Common variants in <Emphasis Type="Italic">CNDP1</Emphasis> and <Emphasis Type="Italic">CNDP2</Emphasis>, and risk of nephropathy in type 2 diabetes

Aims/hypothesis  

Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-l-histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden.     

Joint effects of HLA, <Emphasis Type="Italic">INS</Emphasis>, <Emphasis Type="Italic">PTPN22</Emphasis> and <Emphasis Type="Italic">CTLA4</Emphasis> genes on the risk of type 1 diabetes

Background/hypothesis HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. Methods We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, −DQA1 and −DQB1, the insulin gene (INS, −23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). Results The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene–gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). Conclusion Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Polymorphism of <Emphasis Type="Italic">HMGA1</Emphasis> is associated with increased risk of type 2 diabetes among Chinese individuals

Aims/hypothesis  

Variants of the high-mobility group A1 (HMGA1) gene have been shown to be associated with insulin resistance and type 2 diabetes in individuals of European origin. We aimed to determine whether this locus confers significant susceptibility to type 2 diabetes in the Han Chinese population, and thus cross-race susceptibility to type 2 diabetes.     

<Emphasis Type="Italic">T-</Emphasis>Scores and <Emphasis Type="Italic">Z</Emphasis>-Scores

Bone mineral density (BMD) can be measured by a variety of techniques at several skeletal sites. Once measured, the manufacturers’ software uses the BMD to calculate a T-score and/or Z-score. Both T-scores and Z-scores are derived by comparison to a reference population on a standard deviation scale. The recommended reference group for the T-score is a young gender-matched population at peak bone mass, while the Z-score should be derived from an age-matched reference population. T-scores and Z-scores are widely quoted in scientific publications on osteoporosis and BMD studies, and are the values used for DXA diagnostic criteria and current clinical guidelines for the management of osteoporosis. Errors in BMD measurement, differences in reference populations, and variations in calculation methods used, can all affect the actual T-score and Z-score value. Attempts to standardize these values have made considerable progress, but inconsistencies remain within and across BMD technologies. This can be a source of confusion for clinicians interpreting BMD results. A clear understanding of T-scores and Z-scores is essential for correct interpretation of BMD studies in clinical practice.     

D-Galactose-caused life shortening in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> and <Emphasis Type="Italic">Musca domestica</Emphasis> is associated with oxidative stress

D-Galactose causes aging acceleration in different animal models but the mechanism is unclear. In the present study, we investigated the effects of D-galactose on lifespan and oxidative stress biomarkers in the fruit fly (Drosophila melanogaster) and housefly (Musca domestica). D-Galactose was added to drinking water (20mg/ml) for housefly and to culture medium (6.5%) for fruit fly from 24h after emergence. Oxidative stress was estimated by measuring the activity of Cu–Zn-superoxide dismutase (SOD) and the levels of lipid peroxidation products, namely malondialdehyde (MDA) and lipofuscin in housefly brain (male) and in fruit fly (male and female). D-Galactose caused a significant decrease in mean lifespan (by 12.6% of male and 15.9% of female) and maximum lifespan (by 12.9% of male and 17.1% of female) in fruit fly, and also a significant decrease in mean lifespan (by 27.1% of male, 19.8% of female) and maximum lifespan (by 27.1% of male, 21.9% of female) in housefly. MDA and lipofuscin increased with age in fruit fly and in housefly brains while change of the SOD activity showed a biphasic shape with age. D-Galactose caused a significant increase in MDA and lipofuscin and decrease in SOD activity in the age-matched fruit flies and houseflies. These data indicate that D-galactose shortens the lifespan of the two different fly species and that the life shortening effect is associated with an increase in oxidative stress.This revised version was published online in October 2005 with corrections to the Cover Date.     

Novel mutations in <Emphasis Type="Italic">WWOX</Emphasis>, <Emphasis Type="Italic">RARS2</Emphasis>, and <Emphasis Type="Italic">C10orf2</Emphasis> genes in consanguineous Arab families with intellectual disability

Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.     

Association of <Emphasis Type="Italic">Lewis</Emphasis> and <Emphasis Type="Italic">Secretor</Emphasis> gene polymorphisms and <Emphasis Type="Italic">Helicobacter pylori</Emphasis> seropositivity among Japanese-Brazilians

Background Secretor (Se) and Lewis (Le) genes are involved in the synthesis of Lewis b (Le^b) and type I antigens throughout the body, especially in the epithelial cells of gastric mucosa. Helicobacter pylori can attach to the gastric epithelial cells with the blood group antigen-binding adhesin, which binds to Le^b or H type I carbohydrate structures. In a previous study, a marked association between H. pylori seropositivity and polymorphism of the Se and Le genes was observed among Japanese outpatients of a gastroenterology clinic. The present work aims to investigate the associations between Se and Le gene polymorphisms and H. pylori infection among Japanese-Brazilians.Methods The subjects consisted of 942 healthy volunteer Japanese-Brazilians, who were tested for the presence of anti-H. pylori IgG antibodies and genotyped for Se and Le polymorphisms.Results The sex-age-adjusted odds ratios (aORs) for H. pylori seropositivity were 0.99 for the Sese genotype relative to the SeSe genotype (95% confidence interval [CI], 0.73–1.33), and 1.03 for sese relative to SeSe (95% CI, 0.71–1.48). On the other hand, the aOR for the subjects with the le allele (Lele or lele) relative to the LeLe genotype was 1.48 (95% CI, 1.07–1.79). When the Se and Le genotypes were analyzed in combination according to risk group, no statistically significant association was observed.Conclusions These results are inconsistent with previous work and may have been modulated by an external factor or some other unidentified factor. Japanese-Brazilians are genotypically the same as Japanese, but their lifestyle is adapted to that of Brazil. Further investigations are necessary to clarify this influence on susceptibility to H. pylori infection.     

Polymorphisms in the <Emphasis Type="Italic">TCF7L2</Emphasis>, <Emphasis Type="Italic">CDKAL1</Emphasis> and <Emphasis Type="Italic">SLC30A8</Emphasis> genes are associated with impaired proinsulin conversion

Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion. Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion. Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p < 0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p < 0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p > 0.6). Conclusions/interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

<Emphasis Type="Italic">Fas/FasL,Bcl2</Emphasis> and <Emphasis Type="Italic">Caspase</Emphasis>-<Emphasis Type="Italic">8</Emphasis> gene polymorphisms in Chinese patients with rheumatoid arthritis

Apoptosis signals are necessary for maintaining homeostasis and an adequate immune response. Dysregulation of apoptosis-related genes in the immune system has an important impact on autoimmune diseases such as rheumatoid arthritis (RA). Thus, we investigated the association between Fas rs2234767 G/A, FasL rs763110 C/T, Bcl2 rs12454712 T/C, Bcl2 rs17757541 C/G, and Caspase-8 rs1035142 G/T polymorphisms and RA susceptibility in a Chinese population. These five single-nucleotide polymorphisms (SNPs) were studied in a Chinese population consisting of 615 patients with RA and 839 controls. Genotyping was performed using a custom-by-design 48-Plex SNP scan TM kit. Furthermore, we undertook a meta-analysis between FasL rs763110 C/T and RA. This study indicated that Fas rs2234767 and Bcl2 rs17757541 polymorphisms were risk factors for RA. No association was observed between FasL rs763110 C/T, Bcl2 rs12454712 T/C, and Caspase-8 rs1035142 G/T polymorphisms and RA in this study. The results of this meta-analysis suggested no significant association between FasL rs763110 C/T and RA. However, stratification analysis of this meta-analysis indicated that FasL rs763110 C/T increased the risk of Caucasian RA patients. In conclusion, this study demonstrated that Fas rs2234767 G/A and Bcl2 rs17757541 T/C polymorphisms might be associated with an increased risk of RA. This meta-analysis revealed that FasL rs763110 C/T was associated with an increased risk of Caucasian RA patients.     

<Emphasis Type="Italic">MHC2TA</Emphasis> and <Emphasis Type="Italic">FCRL3</Emphasis> genes are not associated with rheumatoid arthritis in Mexican patients

Rheumatoid arthritis (RA) is a multifactorial disease. A combination of genetic and environmental risk factors contributes to its etiology. Several genes have been reported to be associated with susceptibility to the development of RA. The MHC2TA and FCRL3 genes have been associated previously with RA in Swedish and Japanese populations, respectively. In two recent reports, we show an association between FCRL3 and juvenile rheumatoid arthritis (JRA), and MHC2TA and acute coronary syndrome (ACS) in Mexican population. We assessed the association between three single nucleotide polymorphisms (SNPs) of the MHC2TA (?168G/A; rs3087456, and +16G/C; rs4774) and FCRL3 (?169T/C; rs7528684) genes and rheumatoid arthritis in Mexican population through a genotyping method using allelic discrimination assays with TaqMan probes. Our case–control study included 249 patients with RA and 314 controls. We found no evidence of an association between the MHC2TA ?168G/A and +1614G/C or FCRL3 ?169T/C polymorphisms and RA in this Mexican population. In this cohort of Mexican patients with RA, we observed no association between the MHC2TA or FCRL3 genes and this autoimmune disease.     

Cardiovascular Concerns in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> Mutation Carriers

Purpose of review

BRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines.

Recent findings

BRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks.

Summary

Understanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important.

     

Epigenetic factors Polycomb (<Emphasis Type="Italic">Pc</Emphasis>) and Suppressor of zeste (<Emphasis Type="Italic">Su</Emphasis>(<Emphasis Type="Italic">z</Emphasis>)2) negatively regulate longevity in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

The process of aging is a hallmark of the natural life span of all organisms and individuals within a population show variability in the measures of age related performance. Longevity and the rate of aging are influenced by several factors such as genetics, nutrition, stress, and environment. Many studies have focused on the genes that impact aging and there is increasing evidence that epigenetic factors regulate these genes to control life span. Polycomb (PcG) and trithorax (trxG) protein complexes maintain the expression profiles of developmentally important genes and regulate many cellular processes. Here, we report that mutations of PcG and trxG members affect the process of aging in Drosophila melanogaster, with perturbations mostly associated with retardation in aging. We find that mutations in polycomb repressive complex (PRC1) components Pc and Su(z)2 increase fly survival. Using an inducible UAS-GAL4 system, we show that this effect is tissue-specific; knockdown in fat body, but not in muscle or brain tissues, enhances life span. We hypothesize that these two proteins influence life span via pathways independent of their PRC1 functions, with distinct effects on response to oxidative stress. Our observations highlight the role of global epigenetic regulators in determining life span.     

<Emphasis Type="Italic">Anisakis</Emphasis> spp. burden in <Emphasis Type="Italic">Trachurus trachurus</Emphasis>

Anisakis is a parasite of marine mammals that uses a great number of fish species as intermediate or paratenic hosts. It is common in commercially important marine fishes and its presence is of great concern for both human health and economic reasons. Horse mackerels (Trachurus trachurus) originated from the Northern Aegean Sea were examined for the presence of Anisakis spp. larvae. The prevalence of Anisakis spp. was found 98.8 %. The number of parasites was significantly related to the host’s length but was not related to the fish gender. The month of sampling affected the size of the fishes and consequently the number of parasites. The length of larvae was not related to the host’s length. The present study resulted in the design of a prediction model for the number of existing parasites in the fish by measuring only its Fixed Length.     

Spontaneous bleeding associated with <Emphasis Type="Italic">Ginkgo biloba</Emphasis>

BACKGROUND: Ginkgo biloba (ginkgo) is a herbal remedy used by over 2% of the adult population in the United States. Several review articles have suggested that ginkgo may increase the risk of bleeding. OBJECTIVE: To report a case of bleeding associated with using ginkgo, to systematically review the literature for similar case reports, and to evaluate whether using ginkgo is causally related to bleeding. DATA SOURCES: We searched MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004 with no language restrictions. REVIEW METHODS: Published case reports of bleeding events in persons using ginkgo were selected. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event. RESULTS: Fifteen published case reports described a temporal association between using ginkgo and a bleeding event. Most cases involved serious medical conditions, including 8 episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for bleeding. Only 6 reports clearly described that ginkgo was stopped and that bleeding did not recur. Bleeding times, measured in 3 reports, were elevated when patients were taking ginkgo. CONCLUSION: A structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. Given the widespread use of this herb and the serious nature of the reported events, further studies are needed. Patients using ginkgo, particularly those with known bleeding risks, should be counseled about a possible increase in bleeding risk. None of the authors have any financial or other conflicts of interest to report regarding this study or this article. Grant support: This work was supported by Grant Number 1 K08 ATO1338-01 (Dr. Bent) from the National Center for Complementary and Alternative Medicine (NCCAM).     

Polymorphisms in <Emphasis Type="Italic">PARK2</Emphasis> and <Emphasis Type="Italic">MRPL37</Emphasis> are associated with higher risk of recurrent venous thromboembolism in a sex-specific manner

Recent studies indicate that mitochondrial DNA (mtDNA) dysfunction is a biomarker of oxidative stress and can predict the risk of cardiovascular diseases (CVDs). Genetic variants in PARK2 (rs4708928) and MRPL37 (rs10888838) genes have been shown to be associated with altered levels of mtDNA in a sex-specific manner. However, the role of these genetic variants in risk assessment of recurrent venous thromboembolism (VTE) is unknown. We investigated the role of these polymorphisms in VTE recurrence in patients from the Malmö thrombophilia study (MATS, n?=?1465), followed for ~?10 years. Genotyping was performed by TaqMan polymerase chain reaction. Female patients with PARK2 polymorphism had significantly higher risk of VTE recurrence (Hazard ratio [HR]?=?2.39, 95% confidence interval [CI] 1.09–5.24) and male patients with MRPL37 polymorphism had a significantly higher risk of VTE recurrence (HR?=?1.79, 95% CI 1.01–3.17) on multivariate Cox regression analysis. Combined analysis of these polymorphism with factor V Leiden (FVL) showed that female patients with both, FVL and PARK2 polymorphism had even higher risk of VTE recurrence (HR?=?4.49, 95% CI 1.58–12.75) compared to FVL or PARK2 polymorphism alone or both wild-type (reference). Similarly, male patients with both FVL and MRPL37 polymorphism had significantly higher risk of VTE recurrence (HR?=?2.97, 95% CI 1.45–6.08) compared to those with FVL or MRPL37 polymorphisms alone or the reference group. Polymorphisms in nuclear genome regulating mtDNA together with FVL may be promising biomarkers for predicting VTE recurrence in a sex specific manner. The abstract should be followed by 3-4 bullet points that highlight the major findings. The final bullet point should address future research.     

Permanent neonatal diabetes due to activating mutations in <Emphasis Type="Italic">ABCC8</Emphasis> and <Emphasis Type="Italic">KCNJ11</Emphasis>

The ATP-sensitive potassium (K_ATP) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K_ATP mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K_ATP channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.