2. The prevalence of the Z-2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z-2, and 81% had one copy or more of the Z-2 allele. In contrast, in group II, 4% were homozygous for Z-2, and 36% had one copy or more of the Z-2 allele. IDDM patients homozygous for Z-2 had an increased risk for DN compared with those lacking the Z-2 allele (OR, 18; 95% confidence interval, 2–159). IDDM patients who had one copy or more of Z-2 had increased risk (OR, 7.5; 95% confidence interval, 1.9–29.4) for DN compared with those without the Z-2 allele.
These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z-2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression. This interaction may explain the observed association between the Z-2 allele and DN.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One candidate gene that may modulate the risk for DN is aldose reductase (ALDR1). ALDR1, the rate-limiting enzyme in the polyol pathway, catalyzes the NADPH-dependent reduction of sugar aldehydes to their corresponding sugar polyols. ALDR1 is expressed in tissues that are targets for the chronic complications of diabetes (8, 9, 10, 11), including the renal cortex (12, 13, 14, 15). Increased activity of the polyol pathway has been implicated in the pathogenesis of DN in humans and animals (16, 17, 18). Sibling pair analyses in Pima Indians has shown linkage of DN with the ALDR1 microsatellite locus of chromosome 7 (7). Therefore, a gene(s) located at or near the ALDR1 locus may play a role in determining susceptibility to DN.
Studies of ALDR1 messenger ribonucleic acid (mRNA) and activity levels also support a role for the polyol pathway in the pathogenesis of DN. We previously demonstrated that expression of renal cortical ALDR1 mRNA is regulated (12). Other laboratories have demonstrated reversal of diabetes-related renal microvascular complications by administration of ALDR1 inhibitors (19, 20, 21). Conversely, increased ALDR1 levels lead to an accelerated rate of microvascular complications in transgenic mice overexpressing the ALDR1 gene (22, 23). Significant heterogeneity in ALDR1 expression has been observed in humans. Elevated ALDR1 levels have been reported in neutrophils (24), erythrocytes (25, 26), and peripheral blood mononuclear cells (PBMC) (27) isolated from patients with diabetic complications. We recently reported that ALDR1 mRNA levels in PBMC were 3-fold higher in insulin-dependent diabetes mellitus (IDDM) patients with DN than in those without DN (28). In contrast, ALDR1 mRNA levels were not elevated in nondiabetics with renal disease.
Ko et al. (29) and Hessom et al. (30) identified a highly polymorphic microsatellite DNA sequence located 2.1 kb upstream of the transcription start site of the ALDR1 gene. Ko et al. observed a strong association between the Z-2 allele and early-onset diabetic retinopathy in patients with NIDDM (29). Hessom et al. demonstrated a significant association of the Z-2 allele with DN in IDDM patients (30).
The present study explores the hypothesis that the ALDR1 Z-2 microsatellite is linked to increased ALDR1 expression and DN. We characterized the relationship between ALDR1 genotype and ALDR1 mRNA in volunteers of two different institutions, the University of New Mexico Health Science Center (UNMHSC) in Albuquerque, NM, and the Istituto Scientifico H San Raffaele (HSR) in Milan, Italy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The protocol was approved by the human subjects research review committees at the UNMHSC and HSR. Informed written consent was obtained from all volunteers. We studied 175 individuals (108 from UNMHSC and 67 from HSR). Sixty of the volunteers from UNMHSC participated in a study previously reported in this journal (28). For all subjects we recorded a medical history and results of a physical examination, serum chemistry profile, hemoglobin A1c (HbA1c), and dipstick, and for all diabetic patients, a dilated retinal exam was conducted by blinded ophthalmologists with expertise in diabetic retinopathy.
UNMHSC. Volunteers were recruited from an advertisement
placed at the out-patient internal medicine and nephrology clinics. We
studied four groups of volunteers: group I, normal volunteers (n =
33); group II, IDDM without DN (n = 27); group III, IDDM with DN
(n = 31); and group IV, nondiabetics with renal disease (n =
17). Three random, daytime, spot urine samples were obtained from each
volunteer for determination of the urinary albumin/creatinine ratio
(UACR). Proteinuria was categorized using the mean UACR as normal
(<0.03), subclinical (
0.03 to <0.3), or clinical (0.3).
HbA1c, serum and urinary creatinine, and urinary albumin
were measured as previously described (28). The diagnosis of diabetes
was confirmed by measuring plasma glucose, C peptide (31), and serum
free insulin (32) concentrations, fasting and 2 h after
Sustacal (Mead Johnson, Evansville, IN) challenge (33).
HSR. We studied three groups of volunteers recruited from the diabetes clinics: group I, normal volunteers (n = 21); group II, IDDM without DN (n = 25); and group III, IDDM with DN (n = 21). Group III included patients who had received a kidney (n = 4) or a combined kidney and pancreas (n = 12) transplant, patients with microalbuminuria (n = 4), and patients with clinical proteinuria (n = 1). A timed overnight urine collection was obtained from each volunteer for determination of the urinary albumin excretion rate. Urinary albumin excretion was categorized as normal (<20 µg/min), microalbuminuria (20–200 µg/min), or clinical (>200 µg/min). HbA1c, serum and urinary creatinine, and urinary albumin were measured as previously described (28). IDDM was diagnosed by clinical criteria, i.e. all IDDM patients were diagnosed before 30 yr of age, were ketosis prone, and were insulin dependent (34).
Structural and functional polymorphism of the ALDR1 gene
PBMC were isolated from 20 mL uncoagulated blood using a standard method of Ficoll-Hypaque density gradient centrifugation. RNA and DNA were isolated from the same sample of PBMC using RNA-DNA STAT 60 kit (Tel-Test B, Friendswood, TX).
Automated fluorescent gene scanning detection and analysis of PCR product containing the (A-C)n repeat sequence
The sense primer (5'-GAATCTTAACATGCTCTGAACC-3' as AR1) end labeled at the 5'-end with the fluorescent dye ROX (red fluorescent, Genosys Biotechnologies, The Woodlands, TX) and the antisense primer (5'-GCCCAGCCCTATACCTAGT-3' as AR2) flanking the 138-bp region were used in PCR amplification of the sequence containing the (A-C)n repeat. Thirty cycles of PCR amplification consisted of denaturation for 1 min at 94 C and annealing-extension for a total of 1 min at 61 C. The PCR product was combined with an aliquot of the internal lane standard labeled with fluorescent dye TAMRA (yellow fluorescent; Perkin-Elmer, Norwalk, CT). The mixture was then resolved by electrophoresis on a denaturing gel (6% urea-PAGE) using ABI 373 DNA sequencer (Perkin-Elmer). The internal lane standard was used to create a calibration curve of peak arrival time, which, in turn, was used to calculate the length of unknown PCR product automatically by ABI GENESCAN 672 software (Perkin-Elmer).
Automated DNA sequencing of PCR products containing the (A-C)n repeat sequence
All PCR products were sequence analyzed using the sense (AR1) and anti-sense (AR2) primers, as described above, with the same cycling conditions. The amplified PCR products were purified using Qiaquick spin column (Qiagen, Chatsworth, CA) to remove the primer contamination. A second sense primer (5'-AGTAATCTCCCACTATGGGAA-3' as AR3) internal to the AR1 sense primer was used for extension reaction during the cycle sequencing amplification. PCR sequence cycling and purification of the extended product were performed as recommended by the manufacturer (Perkin-Elmer). The cycle sequencing products were electrophoresed on 6% urea-PAGE denaturing gel to confirm the (A-C)n repeat sequence of the PCR products.
Ribonuclease protection assay for measuring ALDR1 mRNA in PBMC
This method was performed as previously described (28).
Statistical analysis
All statistical analyses were performed using SAS version 11.0
(Cary, NC) and LogXact (Cytel Software Corp., Cambridge, MA).
Descriptive statistics for each group were computed for the following
variables: age, blood pressure, UACR, serum creatinine,
HgbA1c, and ALDR1 mRNA. Data were tested for normality.
Normally distributed data were presented as the mean and
SD. Data that were not normally distributed were log
transformed and tested again for normality. To test for differences
between groups, we used ANOVA when the raw or transformed data were
normally distributed. For data that were not normally distributed, we
used the nonparametric Kruskal-Wallis procedure. If significant
differences between groups were noted, we used multiple range tests
(Newman-Keuls), as appropriate, to locate the differences. A three-way
ANOVA for unbalanced design was used to examine the effects of
diabetes, kidney disease, and specific ALDR1 polymorphisms on ALDR1
gene expression. Differences in the distributions of specific alleles
among the four study groups were evaluated using either
2 or Fisher’s exact test. Exact logistic regression
models were used to assess the association between specific alleles and
kidney disease, adjusting for diabetes.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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UNMHSC. We studied 108 volunteers (48 women and 60 men;
Caucasians, n = 65; Hispanics, n = 35; others, n = 8).
The distributions of gender and ethnicity were similar
(P = NS) in each group. The clinical characteristics of
the study participants are shown in Table 1A
. The mean age was
similar in the 4 groups (P = NS). The 2 diabetic groups
were similar with respect to age (P = NS), duration of
diabetes (P = NS), and glycemic control
(P = NS). Mean values for UACR and serum creatinine,
respectively, were similar in diabetics (group III) and nondiabetics
(group IV) with kidney disease. The types of renal disease represented
in group IV included hypertensive nephrosclerosis (n = 3),
autosomal dominant polycystic kidney disease (n = 3),
glomerulonephritis (n = 5), membranous nephropathy (n = 2),
Wegner’s granulomatosis (n = 1), and end-stage renal disease of
unknown etiology (n = 3).
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. In IDDM patients
without DN (group II), the mean duration of diabetes was 25.4 ±
7.4 yr, exceeding 20 yr in all but 1 patient. The relatively low serum
creatinine level observed in the group with DN (group III) reflects the
fact that 16 patients had functioning renal grafts.
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UNMHSC
We identified 10 alleles ranging from Z-10 to Z+8 (Tables 2A and 3A). There were no
significant correlations between different alleles of the (A-C)n repeat
and the age, sex, and ethnicity of the study participants. The presence
of the Z-2 allele was increased in diabetics (groups II and III
combined) compared with that in nondiabetics (groups I and IV combined;
P < 0.001). Among diabetics, 60% of group III and
22% of group II were homozygous for Z-2. Moreover, 90% and 67% of
groups III and II, respectively, had 1 copy or more of Z-2. In
contrast, among nondiabetics, 19% of group IV and 3% of group I were
homozygous for Z-2, and 69% and 33%, respectively, had 1 copy or
more of Z-2. It is possible that some of the patients in group II with
IDDM of less than 10-yr duration may develop DN. Therefore, we
conducted a post-hoc analysis to compare the frequency of
the Z-2 allele in those members of group II who had IDDM of more than
10-yr duration with that in those with DN (group III). The frequency of
the Z-2 allele was higher in group III than in group II
(P < 0.05). Among diabetics, homozygosity for the Z-2
allele was associated with renal disease [odds ratio (OR),
5.25; 95% confidence interval, 1.71–17.98; P =
0.005). Among nondiabetics, the prevalence of Z-2 homozygosity tended
to be higher in patients with renal disease (group IV; OR, 7.38; 95%
confidence interval, 0.858–157.06) than in normal subjects
(group I); however, this difference did not attain statistical
significance.
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HSR. We identified eight alleles ranging from Z-12 to Z +2
(Tables 2B and 3B). The prevalence of the Z-2 allele was higher in
IDDM patients with DN (group III) than in those without DN (group II).
In group III, 43% of patients were homozygous for Z-2, and 81% of
patients had one copy or more of the Z-2 allele. In contrast, in group
II only 4% of patients were homozygous for Z-2, and only 36% had one
copy or more of the Z-2 allele. Diabetics who were homozygous for Z-2
had an increased risk for DN compared with those homozygous for other
alleles (OR, 22.5; 95% confidence interval, 1.6–314) and those
in whom the Z-2 allele was absent (OR, 18; 95% confidence
interval, 2–159). IDDM volunteers who had one copy or more of
Z-2 had increased risk (OR, 7.5; 95% confidence interval,
1.9–29.4) for DN compared with those without the Z-2 allele.
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The overall mean levels of ALDR1 mRNA in the UNMHSC (0.06 ± 0.04) and HSR (0.04 ± 0.03) studies were different (P < 0.05). The distributions of ALDR1 mRNA levels within the UNMHSC and HSR volunteers were approximately normal. Moreover, the relationships between the respective groups at each study site were similar.
In the UNMHSC study, ALDR1 mRNA levels were higher in diabetics with
renal disease (group III) than in all other groups (P
< 0.01; Table 4). In contrast, ALDR1
mRNA levels were lower in volunteers with nondiabetic renal disease
than in any other group (P < 0.01). These data
indicate that renal disease per se did not lead to
up-regulation of ALDR1 gene expression. In the HSR study, ALDR1 mRNA
levels were higher in group III than in group I (P <
0.01) and group II (P < 0.01; Table 4).
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We studied the relationship of ALDR1 mRNA levels to Z-2
allele in diabetics and nondiabetics in both the UNMHSC and HSR
studies (Table 4
). In both studies, diabetics with one or more copy of
the Z-2 allele had higher ALDR1 mRNA levels than did diabetics without
the Z-2 allele. In the UNMHSC study, diabetics who were homozygous for
Z-2 had higher ALDR1 mRNA levels than did diabetics who had only a
single copy of Z-2. In contrast, in the HSR study ALDR1 mRNA levels
were similar in IDDM patients homozygous and heterozygous for the Z-2
allele (P = NS). In nondiabetics in both the UNMHSC and
HSR studies, there appeared to be no relationship between the Z-2
allele and the levels of ALDR1 mRNA expression. These results are
consistent with the hypothesis that increased expression of the
structural ALDR1 gene in subjects with the Z-2 microsatellite allele
requires the presence of diabetes and/or hyperglycemia. This
observation is in concert with previous reports that glucose plays an
important role in the regulation of ALDR1 gene expression (35).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Results from the UNMHSC and HSR groups are reported separately because of differences in these two population samples. Overall, the ALDR1 mRNA levels were higher in participants from UNMHSC than in those from HSR. This may reflect differences in the composition of the study groups and/or the effect of storing and transporting HSR samples to UNMHSC for analysis. The ethnic composition of the UNMHSC population sample reflects the ethnic diversity of New Mexico, in contrast with the more homogeneous population sample studied at HSR. It is possible that population admixture may contribute to the observed differences in the frequency of Z-2 alleles in the four groups studied at UNMHSC. However, ad-hoc analysis revealed that there were no observed differences in the frequency of the Z-2 allele between Hispanics and Caucasians in the study population. The UNMHSC study population was older than the HSR population (P < 0.01). The duration of diabetes in group II was greater in the HSR (25.4 ± 7.5 yr) than in the UNMHSC (17.8 ± 10.4 yr) population (P < 0.01). The degree of glycemic control, reflected by HbA1c levels, was similar in diabetics at UNMHSC and HSR (P = NS). ALDR1 mRNA levels were significantly higher in groups I (P < 001) and III (P < 0.01) in the UNMHSC study than in the HSR study. However, the relationships of ALDR1 mRNA levels among the different groups were similar in both studies. The prevalence of Z-2 in groups I, II, and III, respectively, was similar in the UNMHSC and HSR studies.
Our study confirms the observation that the frequency of the Z-2 allele is increased in IDDM patients with DN. However, in contrast to the report by Hessom et al., the frequency of the Z+2 allele in our study was low in IDDM patients with and without DN. The protective effect of Z+2 observed by Hessom et al. could be due to the absence of Z-2, rather than to a specific protective effect of Z+2. Neither Ko et al. nor Hessom et al. described the relationship between different microsatellite polymorphisms and the level of ALDR1 gene expression (29, 30).
The results of our study are consistent with the hypothesis that specific polymorphisms may modulate the level of ALDR1 gene expression and the risk for DN in patients with IDDM. The effect of microsatellite polymorphisms on ALDR1 gene expression appears to be different in diabetics than that in nondiabetics. Among diabetics, ALDR1 mRNA levels were higher in those with one copy or more of the Z-2 alleles compared with those lacking the Z-2 allele. In contrast, among nondiabetics, ALDR1 mRNA levels in subjects homozygous or heterozygous for Z-2 were similar to levels in those lacking the Z-2 allele. These results indicate that diabetes and/or hyperglycemia are required for the Z-2 allele to lead to up-regulation of the ALDR1 gene.
These observations are consistent with the hypothesis that the associations of specific polymorphisms of the ALDR1 locus with DN may be mediated by changes in ALDR1 gene expression. Our study did not identify the mechanism by which these microsatellite polymorphisms may regulate ALDR1 gene expression. However, as this microsatellite is located in the 5'-region of the gene, different populations may be associated with differential binding of transcription factors. The expression of other genes (constitutive nitric oxide synthase and the T cell receptor ß-chain) near this locus may also be altered and may also modulate the risk for DN. The osmotic response element (36) located at this locus may also contribute to environmental-genetic interactions that predispose to DN.
The present study has the limitations inherent in a case-control study that is not family or population based. Nevertheless, we were able to demonstrate an association among polymorphisms of the ALDR1 locus, ALDR1 gene expression, and DN. Family-based studies designed to assess linkage of DN have produced conflicting results. Imperatore et al. conducted genome-wide scans in affected Pima Indian sibling pairs (7). Both two-point and multipoint analyses revealed evidence of linkage between DN and D7S1840. This marker corresponds to cytogenetic location 7q35, which contains the ALDR1 gene. In contrast, a sibling pair study in Caucasians with IDDM conducted by Moczulski et al. found no evidence to support a role for ALDR1 as a major locus for DN (37). The genetics of DN may differ significantly between ethnic groups and also between IDDM and NIDDM patients. Additional family-based studies are needed to clarify the putative role of ALDR1 in the pathogenesis of DN.
In summary, the present study supports our hypothesis that the Z-2 allele may be associated with up-regulation of ALDR1 gene expression and may increase the risk for DN in IDDM patients. This suggests a potential interaction between ALDR1 polymorphisms genotype and hyperglycemia and diabetes. These findings are consistent with a role for ALDR1 in the pathogenesis of DN and identify a possible mechanistic relationship among ALDR1 genotype, hyperglycemia, and ALDR1 gene expression.
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Acknowledgments |
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Footnotes |
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Received November 21, 1997.
Revised April 13, 1998.
Accepted May 5, 1998.
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