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Identified single-nucleotide polymorphisms and haplotypes at 16q22.1 increase diabetic nephropathy risk in Han Chinese population.

Liao LN, Chen CC, Wu FY, Lin CC, Hsiao JH, Chang CT, Kardia SL, Li TC, Tsai FJ - BMC Genet. (2014)

Bottom Line: In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN.The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10⁻⁷), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10⁻⁷), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10⁻⁶).Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case-control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes.

Results: We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10⁻⁷), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10⁻⁷), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10⁻⁶).

Conclusions: Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN.

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Related in: MedlinePlus

Graphical summary of DN in single-SNP association analysis under additive-effect disease model.
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Fig1: Graphical summary of DN in single-SNP association analysis under additive-effect disease model.

Mentions: The graphical summary plot of DN in single-SNP association analysis under additive-effect disease model is shown in Figure 1. There were four SNPs with p-value <10−5 (above the red line), including rs10963767 (intron; ADAMTSL1 gene; 9p21.3), rs2058289 (intergenic; 12q24.3), rs11645214 (3’ UTR; SF3B3 gene; 16q22.1), and rs6499323 (intron; IL34; 16q22.1). Furthermore, two signals with p-value <10−4 were observed, indicating the SNPs around this areas may be potential susceptibility variants for DN; one signal (rs876142, rs9928626, rs11647932, rs11645214, and rs6499323) was on chromosome 16 (16q21-16q22.1 regions) and the other (rs1028555, rs4815800, rs6065925, rs6131015, rs4812997, rs6074024, rs6127983, rs182784, rs1885580, rs7273764, rs6127999, rs6014975, rs4811839, rs6025517, and rs2426712) was on chromosome 20 (20p12.3 and 20q13.1-20q13.3 regions). Among these 15 SNPs on chromosome 20, only SNPs rs6127983 and rs182784 (intron; BMP7 gene; 20q13.3) and SNPs rs4811839 and rs6025517 (intron; RAE1 gene; 20q13.3) were inside of genes. A previous study reviewed in a meta-analysis by Mooyaart et al. showed that the Hp 1/2 variant in the HP gene (located at 16q22.2) was associated with DN. Therefore, a total of 383 genotyped SNPs at the 16q22.1-16q22.2 regions were selected for this study. Significant SNPs (p-value <10−4) identified from single-SNP association analysis, along with the other 8 SNPs identified from haplotype association analysis, are presented in Table 2. The SNP with the lowest p-value (6.25 × 10−7) was rs11645214 located on chromosome 16q22.1. This SNP, with a higher risk of DN (adjusted odds ratio [AOR] 1.94, 95% confidence interval [CI] 1.49-2.51), is inside the SF3B3 gene (Additional file 1: Figure S1). Two other SNPs that showed a significant or borderline significant association with DN, each with an additive-effect, were rs6499323 (IL34) and rs11647932 (ST3GAL2) on chromosome 16q22.1 (Additional file 1: Figure S1). No significant variants were detected for DN at the 16q22.2 region.Figure 1


Identified single-nucleotide polymorphisms and haplotypes at 16q22.1 increase diabetic nephropathy risk in Han Chinese population.

Liao LN, Chen CC, Wu FY, Lin CC, Hsiao JH, Chang CT, Kardia SL, Li TC, Tsai FJ - BMC Genet. (2014)

Graphical summary of DN in single-SNP association analysis under additive-effect disease model.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222374&req=5

Fig1: Graphical summary of DN in single-SNP association analysis under additive-effect disease model.
Mentions: The graphical summary plot of DN in single-SNP association analysis under additive-effect disease model is shown in Figure 1. There were four SNPs with p-value <10−5 (above the red line), including rs10963767 (intron; ADAMTSL1 gene; 9p21.3), rs2058289 (intergenic; 12q24.3), rs11645214 (3’ UTR; SF3B3 gene; 16q22.1), and rs6499323 (intron; IL34; 16q22.1). Furthermore, two signals with p-value <10−4 were observed, indicating the SNPs around this areas may be potential susceptibility variants for DN; one signal (rs876142, rs9928626, rs11647932, rs11645214, and rs6499323) was on chromosome 16 (16q21-16q22.1 regions) and the other (rs1028555, rs4815800, rs6065925, rs6131015, rs4812997, rs6074024, rs6127983, rs182784, rs1885580, rs7273764, rs6127999, rs6014975, rs4811839, rs6025517, and rs2426712) was on chromosome 20 (20p12.3 and 20q13.1-20q13.3 regions). Among these 15 SNPs on chromosome 20, only SNPs rs6127983 and rs182784 (intron; BMP7 gene; 20q13.3) and SNPs rs4811839 and rs6025517 (intron; RAE1 gene; 20q13.3) were inside of genes. A previous study reviewed in a meta-analysis by Mooyaart et al. showed that the Hp 1/2 variant in the HP gene (located at 16q22.2) was associated with DN. Therefore, a total of 383 genotyped SNPs at the 16q22.1-16q22.2 regions were selected for this study. Significant SNPs (p-value <10−4) identified from single-SNP association analysis, along with the other 8 SNPs identified from haplotype association analysis, are presented in Table 2. The SNP with the lowest p-value (6.25 × 10−7) was rs11645214 located on chromosome 16q22.1. This SNP, with a higher risk of DN (adjusted odds ratio [AOR] 1.94, 95% confidence interval [CI] 1.49-2.51), is inside the SF3B3 gene (Additional file 1: Figure S1). Two other SNPs that showed a significant or borderline significant association with DN, each with an additive-effect, were rs6499323 (IL34) and rs11647932 (ST3GAL2) on chromosome 16q22.1 (Additional file 1: Figure S1). No significant variants were detected for DN at the 16q22.2 region.Figure 1

Bottom Line: In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN.The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10⁻⁷), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10⁻⁷), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10⁻⁶).Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case-control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes.

Results: We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10⁻⁷), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10⁻⁷), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10⁻⁶).

Conclusions: Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN.

Show MeSH
Related in: MedlinePlus