Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

Masumi Kamiyama; Masaaki Kobayashi; Shin-ichi Araki; Aritoshi Iida; Tatsuhiko Tsunoda; Koichi Kawai; Masahito Imanishi; Makoto Nomura; Tetsuya Babazono; Yasuhiko Iwamoto; Atsunori Kashiwagi; Kohei Kaku; Ryuzou Kawamori; Daniel P K Ng; Torben Hansen; Peter Gaede; Oluf Pedersen; Yusuke Nakamura; Shiro Maeda

doi:10.1007/s00439-007-0414-3

Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

Masumi Kamiyama, Masaaki Kobayashi, Shin-ichi Araki, Aritoshi Iida, Tatsuhiko Tsunoda, Koichi Kawai, Masahito Imanishi, Makoto Nomura, Tetsuya Babazono, Yasuhiko Iwamoto, Atsunori Kashiwagi, Kohei Kaku, Ryuzou Kawamori, Daniel P K Ng, Torben Hansen, Peter Gaede, Oluf Pedersen, Yusuke Nakamura, Shiro Maeda

52 Citations (Scopus)

Abstract

Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of alpha smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy.

Original language	English
Journal	Human Genetics
Volume	122
Issue number	3-4
Pages (from-to)	397-407
Number of pages	11
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-007-0414-3
Publication status	Published - 2007

Keywords

3' Untranslated Regions
Alleles
Base Sequence
Case-Control Studies
Cells, Cultured
Cohort Studies
DNA Primers
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Diabetic Neuropathies
Gene Expression Profiling
Genetic Predisposition to Disease
Humans
Linkage Disequilibrium
Neurocalcin
Polymorphism, Single Nucleotide
Prospective Studies
RNA Interference
RNA Stability
RNA, Messenger
Transcription Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00439-007-0414-3

Cite this

Kamiyama, M., Kobayashi, M., Araki, S., Iida, A., Tsunoda, T., Kawai, K., Imanishi, M., Nomura, M., Babazono, T., Iwamoto, Y., Kashiwagi, A., Kaku, K., Kawamori, R., Ng, D. P. K., Hansen, T., Gaede, P., Pedersen, O., Nakamura, Y., & Maeda, S. (2007). Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Human Genetics, 122(3-4), 397-407. https://doi.org/10.1007/s00439-007-0414-3

Kamiyama, M, Kobayashi, M, Araki, S, Iida, A, Tsunoda, T, Kawai, K, Imanishi, M, Nomura, M, Babazono, T, Iwamoto, Y, Kashiwagi, A, Kaku, K, Kawamori, R, Ng, DPK, Hansen, T, Gaede, P, Pedersen, O, Nakamura, Y & Maeda, S 2007, 'Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy', Human Genetics, vol. 122, no. 3-4, pp. 397-407. https://doi.org/10.1007/s00439-007-0414-3

@article{06ed7dd29c1d4e3c955b93705dfbaaf2,

title = "Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy",

abstract = "Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of alpha smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy.",

keywords = "3' Untranslated Regions, Alleles, Base Sequence, Case-Control Studies, Cells, Cultured, Cohort Studies, DNA Primers, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Neurocalcin, Polymorphism, Single Nucleotide, Prospective Studies, RNA Interference, RNA Stability, RNA, Messenger, Transcription Factors",

author = "Masumi Kamiyama and Masaaki Kobayashi and Shin-ichi Araki and Aritoshi Iida and Tatsuhiko Tsunoda and Koichi Kawai and Masahito Imanishi and Makoto Nomura and Tetsuya Babazono and Yasuhiko Iwamoto and Atsunori Kashiwagi and Kohei Kaku and Ryuzou Kawamori and Ng, {Daniel P K} and Torben Hansen and Peter Gaede and Oluf Pedersen and Yusuke Nakamura and Shiro Maeda",

year = "2007",

doi = "10.1007/s00439-007-0414-3",

language = "English",

volume = "122",

pages = "397--407",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer",

number = "3-4",

}

TY - JOUR

T1 - Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

AU - Kamiyama, Masumi

AU - Kobayashi, Masaaki

AU - Araki, Shin-ichi

AU - Iida, Aritoshi

AU - Tsunoda, Tatsuhiko

AU - Kawai, Koichi

AU - Imanishi, Masahito

AU - Nomura, Makoto

AU - Babazono, Tetsuya

AU - Iwamoto, Yasuhiko

AU - Kashiwagi, Atsunori

AU - Kaku, Kohei

AU - Kawamori, Ryuzou

AU - Ng, Daniel P K

AU - Hansen, Torben

AU - Gaede, Peter

AU - Pedersen, Oluf

AU - Nakamura, Yusuke

AU - Maeda, Shiro

PY - 2007

Y1 - 2007

N2 - Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of alpha smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy.

AB - Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of alpha smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy.

KW - 3' Untranslated Regions

KW - Alleles

KW - Base Sequence

KW - Case-Control Studies

KW - Cells, Cultured

KW - Cohort Studies

KW - DNA Primers

KW - DNA-Binding Proteins

KW - Diabetes Mellitus, Type 2

KW - Diabetic Neuropathies

KW - Gene Expression Profiling

KW - Genetic Predisposition to Disease

KW - Humans

KW - Linkage Disequilibrium

KW - Neurocalcin

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - RNA Interference

KW - RNA Stability

KW - RNA, Messenger

KW - Transcription Factors

U2 - 10.1007/s00439-007-0414-3

DO - 10.1007/s00439-007-0414-3

M3 - Journal article

C2 - 17671797

SN - 0340-6717

VL - 122

SP - 397

EP - 407

JO - Human Genetics

JF - Human Genetics

IS - 3-4

ER -

Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this