Results of Nephrectomy in Hypertension Associated with Unilateral Renal Disease

Nephrectomy has been carried out in 34 patients with hypertension associated with unilateral parenchymal renal disease (28 with unilateral pyelonephritis, 3 tuberculosis, 2 hypoplasia, and 1 adenocarcinoma). In 13 of the patients the blood pressure was corrected, in four it was improved, and in 17 it was unaffected. The intravenous pyelogram (by the infusion technique with nephrotomography if necessary) and renogram give adequate information in most patients with unilateral parenchymal renal disease but may need to be supplemented by aortography, or retrograde pyelography, or divided renal function studies in a few special circumstances. When the function of the damaged kidney is less than 25% of the total (which is well maintained), and the contralateral kidney is intact, nephrectomy is recommended provided the hypertension is significant; success is more likely in younger patients with a short history of hypertension.     

Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

Background

Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD.

Methods

A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis.

Results

Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61) and G/A/G haplotype (P = 0.0365, OR = 1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses.

Conclusion

CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness.     

Naturally Occurring Human Urinary Peptides for Use in Diagnosis of Chronic Kidney Disease

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.Chronic kidney disease (CKD)1 is often characterized by a slow, progressive loss of renal function with a loss of glomerular filtration over a period of months or years that may eventually lead to end stage renal disease (ESRD). Patients with ESRD require renal replacement therapy (dialysis or kidney transplantation). The most common causes of CKD in North America, Europe, and Japan are diabetic nephropathy, hypertension, and glomerulonephritis (1). Together, these diseases account for ∼75% of all adult cases of ESRD. Historically, kidney diseases were classified according to the anatomical compartment of the kidney that is involved. On this basis, vascular diseases include large and small vessel diseases, such as hypertensive nephropathy and vasculitis. Glomerular diseases comprise a diverse group of histologically defined primary glomerulopathies (e.g. focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), minimal change disease (MCD), and IgA nephropathy (IgAN)) and secondary glomerulopathies due to diabetes mellitus (diabetic nephropathy), systemic autoimmune disorders (e.g. lupus erythematosus and hemolytic-uremic syndrome), or chronic viral infection (e.g. hepatitis and HIV). Tubular diseases are characterized by low molecular weight proteinuria and multiple transport defects (e.g. DeToni-Debré-Fanconi syndrome).In clinical practice, renal damage is generally detected by proteinuria/albuminuria on urinalysis or quantitative measurement, changes in serum creatinine concentration for estimation of glomerular filtration rate, or both. However, these methods have major limitations as they are nonspecific and frequently are also late manifestations of renal damage. Therefore, we have sought to define alternative biomarkers for renal damage that may enable earlier and more accurate disease assessment.Analysis of urine plays a central role in clinical diagnostics as it can be collected non-invasively. Urine as a body fluid for clinical analysis is relatively stable, probably due to the fact that it is “stored” for hours in the bladder; hence, proteolytic degradation by endogenous proteases may be essentially complete by the time of voiding (2). This is in sharp contrast to blood for which the activation of proteases and, consequently, generation of an array of proteolytic breakdown products are inevitably associated with its collection (3). The human urinary peptidome has been extensively investigated to gain insight about disease processes affecting the kidney and the urogenital tract (4–6). Urinary proteins and peptides originate not only from glomerular filtration but also from tubular secretion, epithelial cells shed from the kidney and urinary tract, secreted exosomes, and seminal secretions (7–9). Urine is a rich source of biomarkers for a wide range of diseases due to specific changes in its proteome (10–13). To test the feasibility of urinary proteomics as a non-invasive diagnostic tool, large scale studies are needed to analyze urine samples with reliable and quantitative experimental procedures. Various techniques have been applied to this effort, including two-dimensional electrophoresis combined with mass spectrometry (MS) and/or immunochemical identification of proteins (14–16), liquid chromatography coupled to mass spectrometry (LC-MS) (17, 18), and surface-enhanced laser desorption/ionization mass spectrometry (SELDI-MS) (19).Because of mostly technical challenges, studies relying on proteomics experimental procedures are often restricted to the comparison of two groups of subjects (i.e. healthy controls versus patients with a well defined disease entity) with only a few individuals in each group. The lack of comparability severely limits the suitability of such data for a meta-analysis approach to define broadly applicable biomarkers. Consequently, findings from several studies cannot be used to explore the human urinary proteome/peptidome in its entirety. In addition, the health state of patients with kidney disease is often too heterogeneous to be reliably classified by biomarkers identified by such a strictly single disease-oriented approach. Diagnosis of individuals with different stages or types of kidney disease (disease controls) is conceivable by multiplex screening of proteomics data. Realization of such an approach critically depends on the use of a measurement platform allowing analysis of proteomic profiles within a reasonably short time and with high resolution and on the generation of a reference database for the human urinary proteome/peptidome.Capillary electrophoresis coupled to mass spectrometry (CE-MS) enables reproducible and robust high resolution analysis of several thousand low molecular weight urinary proteins/peptides in less than an hour (5). In comparison with other proteomics methods, CE-MS offers several advantages. (i) It provides fast separation with high resolution. (ii) It is robust: capillaries are inexpensive and can be reconditioned efficiently using NaOH. (iii) It is compatible with most volatile buffers and analytes generally required for ESI. (iv) It provides a stable constant flow, avoiding the necessity of buffer gradients (for more details, see recent reviews (3, 5, 20)).This approach has recently been used to analyze urine samples from healthy individuals and patients with various chronic kidney diseases in several independent masked studies (21–27), including IgAN (28), diabetic nephropathy (29), and ANCA-associated vasculitis (30). The high number of data sets analyzed under identical conditions using the same technological platform allows comprehensive characterization of the low molecular weight proteome (peptidome) that can then become a primary source of information for the diagnosis, classification, and monitoring of a wide range of diseases. Here, we report the analysis of the human urinary peptidome by CE-MS and the identification of peptide urinary biomarkers for the detection of pathological changes in the kidney during the development of many forms of CKD. Furthermore, we have replicated these findings in an independent cohort.     

Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease

Background

Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer''s disease (AD).

Methods

We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log₁₀ transformed rank invariant normalized expression data.

Results

In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D′>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18×10−5 and p<0.0001).

Conclusions

Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.     

Two Naturally Occurring Nuclear Polyhedrosis Virus Variants of Neodiprion sertifer Geoffr. (Hymenoptera; Diprionidae)

Two isolates of Neodiprion sertifer (Geoffr.) nuclear polyhedrosis virus from Britain and North America were compared using three biochemical techniques. Alkaline protease assays of polyhedra revealed the presence of endogenous enzyme activity in the British isolate but not in the North American isolate. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of virus particle structural polypeptides revealed only minor differences, with the exception that the North American virus was contaminated with polyhedral protein. The restriction endonucleases SalI, HindIII, and HpaII were used as a definitive method of distinguishing the two variants, with all endonucleases achieving this to a greater or lesser extent. The possible significance of all of these observations is discussed in terms of their possible influence on the registration and field application of this virus.     

A Naturally Occurring Variant in Human TLR9, P99L, Is Associated with Loss of CpG Oligonucleotide Responsiveness

The innate immune system employs Toll-like receptors (TLRs) for the detection of invading microorganisms based on distinct molecular patterns. For example, TLR9 is activated by microbial DNA and also by short therapeutic CpG-containing oligonucleotides (CpG-ODN). TLR9 activation leads to the production of interferons and the priming of humoral adaptive immune responses. Unfortunately, the principles of ligand recognition by TLR9 are poorly understood, and genetic variants of TLR9, which may affect its function, have not been characterized systematically on the molecular level. We therefore sought to functionally characterize reported single nucleotide polymorphisms of TLR9 in the HEK293 model system. We discovered that two variants, P99L and M400I, are associated with altered receptor function regarding NF-κB activation and cytokine induction. Our investigations show that for the most functionally impaired variant, P99L, the ability to respond to physiological and therapeutic TLR9 ligands is severely compromised. However, CpG-ODN binding is normal. CpG-ODN recognition by TLR9 thus appears to involve two separate events, CpG-ODN binding and sensing. Our studies highlight Pro-99 as a residue important for the latter process. In genotyping studies, we confirmed that both M400I (rs41308230) and P99L (rs5743844) are relatively rare variants of TLR9. Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG-ODN-based therapies.     

Genetic Variants in RKIP Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population

Background

Raf-1 kinase inhibitor protein (RKIP) plays a critical role in tumor development by regulating cell functions such as invasion, apoptosis and differentiation. Down-regulation of RKIP expression has been implicated in the development and progression of renal cell carcinoma (RCC). Herein, we hypothesized that genetic polymorphisms in RKIP might be associated with susceptibility and progression of RCC.

Methods

A total of 5 tagging single-nucleotide polymorphisms (tSNPs) in RKIP were selected and genotyped by SNapShot method in a case-control study of 859 RCC patients and 1004 controls. The logistic regression was used to evaluate the genetic association with occurrence and progression of RCC. The functionality of the important SNP was preliminary examined by qRT-PCR.

Result

We found that the rs17512051 in the promoter region of RKIP was significantly associated with decreased clear cell RCC (ccRCC) risk (TA/AA vs. TT: P = 0.039, OR = 0.78, 95%CI = 0.62–0.99). Another SNP (rs1051470) in the 3′UTR region of RKIP was marginally associated with increased ccRCC risk (TT vs. CC+CT: OR = 1.45, 95%CI = 1.01–2.09). In the stratified analysis, the protective effect of rs17512051 was more predominant in the subgroups of male, non-smokers, non-drinkers as well as subjects without history of diabetes. Furthermore, we observed higher RKIP mRNA levels in the presence of the rs17512051A allele in normal renal tissues.

Conclusion

Our results suggest that the potentially functional RKIP rs17512051 polymorphism may affect ccRCC susceptibility through altering the endogenous RKIP expression level. Risk effects and the functional impact of this polymorphism need further validation.     

Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study

Objective

To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement.

Methods

This study investigated the association between 3 SNPs (ABCC2–24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m² decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m²) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5’-nuclease assays.

Results

95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/μl, median baseline eGFR of 96ml/min/1.73m² (IQR 84.6–109.2), and median exposure to TDF of 3.66 years (IQR 1.93–5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m² and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m²: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.

Conclusions

SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.     

A Novel Quasi-Species of Glutathione Transferase with High Activity towards Naturally Occurring Isothiocyanates Evolves from Promiscuous Low-Activity Variants

Glutathione transferases (GSTs) are known as promiscuous enzymes capable of catalyzing the conjugation of glutathione with a broad range of electrophilic substrates. A previous study based on recombinant chimeras derived from human GST M1-1 and GST M2-2 demonstrated the formation of a subset of F1 generation GSTs, which had lost high activity with substrates distinguishing parental enzymes. In the present study, the members of this subset were recombined by DNA shuffling to produce an F2 generation of GSTs. Screening of 930 bacterial clones demonstrated that 83% of recombinant enzyme variants were active with at least one of three alternative substrates: phenethyl isothiocyanate (PEITC), 1-chloro-2,4-dinitrobenzene, or p-nitrophenyl acetate. The majority had similar low activity as the parental GSTs in the F1 generation. However, 17 novel enzymes displayed high activity with PEITC. Half of these enzymes were similar to GST M1-1, which also has high activity with the same substrate, and all of these GSTs featured Tyr116/Ser210 in the active site. This group of F2 variants apparently had reverted to the GST M1-1 type. A second group of F2 variants with high PEITC activity was characterized by His116 in the active site. This category represented a new variety of GSTs, which demonstrated higher selectivity for isothiocyanate substrates than the GST M1-1 type. The different groups of GSTs can be considered as distinct molecular quasi-species, each of which comprises variant amino acid sequences. The quasi-species are structurally distinguished by active-site residues that govern their substrate selectivities. Clearly, minimal alterations of the active site can generate enzymes with highly distinctive functional properties.     

Naturally Occurring Mutations Alter the Stability of Polycystin-1 Polycystic Kidney Disease (PKD) Domains

Mutations in polycystin-1 (PC1) can cause autosomal dominant polycystic kidney disease, which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 amino acids) with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. Here we investigate the effects of several naturally occurring mutations on the mechanical stability of the first PKD domain of human PC1 (HuPKDd1). We found that several missense mutations alter the mechanical unfolding pathways of HuPKDd1, resulting in distinct mechanical phenotypes. Moreover, we found that these mutations also alter the thermodynamic stability of a structurally homologous archaeal PKD domain. Based on these findings, we hypothesize that missense mutations may cause autosomal dominant polycystic kidney disease by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals.     

Common Genetic Variants of Surfactant Protein-D (SP-D) Are Associated with Type 2 Diabetes

Context

Surfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D).

Research Design and Methods

We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met³¹Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC).

Results

We found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC.

Conclusions

SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.     

Naturally Occurring Major and Minor Capsid Protein Variants of Human Papillomavirus 45 (HPV45): Differential Recognition by Cross-Neutralizing Antibodies Generated by HPV Vaccines

We investigated naturally occurring variation within the major (L1) and minor (L2) capsid proteins of human papillomavirus genotype 45 (HPV45). Pseudoviruses (PsVs) representing HPV45 sublineages A1, A2, A3, B1, and B2 exhibited comparable particle-to-infectivity ratios and morphologies but demonstrated both increased (A2, A3, and B1) and decreased (B2) sensitivities to cross-neutralization by HPV vaccine antibodies compared to that of the A1 sublineage. Mutant PsVs identified HI loop residue 357 as being critical for conferring this differential sensitivity.     

A Naturally Occurring Variant of Porcine Mx1 Associated with Increased Susceptibility to Influenza Virus In Vitro

Mx1 has been implicated in resistance to the influenza virus. We have now identified four alleles of the Mxl gene in domesticated breeds of pigs. Two of the alleles encode deletion variants (a 3-bp deletion in exon 13 and an 11-bp deletion in exon 14), which might be expected to interfere with Mx activity. The porcine Mxl genes corresponding to wild type, the 3-bp deletion mutant, and the 11-bp deletion mutant were cloned and expressed in NIH3T3 cells, and the antiviral activity for influenza virus was assayed. Virus yield was observed to be 10–100-fold greater with the 11-bp deletion allele than that for wild type and the 3-bp deletion alleles. The results suggest that the 11-bp deletion type is lacking antiviral activity able to contribute to the interference of influenza virus replication.     

Naturally Occurring Human Monoclonal Antibodies Neutralize both 1918 and 2009 Pandemic Influenza A (H1N1) Viruses

The 2009 pandemic influenza A (H1N1) virus exhibits hemagglutinin protein sequence homology with the 1918 pandemic influenza virus. We found that human monoclonal antibodies recognized the Sa antigenic site on the head domains of both 1918 and 2009 hemagglutinins, a site that is hypervariable due to immune selection. These antibodies exhibited high potency against the 2009 virus in vitro, and one exerted a marked therapeutic effect in vivo.In March and April of 2009, an outbreak of a swine-origin novel H1N1 influenza A virus began in Mexico (2). As of 29 November 2009, worldwide, more than 207 countries and overseas territories or communities have reported laboratory-confirmed cases of 2009 A (H1N1), including at least 8,768 deaths. (http://www.who.int/csr/don/2009_12_04/en/index.html). The hemagglutinin (HA) gene of the 2009 A (H1N1) strain has been present in classical swine H1N1 viruses that have circulated in pigs at least since the discovery by Shope in the 1930s (Table 10, 11, 16). In contrast, the HA of human H1N1 influenza viruses circulating from 1918 to 1957 and from 1977 to present drifted progressively away from the 1918 virus HA (Table ​(Table1d)1d) (8, 14). Elderly subjects born prior to 1918 were found to have serum neutralizing antibody titers to the A/California/04/2009 (CA04) virus (5, 6).

TABLE 1.

Alignment of the amino acids in site Sa of the HA of representative swine or human influenza viruses from the 20th century^a

Mitochondrial Genetic Variants Identified to Be Associated with BMI in Adults

It has been suggested that mitochondrial dysfunction plays a role in metabolic disorders including obesity, diabetes, and hypertension. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why some individuals can eat all sorts of foods and remain at normal weight while they are young. However, around the fourth decade of life there is a trend towards “middle-age spread” with weight gain and the body''s decreasing ability to metabolize calories efficiently. To test the hypothesis that mitochondrial variants are associated with BMI in adults, we analyzed a total number of 984 mitochondrial single nucleotide polymorphisms (mtSNPs) in a sample of 6,528 individuals participating in the KORA studies. To assess mtSNP association while taking heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Significant results were obtained for 2 mtSNPs located in the Cytochrome c oxidase subunit genes (MT-CO1: P_adjusted = 0.0140 and MT-CO3: P_adjusted = 0.0286) and 3 mtSNPs located in the NADH dehydrogenase subunit genes (MT-ND1, MT-ND2 and MT-ND4L: P_adjusted = 0.0286). Polymorphisms located in the MT-CO3 and MT-ND4L genes have not been associated with BMI or related phenotypes in the past. Our results highlight the importance of the mitochondrial genome among the factors that contribute to the risk of high BMI. Focusing on mitochondrial variants may lead to further insights regarding effects of existing medications, or even to the development of innovative treatments.     

Familial Young-Onset Diabetes,Pre-Diabetes and Cardiovascular Disease Are Associated with Genetic Variants of DACH1 in Chinese

In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40-year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57–3.96, P = 8.4×10⁻⁵). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02–1.12, P_meta = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07–2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19–9.19, P = 0.0214) and 3.27(1.25–11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese.