Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy

Vallabh O. Shah, Marina Scavini, Jovanka Nikolic, Yijuan Sun, Silvia Vai, Jeffrey K. Griffith, Richard I. Dorin, Christine Stidley, Mona Yacoub, David L. Vander Jagt, R. Philip Eaton, Philip G. Zager

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Abstract

Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A- C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. 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.

Original languageEnglish
Pages (from-to)2886-2891
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume83
Issue number8
DOIs
Publication statusPublished - 1998

Fingerprint

Aldehyde Reductase
Diabetic Nephropathies
Medical problems
Microsatellite Repeats
Genes
Alleles
Insulin
RNA
Type 1 Diabetes Mellitus
Health
Odds Ratio
Dinucleotide Repeats
Transcription Initiation Site
Ribonucleases
Homozygote
Polymorphism
Confidence Intervals
Gene expression
Heterozygote
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy. / Shah, Vallabh O.; Scavini, Marina; Nikolic, Jovanka; Sun, Yijuan; Vai, Silvia; Griffith, Jeffrey K.; Dorin, Richard I.; Stidley, Christine; Yacoub, Mona; Vander Jagt, David L.; Eaton, R. Philip; Zager, Philip G.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 83, No. 8, 1998, p. 2886-2891.

Research output: Contribution to journalArticle

Shah, VO, Scavini, M, Nikolic, J, Sun, Y, Vai, S, Griffith, JK, Dorin, RI, Stidley, C, Yacoub, M, Vander Jagt, DL, Eaton, RP & Zager, PG 1998, 'Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy', Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 8, pp. 2886-2891. https://doi.org/10.1210/jc.83.8.2886
Shah, Vallabh O. ; Scavini, Marina ; Nikolic, Jovanka ; Sun, Yijuan ; Vai, Silvia ; Griffith, Jeffrey K. ; Dorin, Richard I. ; Stidley, Christine ; Yacoub, Mona ; Vander Jagt, David L. ; Eaton, R. Philip ; Zager, Philip G. / Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy. In: Journal of Clinical Endocrinology and Metabolism. 1998 ; Vol. 83, No. 8. pp. 2886-2891.
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abstract = "Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A- C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. 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.",
author = "Shah, {Vallabh O.} and Marina Scavini and Jovanka Nikolic and Yijuan Sun and Silvia Vai and Griffith, {Jeffrey K.} and Dorin, {Richard I.} and Christine Stidley and Mona Yacoub and {Vander Jagt}, {David L.} and Eaton, {R. Philip} and Zager, {Philip G.}",
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TY - JOUR

T1 - Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy

AU - Shah, Vallabh O.

AU - Scavini, Marina

AU - Nikolic, Jovanka

AU - Sun, Yijuan

AU - Vai, Silvia

AU - Griffith, Jeffrey K.

AU - Dorin, Richard I.

AU - Stidley, Christine

AU - Yacoub, Mona

AU - Vander Jagt, David L.

AU - Eaton, R. Philip

AU - Zager, Philip G.

PY - 1998

Y1 - 1998

N2 - Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A- C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. 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.

AB - Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A- C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. 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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