Low alpha-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Here, we performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of Southern Chinese Han (total1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 (P=3.99×10-9, OR=0.88), DEFA3 (P=6.55×10-5, OR=0.82) and a noncoding deletion variant (211bp) (P=3.50×10-16, OR=0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with increased risk for IgAN (P=9.56×10-20), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P=0.03, HR=3.69, after controlling for the effects of known prognostic factors) as well as high serum IgA1 (P=0.02) and a high proportion of galactose-deficient IgA1 (P=0.03). For replication, we confirmed the associations of DEFA1A3 (P=4.42×10-4, OR=0.82) and DEFA3 copy numbers (P=4.30×10-3, OR=0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. Interestingly, we also observed an association of the 211bp copy number with membranous nephropathy (P=1.11×10-7, OR=0.74 in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing the renal dysfunction in IgAN, the DEFA1A3 CNV locus is a potential candidate for therapeutic target and prognostic marker development

Adjusted hazard ratios of all-cause mortality for CAPD patients with and without diabetes according to PET category.

<p>Adjusted for the variables with <i>P</i><0.1 in the univariate model, including age at initiation of peritoneal dialysis, gender, cardiovascular disease, hemoglobin, serum albumin, DBP, iPTH, total cholesterol, and triglyceride.</p

Baseline demographic and clinical characteristics of the study population.

<p>Results are expressed as mean ± SD, median (interquartile range) or number (%).</p><p>Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; nPCR, normalized protein catabolic rate; iPTH, intact parathyroid hormone; hs-CRP, high-sensitivity C-reactive protein; PET, peritoneal equilibration test; UF, ultrafitration; WCCr, total weekly creatinine clearance; RRF, residual renal function; NDM, non-diabetes mellitus, DM, diabetes mellitus; H, high transport; HA, high average transport; LA, low average transport; L, low transport.</p><p>Baseline demographic and clinical characteristics of the study population.</p

Association of transport status and all-cause mortality by diabetic status.

<p>* Adjusted for the variables with <i>P</i><0.1 in the univariate model, including age at initiation of peritoneal dialysis, gender, cardiovascular disease, hemoglobin, serum albumin, DBP, iPTH, total cholesterol, and triglyceride.</p><p>Association of transport status and all-cause mortality by diabetic status.</p

Kaplan-Meier survival curves for age and sex matched CAPD patients with and without diabetes.

<p>Kaplan-Meier survival curves for age and sex matched CAPD patients with and without diabetes.</p

Kaplan-Meier survival curves for CAPD patients without (a) and with diabetes (b) according to PET category.

<p>Kaplan-Meier survival curves for CAPD patients without (a) and with diabetes (b) according to PET category.</p

Interaction and association of transport status, diabetes and all-cause mortality in entire cohort.

<p>*Adjusted for the variables with <i>P</i><0.1 in the univariate model and RRF, including age at initiation of peritoneal dialysis, gender, cardiovascular disease, hemoglobin, serum albumin, DBP, iPTH, total cholesterol, and triglyceride and RRF (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110445#pone.0110445.s001" target="_blank">Table S1</a>). Transport status was included in the adjusted model as either categorical or continuous variable separately.</p><p>Interaction and association of transport status, diabetes and all-cause mortality in entire cohort.</p

Prevalence and risk factors of CKD in Chinese patients with periodontal disease.

BACKGROUND: Periodontal disease is common among adults and is associated with an increasing risk of chronic kidney disease (CKD). We aimed to investigate the prevalence and risk factors of CKD in patients with periodontal disease in China. METHODS: In the current cross-sectional study, patients with periodontal disease were included from Guangdong Provincial Stomatological Hospital between March 2011 and August 2011. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), the presence of albuminuria, or hematuria. All patients with periodontal disease underwent a periodontal examination, including periodontal probing pocket depth, gingival recession, and clinical attachment level by Florida Probe. They completed a questionnaire and had blood and urine samples taken. The adjusted prevalence of indicators of kidney damage was calculated and risk factors associated with CKD were analyzed. RESULTS: A total of 1392 patients with periodontal disease were invited to participate this study and 1268 completed the survey and examination. After adjusting for age and sex, the prevalence of reduced eGFR, albuminuria, and hematuria was 2.7% (95% CI 1.7-3.7), 6.7% (95% CI 5.5-8.1) and 10.9% (95% CI 9.2-12.5), respectively. The adjusted prevalence of CKD was 18.2% (95% CI 16.2-20.3). Age, male, diabetes, hypertension, history of CKD, hyperuricemia, and interleukin-6 levels (≥7.54 ng/L) were independent risk factors for reduced eGFR. Female, diabetes, hypertension, history of CKD, hyperuricemia, high level of cholesterol, and high sensitivity C-reactive protein (hsCRP) (≥ 1.03 mg/L) and TNF-α levels (≥ 1.12 ng/L) were independently associated with an increased risk of albuminuria. Female, lower education (<high school), and history of CKD were independent risk factors for hematuria. CONCLUSIONS: 18.2% of Chinese patients with periodontal disease have proteinuria, hematuria, or reduced eGFR, indicating the presence of kidney damage. Whether prevention or treatment of periodontal disease can reduce the high prevalence of CKD, however, remains to be further investigated