Publications by authors named "Daniel P K Ng"

34 Publications

Pentosidine levels in nonproteinuric diabetes associated with both low estimated glomerular filtration rate and cataract.

Diabetes Metab Syndr Obes 2012 29;5:155-64. Epub 2012 Jun 29.

Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.

Background: The main objective of this study was to investigate whether plasma pentosidine levels were associated with cataract and low estimated glomerular filtration rate (eGFR) in nonproteinuric type 2 diabetic patients.

Methods: We characterized 888 nonproteinuric type 2 diabetic patients residing in Singapore according to their eGFR values. Proteinuria was excluded on the basis of multiple urinalyses. Patients with low renal function (cases, n = 125) and controls (n = 763) were defined as having eGFR < and ≥60 mL/min/1.73 m(2), respectively. Pentosidine levels were measured by enzyme-linked immunosorbent assay. Multinomial logistic regression was used to test the association between plasma pentosidine levels and the joint phenotype of cataract and low eGFR.

Results: Cases had higher triacylglycerol values, higher systolic blood pressure, and were more likely to be treated with two or more antihypertensive medications. In univariate analysis, cases were potentially more than twice as likely to have had a history of cataract compared with controls. This association persisted in multivariate analyses after adjusting for the significant covariates, hypertension and triacylglycerol, but was attenuated when age was included in the model. Plasma pentosidine levels were significantly higher in cases with low eGFR who also had a history of cataract. This association persisted in multivariate analyses that included the covariates, glycosylated hemoglobin, hypertension, and diabetic retinopathy, as well as age.

Conclusion: Carbonyl stress, as reflected by pentosidine levels, is present in a subset of nonproteinuric diabetic patients. Clinically, this stress was associated with the joint presence of cataract and low eGFR.
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http://dx.doi.org/10.2147/DMSO.S32283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395895PMC
October 2012

Meta-analysis identifies common variants associated with body mass index in east Asians.

Nat Genet 2012 Feb 19;44(3):307-11. Epub 2012 Feb 19.

Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.
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http://dx.doi.org/10.1038/ng.1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288728PMC
February 2012

Estimated glomerular filtration rate and its association with the retinol-binding protein 4 (RBP4) locus on human chromosome 10q23.

Nephrol Dial Transplant 2012 Apr 5;27(4):1511-5. Epub 2011 Aug 5.

Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: We tested for associations between estimated glomerular filtration rate (eGFR) and retinol-binding protein 4 (RBP4) haplotypes found on human chromosome 10q23. This locus had been linked to eGFR in a previous linkage scan in patients with Type 2 diabetes mellitus.

Methods: We analysed 469 patients with Type 2 diabetes and 174 normoalbuminuric controls for associations between RBP4 haplotypes and eGFR. For comparison with controls, 295 cases with proteinuria/end-stage renal disease were tested for associations with advanced diabetic nephropathy. Genotyping was performed using high-resolution DNA melting assays. Data analysis was performed using the haplo.stats package.

Results: Genetic variations in RBP4 were not associated with advanced diabetic nephropathy. Compared with the common A/G/G/C haplotype, C/A/A/C carriers among the normoalbuminuric controls had higher eGFR values among younger patients but lower eGFRs among the older patients (effect size=2.2, P=3.3×10(-7)). Furthermore, while eGFR values were fairly consistent over the range of systolic blood pressure (SBP) values for the common haplotype, eGFR in C/A/A/C carriers increased with SBP (effect size=3.6, P=1.5×10(-2)). There was a significant interaction between the C/A/A/C haplotype and HbA1c as they affect eGFR compared to the common haplotype (effect size=2.1, P=2.1×10(-3)). Power calculations demonstrated that our study had >90% power to detect the observed interactions even while performing multiple hypotheses testing. The interaction between SBP and the C/A/A/C haplotype remained significant (P=2.8×10(-2)) even when these three haplotype-environment interactions were simultaneously estimated.

Conclusion: RBP4 haplotypes may be important in genetically modulating renal function in response to environmental challenges among patients with Type 2 diabetes.
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http://dx.doi.org/10.1093/ndt/gfr442DOI Listing
April 2012

Nephrinuria associates with multiple renal traits in type 2 diabetes.

Nephrol Dial Transplant 2011 Aug 31;26(8):2508-14. Epub 2010 Dec 31.

Department of Epidemiology and Public Health, National University of Singapore.

Background: The involvement of nephrin in controlling renal function is unclear with the literature only emphasizing its role in albuminuria. We therefore investigated the potential association between nephrinuria as evidenced by the appearance of urinary immunopositive nephrin fragments, with multiple renal traits.

Methods: Western blot analysis of the urine samples from a cross-sectional study of 381 Chinese type 2 diabetic patients revealed four distinct protein fragments, indicative of nephrinuria. Albuminuria was measured in random spot urine samples using the albumin/creatinine ratio (ACR), while estimated glomerular filtration rate (eGFR) was calculated using the creatinine-based Modification of Diet in Renal Disease formula.

Results: Each nephrin fragment was associated with a decline in eGFR (smallest P = 0.001). Even with the inclusion of logarithmic form of ACR (ln ACR) in the multivariate model, nephrinuria still remained significantly associated with lower eGFR (smallest P < 0.05). Nephrinuria was also strongly associated with lnACR and this finding was independent of eGFR (smallest P < 0.001). Thus, nephrinuria was independently associated with both renal traits in the form of lnACR and eGFR. Furthermore, nephrinuria was significantly associated with lower eGFR even among normoalbuminuric patients (ACR ≤ 30 mg/g) (smallest P = 0.002), potentially implicating nephrinuria in the development of normoalbuminuric renal insufficiency. Apart from the renal traits under investigation, the presence of nephrinuria did not associate with other patient clinical characteristics.

Conclusions: Nephrinuria was associated with multiple renal traits in type 2 diabetes even in normoalbuminuric patients who are traditionally perceived as having a low risk of chronic kidney disease.
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http://dx.doi.org/10.1093/ndt/gfq738DOI Listing
August 2011

Identification of new genetic risk variants for type 2 diabetes.

PLoS Genet 2010 Sep 16;6(9):e1001127. Epub 2010 Sep 16.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r(2)<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49 × 10(-9) (1.15, 1.10-1.20), 1.45 × 10(-8) (1.13, 1.08-1.18), and 7.14 × 10(-7) (1.13, 1.08-1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.
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http://dx.doi.org/10.1371/journal.pgen.1001127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940731PMC
September 2010

A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B.

Nat Genet 2010 Oct 5;42(10):864-8. Epub 2010 Sep 5.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10⁻⁹; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10⁻⁹). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10⁻¹⁴, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.
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http://dx.doi.org/10.1038/ng.660DOI Listing
October 2010

Human genetics of diabetic retinopathy: current perspectives.

Authors:
Daniel P K Ng

J Ophthalmol 2010 13;2010. Epub 2010 Jul 13.

Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive MD3, Singapore 117597.

Diabetic retinopathy (DR) is a most severe microvascular complication which, if left unchecked, can be sight-threatening. With the global prevalence of diabetes being relentlessly projected to rise to 438 million subjects by 2030, DR will undoubtedly pose a major public health concern. Efforts to unravel the human genetics of DR have been undertaken using the candidate gene and linkage approaches, while GWAS efforts are still lacking. Aside from evidence for a few genes including aldose reductase and vascular endothelial growth factor, the genetics of DR remain poorly elucidated. Nevertheless, the promise of impactful scientific discoveries may be realized if concerted and collaborative efforts are mounted to identify the genes for DR. Harnessing new genetic technologies and resources such as the upcoming 1000 Genomes Project will help advance this field of research, and potentially lead to a rich harvest of insights into the biological mechanisms underlying this debilitating complication.
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http://dx.doi.org/10.1155/2010/172593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913807PMC
July 2011

Ethnicity, gender, genotype, and anger as related to nocturnal dipping.

Psychophysiology 2010 Nov;47(6):1094-101

Department of Psychology, National University of Singapore, Singapore.

Bishop, Pek, and Ngau (2005) found a significant interaction in Singapore between anger and nocturnal dipping among Indians but not Chinese and Malays. The current study examines the role of 5-HTTLPR genotype in this relationship. Two hundred thirty-one undergraduates participated in up to 4 days of 24-h ambulatory monitoring, completed the State-Trait Anger Expression Inventory, and provided blood samples for genotyping of 5-HTTLPR. Results indicated individuals with two copies of the short allele (SS) showed reduced dipping when they were high in Outward Anger (OA) but increased dipping when they were low in OA. Further, for Indian men only, dipping was reduced for individuals having the SS genotype when they were low on Anger In and increased when they were high on Anger In. These data provide further evidence for the role of 5-HTTLPR in cardiovascular risk as well as ethnic differences in the 5-HTTLPR-phenotype relationship. They also provide further evidence for 5-HTTLPR as a "plasticity gene."
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http://dx.doi.org/10.1111/j.1469-8986.2010.01011.xDOI Listing
November 2010

A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.

PLoS Genet 2010 Feb 12;6(2):e1000842. Epub 2010 Feb 12.

Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.
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http://dx.doi.org/10.1371/journal.pgen.1000842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820513PMC
February 2010

International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

Carcinogenesis 2010 Apr 27;31(4):625-33. Epub 2010 Jan 27.

International Agency for Research on Cancer, Lyon 69008, France.

Background: Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3).

Methods: Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk.

Results: Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)].

Conclusion: This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
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http://dx.doi.org/10.1093/carcin/bgq001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847090PMC
April 2010

Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore.

J Clin Endocrinol Metab 2010 Jan 5;95(1):390-7. Epub 2009 Nov 5.

Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Context: Novel type 2 diabetes mellitus (T2DM) susceptibility loci, identified through genome-wide association studies (GWAS), have been replicated in many European and Japanese populations. However, the association in other East Asian populations is less well characterized.

Objective: To examine the effects of SNPs in CDKAL1, CDKN2A/B, IGF2BP2, HHEX, SLC30A8, PKN2, LOC387761, and KCNQ1 on risk of T2DM in Chinese, Malays, and Asian-Indians in Singapore.

Design: We genotyped these candidate single-nucleotide polymorphisms (SNPs) in subjects from three major ethnic groups in Asia, namely, the Chinese (2196 controls and 1541 cases), Malays (2257 controls and 1076 cases), and Asian-Indians (364 controls and 246 cases). We also performed a metaanalysis of our results with published studies in East Asians.

Results: In Chinese, SNPs in CDKAL1 [odds ratio (OR) = 1.19; P = 2 x 10(-4)], HHEX (OR = 1.15; P = 0.013), and KCNQ1 (OR = 1.21; P = 3 x 10(-4)) were significantly associated with T2DM. Among Malays, SNPs in CDKN2A/B (OR = 1.22; P = 3.7 x 10(-4)), HHEX (OR = 1.12; P = 0.044), SLC30A8 (OR = 1.12; P = 0.037), and KCNQ1 (OR = 1.19-1.25; P = 0.003-2.5 x 10(-4)) showed significant association with T2DM. The combined analysis of the three ethnic groups revealed significant associations between SNPs in CDKAL1 (OR = 1.13; P = 3 x 10(-4)), CDKN2A/B (OR = 1.16; P = 9 x 10(-5)), HHEX (OR = 1.14; P = 6 x 10(-4)), and KCNQ1 (OR = 1.16-1.20; P = 3 x 10(-4) to 3 x 10(-6)) with T2DM. SLC30A8 (OR = 1.06; P = 0.039) showed association only after adjustment for gender and body mass index. Metaanalysis with data from other East Asian populations showed similar effect sizes to those observed in populations of European ancestry.

Conclusions: SNPs at T2DM susceptibility loci identified through GWAS in populations of European ancestry show similar effects in Asian populations. Failure to detect these effects across different populations may be due to issues of power owing to limited sample size, lower minor allele frequency, or differences in genetic effect sizes.
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http://dx.doi.org/10.1210/jc.2009-0688DOI Listing
January 2010

cMET and refractive error progression in children.

Ophthalmology 2009 Aug 4;116(8):1469-74, 1474.e1. Epub 2009 Jun 4.

Genetic Medicine Group, Singapore Institute for Clinical Sciences, Singapore.

Objective: To assess whether genetic variation in cMET is associated with refractive error or change in refractive error over time.

Design: Cohort study.

Participants And Controls: Discovery set (Set 1: N = 579 children; 403 cases, 176 controls). Confirmatory set (Set 2: N = 547 children; 338 cases, 209 controls).

Methods: Children in the discovery set were genotyped for a panel of genetic markers within cMET. Markers that were found to be significantly associated with the presence of refractive error or more rapid change in refractive error were then genotyped in the confirmatory set.

Main Outcome Measures: Presence or absence of myopia and the rate of change in refractive error over a 3-year follow-up period.

Results: Carriage of the variant cMET +110703 A allele was found to associate with increased susceptibility to myopia. The variant was also found to associate with a faster rate of change in refractive error in both the discovery set and the confirmatory cohort regardless of the initial refractory ability (School 1; chi(2) for trend P = 0.014) (Schools 2 and 3; chi(2) for trend = 5.42, P = 0.020) (combined N = 1126, overall chi(2) for trend = 10.90, P = 9.6 x 10(-4)). Carriage of the variant allele was also found to be significantly overrepresented in children within the fastest changing quartile (Q4: mean change of -3.01 D over 3 years) compared with the slowest (Q1: mean change of -0.28 D over 3 years) (P(Set1) = 0.004, P(Set2) = 0.02, Combined N = 559, P = 3.0 x 10(-4)).

Conclusions: Our data implicate the involvement of cMET in the pathogenesis of myopia in general, as well as more rapid progression in refractive error regardless of the initial refractory ability. These results underline the importance of eye growth genes in the development of common myopia.
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http://dx.doi.org/10.1016/j.ophtha.2009.02.026DOI Listing
August 2009

Genetic variation in KCNQ1 associates with fasting glucose and beta-cell function: a study of 3,734 subjects comprising three ethnicities living in Singapore.

Diabetes 2009 Jun 27;58(6):1445-9. Epub 2009 Feb 27.

Department of Endocrinology, Singapore General Hospital, Singapore.

Objective: The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, beta-cell function, and other type 2 diabetes-related traits in a sample of Chinese, Malays, and Asian Indians living in Singapore.

Research Design And Methods: We examined the associations between four previously reported KCNQ1 single-nucleotide polymorphisms (SNPs) with type 2 diabetes-related traits in 3,734 participants from the population-based 1998 Singapore National Health Survey cohort (2,520 Chinese, 693 Malay, and 521 Asian Indians). Insulin resistance was calculated from fasting insulin and glucose using the homeostasis model assessment method, whereas pancreatic beta-cell function was assessed using the corrected insulin response at 120 min (CIR(120)).

Results: SNPs rs2237897, rs2237892, and rs2283228 were significantly associated with type 2 diabetes (odds ratio [OR] 1.48, P = 3 x 10(-4); OR 1.38, P = 0.002; OR 1.31, P = 0.012, respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, and rs2283228 were significantly associated with higher fasting glucose levels (P = 0.014, 0.011, and 0.034, respectively) and reduced CIR(120)(P = 0.007, 0.013, and 0.014, respectively). A similar trend was observed among the Malay and Asian Indian minority groups, although this did not reach statistical significance because of limited sample sizes.

Conclusions: The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.
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http://dx.doi.org/10.2337/db08-1138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682664PMC
June 2009

Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

Diabetes 2009 Jun 27;58(6):1403-10. Epub 2009 Feb 27.

Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Objective: Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection.

Research Design And Methods: We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications.

Results: A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney.

Conclusions: We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.
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http://dx.doi.org/10.2337/db08-1514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682673PMC
June 2009

International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

Cancer Epidemiol Biomarkers Prev 2008 Nov;17(11):3081-9

IARC, 150 cours Albert Thomas, 69008 Lyon, France.

Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies.

Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects.

Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk.

Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-08-0411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756735PMC
November 2008

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations.

Nat Genet 2008 Sep;40(9):1098-102

Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama, Kanagawa 230-0045, Japan.

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); OR = 1.26, 95% CI = 1.18-1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 x 10(-9); OR = 1.32, 95% CI = 1.20-1.45, rs2237897, P = 6.8 x 10(-13); OR = 1.41, 95% CI = 1.29-1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 x 10(-3); OR = 1.14, rs2237897, P = 2.4 x 10(-4); OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 x 10(-11); OR = 1.24, rs2237897, P = 1.2 x 10(-4); OR = 1.36).
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http://dx.doi.org/10.1038/ng.208DOI Listing
September 2008

Is the presence of retinopathy of practical value in defining cases of diabetic nephropathy in genetic association studies? The experience with the ACE insertion/deletion polymorphism in 53 studies comprising 17,791 subjects.

Diabetes 2008 Sep 3;57(9):2541-6. Epub 2008 Jun 3.

Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore.

Objective: A key consideration when setting up genetic studies is the case definition. For diabetic nephropathy, the case definition is typically based on the presence of albuminuria. However, it has been long debated whether diabetic nephropathy cases defined in this way may have a high prevalence of nondiabetic kidney disease, especially if diabetic retinopathy is absent.

Research Design And Methods: We performed a meta-analysis of 53 studies comprising 17,791 subjects investigating the angiotensin-I converting enzyme insertion/deletion polymorphism, taking into account the requirement for diabetic retinopathy in the case definition and assuming a random-effects model.

Results: No publication bias was observed. The overall pooled odds ratio (OR) for all 53 studies was 0.78 (95% CI 0.70-0.87; P < 0.001), which indicated a significant protection against diabetic nephropathy for genotype II compared with carriage of the D-allele. The pooled OR for the 11 studies (n = 3,413) requiring diabetic retinopathy in the case definition was 0.68 (0.53-0.86; P = 0.002), and this was not significantly different from the pooled OR of 0.81 (0.71-0.92; P = 0.001) obtained from the 42 remaining studies (n = 14,378) (P = 0.198). This lack of any significant effect of diabetic retinopathy was reiterated in subgroup analyses based on the type of diabetes present.

Conclusions: Stipulating the presence of diabetic retinopathy in the case definition of diabetic nephropathy did not appear to confer tangible benefits when detecting genetic associations. Besides reducing sample sizes, this stipulation makes the interpretation of genetic associations more difficult due to the potential confounding presence of diabetic retinopathy.
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http://dx.doi.org/10.2337/db08-0581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518508PMC
September 2008

An IL-6 haplotype on human chromosome 7p21 confers risk for impaired renal function in type 2 diabetic patients.

Kidney Int 2008 Aug 21;74(4):521-7. Epub 2008 May 21.

Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine,National University of Singapore, Singapore, Singapore.

The human chromosome 7p21 locus harbors a major gene that influences variation of glomerular filtration rate and development of end-stage renal disease. The pro-inflammatory IL-6 cytokine is a candidate gene since chronic inflammation has been implicated in diabetic nephropathy and this gene is located under the peak of linkage. To test this, single nucleotide polymorphism (SNP) and haplotype analyses were performed using a case-control study of 295 patients consisting of 138 with proteinuria, 157 with chronic renal failure and these were compared to 174 control patients with normal albumin excretion. Five tagging SNPs were selected for analysis based on linkage disequilibrium patterns and proximity to the functionally important -634G>C SNP in the IL-6 promoter. Initial analysis suggested that a -174G>C polymorphism may be associated with risk of chronic renal failure but this was not significant after Bonferroni correction. While haplotype analyses showed no association with proteinuria; a significant association with chronic renal failure was found. There was significantly more of the GGGAGC haplotype among patients with chronic renal failure compared to controls and this association remained significant even after correction for multiple testing. Our study has found a specific IL-6 haplotype conferring risk for impaired renal function in patients with type 2 diabetes.
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http://dx.doi.org/10.1038/ki.2008.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756185PMC
August 2008

Genetic variation at the SLC12A3 locus is unlikely to explain risk for advanced diabetic nephropathy in Caucasians with type 2 diabetes.

Nephrol Dial Transplant 2008 Jul 10;23(7):2260-4. Epub 2008 Feb 10.

Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore.

Background: Large-scale genotyping efforts performed on Japanese subjects with type 2 diabetes have implicated polymorphisms in solute carrier family 12 (sodium/chloride transporters) member 3 (SLC12A3) as being associated with advanced diabetic nephropathy. However, it is not known whether these polymorphisms confer a risk for this complication in type 2 diabetic Caucasians.

Methods: A case-control study was conducted that consisted of 295 cases with advanced diabetic nephropathy and 174 controls who have remained normoalbuminuric despite >or=7 years of diabetes. A total of 11 single nucleotide polymorphisms (SNPs) spanning the SLC12A3 locus was analysed including +34372G>A (Arg913Gln) that was the marker previously showing the strongest evidence for disease association in type 2 diabetic Japanese. Power calculations indicated that with an alpha of 0.05, our study has >90% power to detect disease associations of the magnitude previously reported for +34372G>A (Arg913Gln).

Results: Allele and genotype distributions for all 11 SNPs were found to be comparable between cases and controls, consistent with the absence of disease association. This negative result was reiterated in subgroup analysis after taking into account potentially important covariates including gender, diabetes duration, blood pressure and glycaemic control. No significant disease associations were likewise found for SLC12A3 haplotypes. Allele, genotype and haplotype distributions were similar in cases regardless of whether they were proteinuric or had developed chronic renal failure/end-stage renal disease.

Conclusions: Genetic variation at the SLC12A3 locus is unlikely to explain the risk for advanced diabetic nephropathy among type 2 diabetic Caucasians.
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http://dx.doi.org/10.1093/ndt/gfm946DOI Listing
July 2008

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

Hum Genet 2007 Nov 2;122(3-4):397-407. Epub 2007 Aug 2.

Laboratory for Diabetic Nephropathy, SNP Research Centre, Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

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.
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http://dx.doi.org/10.1007/s00439-007-0414-3DOI Listing
November 2007

A disease haplotype for advanced nephropathy in type 2 diabetes at the ACE locus.

Diabetes 2006 Sep;55(9):2660-3

Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore.

Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for disease haplotype associations. A case-control study design was used where case subjects were type 2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >6 years of diabetes. None of the individual markers showed significant disease association when considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of the A.T.D risk haplotype in case subjects (0.136) compared with control subjects (0.075) (P = 0.009), thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE locus.
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http://dx.doi.org/10.2337/db06-0496DOI Listing
September 2006

Saliva as a viable alternative source of human genomic DNA in genetic epidemiology.

Clin Chim Acta 2006 May 4;367(1-2):81-5. Epub 2006 Jan 4.

Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore.

Background: Saliva is a potentially useful but untapped source of genomic DNA for genetic epidemiological studies. However, current commercial methods are mainly concerned with DNA extraction and do not address important issues concerning saliva preservation and storage. As such, we evaluated how various saliva storage conditions affected DNA yield and quality obtained using a new commercially available method that proposes to integrate these aspects in a single kit.

Methods: The conditions involved the extraction of the DNA immediately after saliva collection (condition 1) or when stored at air-conditioned room temperature (20 degrees C) for 1 month (condition 2) and 6 months (condition 3) as well as at -80 degrees C for 6 months (condition 4). The effect of incorporating an additional incubation of saliva samples at 30 degrees C for 2 weeks was also examined.

Results: Overall average DNA yield from 2 ml of saliva was 35.5 microg (8.5-85.2 microg). DNA yield was unaffected by incubation of saliva at 30 degrees C but DNA yield under condition 3 was significantly higher compared to conditions 1 and 2. OD260/280 values were acceptable and comparable across all conditions. Differences in storage conditions did not impact DNA quality in real time PCR experiments and genotyping fidelity remained undiminished.

Conclusion: Saliva is a viable alternative source of human genomic DNA for genetic epidemiological studies and that this new commercial method and possibly other related techniques can be effective means towards this end.
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http://dx.doi.org/10.1016/j.cca.2005.11.024DOI Listing
May 2006

The fatty acid-binding protein-2 A54T polymorphism is associated with renal disease in patients with type 2 diabetes.

Diabetes 2005 Nov;54(11):3326-30

Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

The intestinal fatty-acid binding protein-2 (FABP2) gene codes a protein responsible for the absorption of long-chain fatty acids. To test whether FABP2 is a candidate gene for renal disease in patients with type 2 diabetes, a functional A54T polymorphism was genotyped in 1,042 Brazilians with type 2 diabetes. Patients were classified as having normoalbuminuria (urinary albumin excretion [UAE] <20 microg/min; n = 529), microalbuminuria (UAE 20-199 microg/min; n = 217), or proteinuria (UAE >199 microg/min; n = 160). Patients with end-stage renal disease (ESRD) (n = 136) were also included. The prevalence of the TT genotype was higher in patients with renal involvement compared with those with normoalbuminuria (odds ratio [95% CI] 2.4 [1.1-5.4]) following adjustment for type 2 diabetes duration, BMI, hypertension, A1C, and cholesterol levels. The risk was similar considering different stages of renal involvement. In a second independent patient sample (483 type 2 diabetic Caucasians residing in Massachusetts), a significant association was also observed between the TT genotype and proteinuria or ESRD (2.7 [1.0-7.3]; P = 0.048). This study thus provides evidence that FABP2 confers susceptibility to renal disease in type 2 diabetic patients.
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http://dx.doi.org/10.2337/diabetes.54.11.3326DOI Listing
November 2005

CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation.

Cancer Causes Control 2005 May;16(4):399-405

Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive MD3, Singapore 117597.

Objective: We examined whether polymorphisms of CYP1A1, which plays a role in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs), confer an increased risk of lung cancer in lifetime non-smoking Chinese women.

Methods: A total of 126 incident lung cancer cases, of which 87.7 were pathologically confirmed, and 162 age-matched hospital controls were included. CYP1A1 MspI and Ile(462)Val polymorphisms were genotyped and tested for association with this disease.

Results: An elevated risk of lung cancer was observed among individuals with the MspI CC (OR=1.7, 95 CI=0.9-3.3) and Ile(462)Val ValVal genotypes (OR=2.8, 95 CI=1.1-7.6). After stratifying by environmental tobacco smoke (ETS) exposure, the risk of lung cancer associated with both polymorphisms was higher among individuals with lower exposure to ETS, compared with those who reported at least weekly exposure. Individuals with the MspI CC genotype showed a two-fold higher risk of lung cancer if they were also null for either GSTM1 or T1 (OR=2.3, 95CI=1.0-5.0 and OR=2.7, 95 CI=1.1-6.9, respectively, compared to other genotype combinations combined).

Conclusions: CYP1A1 is a susceptibility gene for lung cancer among non-smoking Asian women and this association can be influenced by ETS exposure and genetic variation at GST genes.
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http://dx.doi.org/10.1007/s10552-004-5476-0DOI Listing
May 2005

Effect of storage conditions on the extraction of PCR-quality genomic DNA from saliva.

Clin Chim Acta 2004 May;343(1-2):191-4

Department of Community, Occupational and Family Medicine (MD3), Faculty of Medicine, National University of Singapore, 16, Medical Drive, Singapore 117597, Singapore.

Background: Saliva is a potentially useful source of genomic DNA for genetic studies since it can be collected in a painless and non-invasive manner. We sought to determine whether different storage conditions of saliva samples impact our ability to extract genomic DNA that is of sufficient quality for use in the polymerase chain reaction (PCR).

Methods: Saliva was collected from healthy volunteers and 2-ml aliquots subjected to different storage conditions: S1--washing of saliva using phosphate-buffered saline (PBS) and extraction of DNA on the same day of collection; S2--washing and centrifugation to yield a pellet, which was stored at-70 degrees C for 1 week prior to DNA extraction; S3--storage of whole saliva at 4 degrees C for 7 days, followed by washing and extraction of DNA; S4--storage at 4 degrees C for 7 days, followed by washing and pellet formation. The pellet was stored at -70 degrees C for 1 month before extraction of the DNA; S5--storage at-70 degrees C for 1 month, followed by washing and extraction of DNA. DNA yield and purity was determined by spectrophotometry at 260 and 280 nm. Twenty nanograms of genomic DNA was used for the polymerase chain reaction, and the resulting PCR band was captured by digital photography and quantified.

Results: The amounts of DNA extracted from 2 ml of saliva varied widely under the different storage conditions, while purity of the DNA extraction, based on OD(260/280) ratios, was good and comparable. PCR resulted in the presence of a single specific product of the correct size from all samples regardless of saliva storage conditions. Quantification of PCR bands showed significant differences between the various storage conditions (P<0.05). Compared to S1 samples, PCR bands from conditions S2 and S3 were not as strong, while those amplified from S4 and S5 samples were the weakest. Post-hoc analyses showed that the means for conditions S4 and S5 were significantly different from S1-S3. Qualitatively similar results were obtained when the PCR experiment was repeated.

Conclusions: Saliva can act as a useful source of genomic DNA, even when stored under less than optimal conditions.
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http://dx.doi.org/10.1016/j.cccn.2004.01.013DOI Listing
May 2004

Scrutiny of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) locus reveals conserved haplotype block structure not associated with diabetic nephropathy.

Diabetes 2004 Mar;53(3):865-9

Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts, USA.

Glutamine-fructose-6-phosphate transaminase 1 (GFAT) is the rate-limiting enzyme of the hexosamine pathway that has been implicated in the pathogenesis of diabetic nephropathy. As such, we hypothesized that GFPT1, which encodes for GFAT, may confer genetic susceptibility to this complication among Caucasians. Screening of all known functional regions of GFPT1 revealed six single nucleotide polymorphisms (SNPs) that were located in the promoter, introns, and 3' untranslated region. The approximately 60 kb GFPT1 locus was encompassed in a single conserved haplotype block, and two tagging SNPs were sufficient to capture >90% of the haplotype diversity. Analysis of these SNPs in a case-control study made up of type 1 diabetic subjects (324 case subjects with diabetic nephropathy and 289 control subjects with normoalbuminuria despite >15 years of diabetes) revealed no significant association even after stratification by sex, diabetes duration, glucose control, and blood pressure. Similar results were obtained among type 2 diabetic subjects (202 case and 114 control subjects). Genetic variation in GFPT1 is thus unlikely to have a major impact on susceptibility to diabetic nephropathy.
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http://dx.doi.org/10.2337/diabetes.53.3.865DOI Listing
March 2004

Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus.

J Am Soc Nephrol 2003 Aug;14(8):2015-24

Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both betaI and betaII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (--1504C/T and --546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the --1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the --546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of >/==" BORDER="0">24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus.
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http://dx.doi.org/10.1097/01.asn.0000077347.27669.5cDOI Listing
August 2003