The Influence of a Single Nucleotide Polymorphism within <em>CNDP1</em> on Susceptibility to Diabetic Nephropathy in Japanese Women with Type 2 Diabetes

<div><h3>Background</h3><p>Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22–23, and polymorphisms within the carnosine dipeptidase 1 gene (<em>CNDP1)</em>, located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the <em>CNDP1/CNDP 2</em> locus with diabetic nephropathy in Japanese subjects with type 2 diabetes.</p> <h3>Methodology/Principal Findings</h3><p>We genotyped a leucine repeat polymorphism (D18S880) that is within <em>CNDP1</em> along with 29 single nucleotide polymorphisms (SNPs) in the <em>CNDP1</em>/<em>CNDP2</em> locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the <em>CNDP1/CNDP2</em> locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in <em>CNDP1</em> was nominally associated with diabetic nephropathy in women (rs12604675-A; <em>p</em> = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19−2.61). Rs12604675 was associated with overt proteinuria (<em>p</em> = 0.002, OR = 2.18, 95% CI, 1.32−3.60), but not with ESRD in Japanese women with type 2 diabetes.</p> <h3>Conclusions/Significance</h3><p>Rs12604675-A in <em>CNDP1</em> may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.</p> </div

Association of rs12604675-A with diabetic nephropathy.

<p>OR represents the odds ratio per copy of risk allele (A). P-values were calculated using a logistic regression analysis with additive model (adjusted for sex, age, log-transformed body mass index and duration of diabetes).</p

Clinical characteristics of the participants.

<p>Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure.</p>a<p>4 unknown,</p>b<p>14 unknown.</p>#<p>Mean ± SD, HbA1c; NGSP.</p

Association of single nucleotide polymorphisms (SNPs) within <i>CNDP1/CNDP2</i> locus with diabetic nephropathy.

<p>Results of association studies are shown using: A) men and women, B) men only, or C) women only. The x-axis represents the position in chromosome 18, and the y-axis shows the absolute values of log₁₀-transformed association <i>p</i> values. Open squares represent unadjusted values, and black squares represent values adjusted for age, log-transformed body mass index, and duration of diabetes. Thresholds for nominal (<i>p</i> = 0.05) or statistical (<i>p</i> = 0.0004) significance are shown as broken lines.</p