Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians

Tarunveer Singh Ahluwalia, Monica Ahuja, Taranjit Singh Rai, Harbir Singh Kohli, Kamal Sud, Anil Bhansali, Madhu Khullar

Research output: Contribution to journalArticle

Abstract

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalMolecular and Cellular Biochemistry
Volume314
Issue number1-2
DOIs
Publication statusPublished - Jul 2008
Externally publishedYes

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Nitric Oxide Synthase Type III
Diabetic Nephropathies
Nitric Oxide Synthase
Haplotypes
Polymorphism
Genes
Medical problems
Introns
Alleles
Genotype
Diabetic Angiopathies
Assays
Linkage Disequilibrium
Association reactions
Serum
Restriction Fragment Length Polymorphisms
Single Nucleotide Polymorphism
Case-Control Studies
Polymerase Chain Reaction

Keywords

  • Aged
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • DNA Mutational Analysis
  • Diabetes Mellitus, Type 2
  • Diabetic Nephropathies
  • Female
  • Haplotypes
  • Humans
  • India
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Nitric Oxide Synthase Type III
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide

Cite this

Ahluwalia, T. S., Ahuja, M., Rai, T. S., Kohli, H. S., Sud, K., Bhansali, A., & Khullar, M. (2008). Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. Molecular and Cellular Biochemistry, 314(1-2), 9-17. https://doi.org/10.1007/s11010-008-9759-8
Ahluwalia, Tarunveer Singh ; Ahuja, Monica ; Rai, Taranjit Singh ; Kohli, Harbir Singh ; Sud, Kamal ; Bhansali, Anil ; Khullar, Madhu. / Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. In: Molecular and Cellular Biochemistry. 2008 ; Vol. 314, No. 1-2. pp. 9-17.
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abstract = "Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95{\%}CI: 1.53-19.79; 894G > T: OR: 1.8, 95{\%}CI: 1.03-3.16; Intron 4: OR: 6.23, 95{\%}CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.",
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Ahluwalia, TS, Ahuja, M, Rai, TS, Kohli, HS, Sud, K, Bhansali, A & Khullar, M 2008, 'Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians' Molecular and Cellular Biochemistry, vol. 314, no. 1-2, pp. 9-17. https://doi.org/10.1007/s11010-008-9759-8

Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. / Ahluwalia, Tarunveer Singh; Ahuja, Monica; Rai, Taranjit Singh; Kohli, Harbir Singh; Sud, Kamal; Bhansali, Anil; Khullar, Madhu.

In: Molecular and Cellular Biochemistry, Vol. 314, No. 1-2, 07.2008, p. 9-17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians

AU - Ahluwalia, Tarunveer Singh

AU - Ahuja, Monica

AU - Rai, Taranjit Singh

AU - Kohli, Harbir Singh

AU - Sud, Kamal

AU - Bhansali, Anil

AU - Khullar, Madhu

PY - 2008/7

Y1 - 2008/7

N2 - Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.

AB - Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.

KW - Aged

KW - Asian Continental Ancestry Group

KW - Case-Control Studies

KW - DNA Mutational Analysis

KW - Diabetes Mellitus, Type 2

KW - Diabetic Nephropathies

KW - Female

KW - Haplotypes

KW - Humans

KW - India

KW - Linkage Disequilibrium

KW - Male

KW - Middle Aged

KW - Nitric Oxide Synthase Type III

KW - Polymorphism, Restriction Fragment Length

KW - Polymorphism, Single Nucleotide

U2 - 10.1007/s11010-008-9759-8

DO - 10.1007/s11010-008-9759-8

M3 - Article

VL - 314

SP - 9

EP - 17

JO - Molecular and Cellular Biochemistry

JF - Molecular and Cellular Biochemistry

SN - 0300-8177

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