Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy.

Circ Cardiovasc Genet. 2017 Apr;10(2):

Authors: Mayosi BM, Fish M, Shaboodien G, Mastantuono E, Kraus S, Wieland T, Kotta MC, Chin A, Laing N, Ntusi NB, Chong M, Horsfall C, Pimstone SN, Gentilini D, Parati G, Strom TM, Meitinger T, Pare G, Schwartz PJ, Crotti L

Abstract
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.
METHODS AND RESULTS: Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype-phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (CDH2) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis.
CONCLUSIONS: These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.

PMID: 28280076 [PubMed - in process]

Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis.

Sci Rep. 2016 Apr 07;6:24226

Authors: Wang J, Liu Y, Liu F, Huang C, Han S, Lv Y, Liu CJ, Zhang S, Qin Y, Ling L, Gao M, Yu S, Li C, Huang M, Liao S, Hu X, Lu Z, Liu X, Jiang T, Tang Z, Zhang H, Guo AY, Liu M

Abstract
Disseminated superficial porokeratosis (DSP) is a rare keratinization disorder of the epidermis. It is characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. We investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, we sequencing identified a nonsense variation c.412C > T (p.Arg138*) in the phosphomevalonate kinase gene (PMVK), which encodes a cytoplasmic enzyme catalyzing the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway. By co-segregation and haplotype analyses as well as exclusion testing of 500 normal control subjects, we demonstrated that this genetic variant was involved in the development of DSP in both families. We obtained further evidence from studies using HaCaT cells as models that this variant disturbed subcellular localization, expression and solubility of PMVK. We also observed apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues, with incomplete differentiation of keratinocytes. Our findings suggest that PMVK is a potential novel gene involved in the pathogenesis of DSP and PMVK deficiency or abnormal keratinocyte apoptosis could lead to porokeratosis.

PMID: 27052676 [PubMed - indexed for MEDLINE]

Association of a Novel Nonsense Mutation in KIAA1279 with Goldberg-Shprintzen Syndrome.

Iran J Child Neurol. 2017;11(1):70-74

Authors: Salehpour S, Hashemi-Gorji F, Soltani Z, Ghafouri-Fard S, Miryounesi M

Abstract
Goldberg-Shprintzen syndrome (OMIM 609460) (GOSHS) is an autosomal recessive multiple congenital anomaly syndrome distinguished by intellectual disability, microcephaly, and dysmorphic facial characteristics. Most affected individuals also have Hirschsprung disease and/or gyral abnormalities of the brain. This syndrome has been associated with KIAA1279 gene mutations at 10q22.1. Here we report a 16 yr old male patient referred to Center for Comprehensive Genetic Services, Tehran, Iran in 2015 with cardinal features of GOSHS in addition to refractory seizures. Whole exome sequencing in the patient revealed a novel nonsense (stop gain) homozygous mutation in KIAA1279 gene (KIAA1279: NM_015634:exon6:c.C976T:p.Q326X). Considering the wide range of phenotypic variations in GOSHS, relying on phenotypic characteristics for discrimination of GOSH from similar syndromes may lead to misdiagnosis. Consequently, molecular diagnostic tools would help in accurate diagnosis of such overlapping phenotypes.

PMID: 28277559 [PubMed - in process]

Identification of Disease-Causing Mutations by Functional Complementation of Patient-Derived Fibroblast Cell Lines.

Methods Mol Biol. 2017;1567:391-406

Authors: Kremer LS, Prokisch H

Abstract
Diagnosis of mitochondrial disorders is still hampered by their phenotypic and genotypic heterogeneity. In many cases, exome sequencing, the state-of-the-art method for genetically diagnosing mitochondrial disease patients, does not allow direct identification of the disease-associated gene but rather results in a list of variants in candidate genes. Here, we present a method to validate the disease-causing variant based on functional complementation assays. First, cell lines expressing a wild-type cDNA of the candidate genes are generated by lentiviral infection of patient-derived fibroblasts. Next, oxidative phosphorylation is measured by the Seahorse XF analyzer to assess rescue efficiency.

PMID: 28276032 [PubMed - in process]

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

JIMD Rep. 2017 Mar 09;:

Authors: Fleger M, Willomitzer J, Meinsma R, Alders M, Meijer J, Hennekam RC, Huemer M, van Kuilenburg AB

Abstract
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of pyrimidine metabolism that impairs the first step of uracil und thymine degradation. The spectrum of clinical presentations in subjects with the full biochemical phenotype of DPD deficiency ranges from asymptomatic individuals to severely affected patients suffering from seizures, microcephaly, muscular hypotonia, developmental delay and eye abnormalities.We report on a boy with intellectual disability, significant impairment of speech development, highly active epileptiform discharges on EEG, microcephaly and impaired gross-motor development. This clinical presentation triggered metabolic workup that demonstrated the biochemical phenotype of DPD deficiency, which was confirmed by enzymatic and molecular genetic studies. The patient proved to be homozygous for a novel c.2059-22T>G mutation which resulted in an in-frame insertion of 21 base pairs (c.2059-21_c.2059-1) of intron 16 of DPYD. Family investigation showed that the asymptomatic father was also homozygous for the same mutation and enzymatic and biochemical findings were similar to his severely affected son. When the child deteriorated clinically, exome sequencing was initiated under the hypothesis that DPD deficiency did not explain the phenotype completely. A deletion of the maternal allele on chromosome 15q11.2-13-1 was identified allowing the diagnosis of Angelman syndrome (AS). This diagnosis explains the patient's clinical presentation sufficiently; the influence of DPD deficiency on the phenotype, however, remains uncertain.

PMID: 28275972 [PubMed - as supplied by publisher]

Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.

Genome Biol. 2017 Mar 08;18(1):48

Authors: Gui H, Schriemer D, Cheng WW, Chauhan RK, Antiňolo G, Berrios C, Bleda M, Brooks AS, Brouwer RW, Burns AJ, Cherny SS, Dopazo J, Eggen BJ, Griseri P, Jalloh B, Le TL, Lui VC, Luzón-Toro B, Matera I, Ngan ES, Pelet A, Ruiz-Ferrer M, Sham PC, Shepherd IT, So MT, Sribudiani Y, Tang CS, van den Hout MC, van der Linde HC, van Ham TJ, van IJcken WF, Verheij JB, Amiel J, Borrego S, Ceccherini I, Chakravarti A, Lyonnet S, Tam PK, Garcia-Barceló MM, Hofstra RM

Abstract
BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human.
RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS.
CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.

PMID: 28274275 [PubMed - in process]

tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy.

Eur J Hum Genet. 2017 Mar 08;:

Authors: Edvardson S, Prunetti L, Arraf A, Haas D, Bacusmo JM, Hu JF, Ta-Shma A, Dedon PC, de Crécy-Lagard V, Elpeleg O

Abstract
Post-transcriptional tRNA modifications are numerous and require a large set of highly conserved enzymes in humans and other organisms. In yeast, the loss of many modifications is tolerated under unstressed conditions; one exception is the N(6)-threonyl-carbamoyl-adenosine (t(6)A) modification, loss of which causes a severe growth phenotype. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with global developmental delay, failure to thrive and a renal defect manifesting in proteinuria and hypomagnesemia. Using exome sequencing, the patients were found to be homozygous for the c.974G>A (p.(Arg325Gln)) variant of the KAE1 gene. KAE1 is a constituent of the KEOPS complex, a five-subunit complex that catalyzes the second biosynthetic step of t(6)A in the cytosol. The yeast KAE1 allele carrying the equivalent mutation did not rescue the t(6)A deficiency of the kae1Δ yeast strain as efficiently as the WT allele; furthermore, t(6)A levels quantified by LC-MS/MS were lower in the kae1Δ strain which was complemented by the mutation than in the kae1Δ strain, which was complemented by the WT allele. We conclude that homozygosity for c.974G>A (p.(Arg325Gln)) in KAE1 likely exerts its pathogenic effect by perturbing t(6)A synthesis, thereby interfering with global protein production. This is the first report of t(6)A biosynthesis defect in human. KAE1 joins the growing list of cytoplasmic tRNA modification enzymes, all associated with severe neurological disorders.European Journal of Human Genetics advance online publication, 8 March 2017; doi:10.1038/ejhg.2017.30.

PMID: 28272532 [PubMed - as supplied by publisher]

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

JAMA. 2017 03 07;317(9):937-946

Authors: Khera AV, Won HH, Peloso GM, O'Dushlaine C, Liu D, Stitziel NO, Natarajan P, Nomura A, Emdin CA, Gupta N, Borecki IB, Asselta R, Duga S, Merlini PA, Correa A, Kessler T, Wilson JG, Bown MJ, Hall AS, Braund PS, Carey DJ, Murray MF, Kirchner HL, Leader JB, Lavage DR, Manus JN, Hartzel DN, Samani NJ, Schunkert H, Marrugat J, Elosua R, McPherson R, Farrall M, Watkins H, Lander ES, Rader DJ, Danesh J, Ardissino D, Gabriel S, Willer C, Abecasis GR, Saleheen D, Dewey FE, Kathiresan S, Myocardial Infarction Genetics Consortium, DiscovEHR Study Group, CARDIoGRAM Exome Consortium, and Global Lipids Genetics Consortium

Abstract
Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease.
Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD).
Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis.
Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels.
Main Outcomes and Measures: Circulating lipid levels and CAD.
Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides.
Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

PMID: 28267856 [PubMed - in process]

A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis.

J Med Genet. 2017 Mar 06;:

Authors: Frosk P, Arts HH, Philippe J, Gunn CS, Brown EL, Chodirker B, Simard L, Majewski J, Fahiminiya S, Russell C, Liu YP, FORGE Canada Consortium, Canadian Rare Diseases: Models & Mechanisms Network,, Hegele R, Katsanis N, Goerz C, Del Bigio MR, Davis EE

Abstract
BACKGROUND: Hydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism.
METHODS: We used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses. Immunohistochemistry, RT-PCR and imaging in cell lines, and zebrafish models, were used to explore the function of the gene and the effect of the mutation.
RESULTS: We identified a homozygous nonsense mutation in CEP55 segregating with MARCH. Testing the effect of this allele on patient-derived cells indicated both a reduction of the overall CEP55 message and the production of a message that likely gives rise to a truncated protein. Suppression or ablation of cep55l in zebrafish embryos recapitulated key features of MARCH, most notably renal dysplasia, cerebellar hypoplasia and craniofacial abnormalities. These phenotypes could be rescued by full-length but not truncated human CEP55 message. Finally, we expressed the truncated form of CEP55 in human cells, where we observed a failure of truncated protein to localise to the midbody, leading to abscission failure and multinucleated daughter cells.
CONCLUSIONS: CEP55 loss of function mutations likely underlie MARCH, a novel multiple congenital anomaly syndrome. This association expands the involvement of centrosomal proteins in human genetic disorders by highlighting a role in midbody function.

PMID: 28264986 [PubMed - as supplied by publisher]

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.

PLoS One. 2017;12(3):e0172427

Authors: Zhou T, Souzeau E, Sharma S, Landers J, Mills R, Goldberg I, Healey PR, Graham S, Hewitt AW, Mackey DA, Galanopoulos A, Casson RJ, Ruddle JB, Ellis J, Leo P, Brown MA, MacGregor S, Lynn DJ, Burdon KP, Craig JE

Abstract
PURPOSE: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants.
METHODS: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB.
RESULTS: POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG.
CONCLUSION: This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.

PMID: 28264060 [PubMed - in process]

Genetic variants of the DNA repair genes from Exome Aggregation Consortium (EXAC) database: significance in cancer.

DNA Repair (Amst). 2017 Feb 22;:

Authors: Das R, Ghosh SK

Abstract
DNA repair pathway is a primary defense system that eliminates wide varieties of DNA damage. Any deficiencies in them are likely to cause the chromosomal instability that leads to cell malfunctioning and tumorigenesis. Genetic polymorphisms in DNA repair genes have demonstrated a significant association with cancer risk. Our study attempts to give a glimpse of the overall scenario of the germline polymorphisms in the DNA repair genes by taking into account of the Exome Aggregation Consortium (ExAC) database as well as the Human Gene Mutation Database (HGMD) for evaluating the disease link, particularly in cancer. It has been found that ExAC DNA repair dataset (which consists of 228 DNA repair genes) comprises 30.4% missense, 12.5% dbSNP reported and 3.2% ClinVar significant variants. 27% of all the missense variants has the deleterious SIFT score of 0.00 and 6% variants carrying the most damaging Polyphen-2 score of 1.00, thus affecting the protein structure and function. However, as per HGMD, only a fraction (1.2%) of ExAC DNA repair variants was found to be cancer-related, indicating remaining variants reported in both the databases to be further analyzed. This, in turn, may provide an increased spectrum of the reported cancer linked variants in the DNA repair genes present in ExAC database. Moreover, further in silico functional assay of the identified vital cancer-associated variants, which is essential to get their actual biological significance, may shed some lights in the field of targeted drug development in near future.

PMID: 28259467 [PubMed - as supplied by publisher]

A novel GJA1 mutation in oculodentodigitaldysplasia with extensive loss of enamel.

Oral Dis. 2017 Mar 04;:

Authors: Porntaveetus T, Srichomthong C, Ohazama A, Suphapeetiporn K, Shotelersuk V

Abstract
OBJECTIVE: To characterize clinical features and identify genetic causes of a patient with oculodentodigital dysplasia (ODDD) SUBJECTS AND METHODS: Clinical, dental, radiological features were obtained. DNA was collected from an affected Thai family. Whole Exome Sequencing (WES) was employed to identify the disease-causing mutation causing ODDD. The presence of the identified variant was confirmed by Sanger sequencing.
RESULTS: The proband suffered with extensive enamel hypoplasia, polysyndactyly and clinodactyly of the 3(rd) -5(th) fingers, microphthalmia, and unique facial characteristics of ODDD.Mutation analysis revealed a novel missense mutation, c. 31C>A, p.L11I, in the GJA1 gene which encodes gap junction channel protein connexin 43. Bioinformatics and structural modelling suggested the mutation to be pathogenic. The parents did not harbor the mutation.
CONCLUSIONS: This study identified a novel de novo mutation in the GJA1 gene associated with severe tooth defects. These results expand the mutation spectrum and understanding of pathologic dental phenotypes related to ODDD. This article is protected by copyright. All rights reserved.

PMID: 28258662 [PubMed - as supplied by publisher]

SCARB1 single nucleotide polymorphism (rs5888) is associated with serum lipid profile and myocardial infarction in an age- and gender-dependent manner.

Lipids Health Dis. 2013;12:24

Authors: Stanislovaitiene D, Lesauskaite V, Zaliuniene D, Smalinskiene A, Gustiene O, Zaliaduonyte-Peksiene D, Tamosiunas A, Luksiene D, Petkeviciene J, Zaliunas R

Abstract
BACKGROUND: Mutation in SCARB1 gene, exon 8 rs5888, has been associated with altered lipid levels and cardiovascular risk in humans though the results have been inconsistent. We analysed the impact of SCARB1 single nucleotide polymorphism (SNP) rs5888 with plasma lipid profile and association with coronary artery disease (CAD) in a Lithuanian population characterized by high morbidity and mortality from CAD and high prevalence of hypercholesterolemia.
METHODS: The study included 1976 subjects from a random sample (reference group) and an myocardial infarction (MI) group of 463 patients. Genotyping of SCARB1 (rs5888) was carried out using the real-time polymerase chain reaction method. RESULTS/PRINCIPAL FINDINGS: Analysis of rs5888 C/T gene polymorphism in the reference group revealed that male TT genotype carriers (25-74 years) had significantly higher total cholesterol and triglyceride concentrations (5.70 mmol/l vs. 5.49 mmol/l; p = 0.036, and 1.70 mmol/l vs. 1.40 mmol/l, p = 0.023, respectively) than CT carriers and the oldest males (65-74 years) TT carriers had significantly higher high density lipoprotein cholesterol concentrations in comparison to heterozygous (1.52 mmol/l vs. 1.36 mmol/l, p = 0.033). The youngest female (25-44 years) TT genotype carriers had significantly lower low density lipoprotein cholesterol concentrations in comparison to C homozygous (2.59 mmol/l vs. 2.92 mmol/l, p = 0.023). The frequency of the SCARB1 TT genotype in the oldest male MI group (65-74 years) was significantly lower than in the corresponding reference group subjects (9.4% vs. 22.3%, p = 0.006). SCARB1 TT genotype was associated with decreased odds of MI in males aged 65-75 years (OR = 0.24, 95% CI 0.10-0.56, p = 0.001).
CONCLUSIONS/SIGNIFICANCE: SCARB1 polymorphism is associated with lipid metabolism and CAD in an age- and gender- dependent manner. Analysis of SCARB1 SNP rs5888 C/T genotypes revealed an atheroprotective phenotype of lipid profile in older men and in young women TT genotype carriers in the reference group. SCARB1 TT genotype was associated with decreased odds of MI in aged men.

PMID: 23510561 [PubMed - indexed for MEDLINE]

T-HOD: a literature-based candidate gene database for hypertension, obesity and diabetes.

Database (Oxford). 2013;2013:bas061

Authors: Dai HJ, Wu JC, Tsai RT, Pan WH, Hsu WL

Abstract
Researchers are finding it more and more difficult to follow the changing status of disease candidate genes due to the exponential increase in gene mapping studies. The Text-mined Hypertension, Obesity and Diabetes candidate gene database (T-HOD) is developed to help trace existing research on three kinds of cardiovascular diseases: hypertension, obesity and diabetes, with the last disease categorized into Type 1 and Type 2, by regularly and semiautomatically extracting HOD-related genes from newly published literature. Currently, there are 837, 835 and 821 candidate genes recorded in T-HOD for hypertension, obesity and diabetes, respectively. T-HOD employed the state-of-art text-mining technologies, including a gene/disease identification system and a disease-gene relation extraction system, which can be used to affirm the association of genes with three diseases and provide more evidence for further studies. The primary inputs of T-HOD are the three kinds of diseases, and the output is a list of disease-related genes that can be ranked based on their number of appearance, protein-protein interactions and single-nucleotide polymorphisms. Unlike manually constructed disease gene databases, the content of T-HOD is regularly updated by our text-mining system and verified by domain experts. The interface of T-HOD facilitates easy browsing for users and allows T-HOD curators to verify data efficiently. We believe that T-HOD can help life scientists in search for more disease candidate genes in a less time- and effort-consuming manner. Database URL: http://bws.iis.sinica.edu.tw/THOD.

PMID: 23406793 [PubMed - indexed for MEDLINE]

Roles of cytochrome P4502E1 gene polymorphisms and the risks of alcoholic liver disease: a meta-analysis.

PLoS One. 2013;8(1):e54188

Authors: Zeng T, Guo FF, Zhang CL, Song FY, Zhao XL, Xie KQ

Abstract
BACKGROUND: Previous studies investigating the association between cytochrome P4502E1 (CYP2E1) polymorphisms and the risk of alcoholic liver diseases (ALD) have yielded conflicting results. Thus, a meta-analysis was performed to clarify the association between CYP2E1 polymorphisms and the risks of ALD.
METHODS: A comprehensive literature search was conducted to identify the relevant studies. The fixed or random effect model was selected based on the heterogeneity test among studies. Publication bias was estimated using Begg's funnel plots and Egger's regression test.
RESULTS: A total of 27 and 9 studies were finally included for the association between the CYP2E1 Pst I/Rsa I or Dra I polymorphisms and the risks of ALD, respectively. Overall, the combined results showed that homozygous genotype c2c2 was significantly associated with increase risk of ALD in worldwide populations (c2c2 vs. c1c1: OR = 3.12, 95%CI 1.91-5.11) when ALD patients were compared with alcoholics without ALD. Significant associations between CYP2E1 Pst I/Rsa I polymorphism and ALD risk were also observed in Asians (c2c2 vs. c1c1: OR = 4.11, 95%CI 2.32-7.29) and in Caucasians (c2c2/c1c2 vs. c1c1: OR = 1.58, 95%CI 1.04-2.42) when ALD patients were compared with alcoholics without ALD. However, subgroup analysis stratified by ALD types showed that CYP2E1 Pst I/Rsa I polymorphism was not significantly associated with the risks of alcoholic cirrhosis (ALC). No significant association was observed between CYP2E1 Dra I polymorphism and ALD risks.
CONCLUSION: This meta-analysis suggested that CYP2E1 Pst I/Rsa I polymorphism might be not significantly associated with advanced form of ALD (ALC), but might be significantly associated with other form of ALD such as steatosis, hepatisis, fibrosis. Furthermore, CYP2E1 Dra I polymorphism might be not significantly associated with the ALD risks. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.

PMID: 23335995 [PubMed - indexed for MEDLINE]

CD24 polymorphisms in breast cancer: impact on prognosis and risk.

Breast Cancer Res Treat. 2013 Feb;137(3):927-37

Authors: Buck K, Hug S, Seibold P, Ferschke I, Altevogt P, Sohn C, Schneeweiss A, Burwinkel B, Jäger D, Flesch-Janys D, Chang-Claude J, Marmé F

Abstract
Overexpression of CD24 has a negative impact on breast cancer prognosis. We have recently reported that the CD24 codon 57 Val/Val genotype (rs52812045) is associated with pathologic complete response after neoadjuvant chemotherapy for primary breast cancer and correlates with intratumoral lymphocyte infiltrates. This study was performed to investigate the influence of CD24 polymorphisms on breast cancer prognosis and risk. A total of 2,514 patients and 4,858 controls recruited as part of the MARIE study, a population-based case-control study, were genotyped for two CD24 polymorphisms (rs52812045, rs3838646) using TaqMan custom genotyping assays. Associations with overall and breast cancer-specific survival were assessed using uni- and multivariable Cox regression models stratified by age at diagnosis and adjusted for prognostic factors. Conditional logistic regression analysis adjusted for major risk factors was used to estimate multivariable odds ratios for risk of putative allele carriers compared to wildtype carriers. CD24 Ala/Val was significantly associated with breast cancer prognosis [Val/Val hazard ratio (HR)(adjusted) = 1.52; 95 % confidence interval (CI): 1.00-2.30, p = 0.05 and HR(adjusted) = 1.83; 95 % CI: 1.10-3.05, p = 0.018 for all-cause and breast cancer-specific mortality, respectively). The association was significant only in patients with a BMI <25 and in those who received adjuvant chemotherapy. None of the CD24 alleles was associated with breast cancer risk. These results provide further evidence of the CD24 Val/Val genotype influencing outcome in primary breast cancer. Together with previous data of CD24 overexpression as a poor prognostic marker, the findings underline the biological importance of CD24 for breast cancer.

PMID: 23314606 [PubMed - indexed for MEDLINE]

IL-21 gene polymorphism is associated with the prognosis of breast cancer in Chinese populations.

Breast Cancer Res Treat. 2013 Feb;137(3):893-901

Authors: You Y, Deng J, Zheng J, Hu M, Li N, Wu H, Li W, Lu J, Zhou Y

Abstract
Interleukin (IL)-21, which is secreted by activated CD4(+) T cells and NKT cells, has been found to be able to influence the humoral and cell-mediated immune responses and have potent antitumor activity in animal models. This study was to investigate the impact of genetic polymorphisms in IL-21 on survival of breast cancer. Four TagSNPs of IL-21 (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G) were selected and then genotyped in 891 patients with breast cancer in Eastern and Southern Chinese populations. We then examined the associations between these SNPs and overall survival. Potential function of rs12508721C>T and association between this variation and breast cancer prognosis were further studied. Overall, 121 of the patients had died over the followed-up period of 5 years. The IL-21 rs12508721T allele predicted longer five-year survival (HR = 0.347, 95 % CI = 0.187-0.644, P < 0.0001) in the discovery cohort, the independent validation cohort (HR = 0.429, 95 % CI = 0.244-0.755, P = 0.012), and combined group (HR = 0.447, 95 % CI = 0.301-0.667, P < 0.0001). Furthermore, our luciferase assay revealed that rs12508721T variant allele had a higher transcription activity and the RT-PCR and ELISA assay showed that rs12508721 variant genotypes (CT and TT) carriers have more IL-21 expression than CC carriers (P < 0.05). Our present study established a robust association between the functional polymorphism (rs12508721C>T) in IL-21 and prognosis of breast cancer, indicating that this polymorphism may be a potential biomarker for prognosis of breast cancer.

PMID: 23288348 [PubMed - indexed for MEDLINE]

Given breast cancer, is fat better than thin? Impact of the estrogen receptor beta gene polymorphisms.

Breast Cancer Res Treat. 2013 Feb;137(3):849-62

Authors: Borgquist S, Hjertberg M, Henningson M, Ingvar C, Rose C, Jernström H

Abstract
The role of estrogen receptor beta (ERβ) in breast cancer has been investigated since its identification in 1996. Studies based on protein expression have indicated that ERβ is a favorable prognostic marker. Further, ERβ expression is lower in obese breast cancer patients. Fewer studies have focused on the prognostic impact of ERβ polymorphisms. Therefore, we analyzed the associations between four previously identified haplotype tagging single nucleotide polymorphisms (htSNPs), associated haplo- and diplotypes, and breast cancer-free survival according to body constitution. The patient cohort included 634 women from the prospective breast cancer and blood study (BC Blood study, Sweden) with a median follow-up of 4.92 years. Four htSNPs (i.e., rs4986938, rs1256049, rs1256031, rs3020450) in the ESR2 gene and the correlating haplo- and diplotypes were analyzed and correlated to selected patient and tumor characteristics and to disease-free survival, including stratification for BMI. Based on the four htSNPs, seven haplotypes and eight diplotypes were identified. The patient and tumor characteristics were well-balanced across all geno- and haplotypes. Disease-free survival differed according to rs4986938 and rs1256031 (Log-Rank P = 0.045 and P = 0.041, respectively) and the number of haplotype copies of the wildtype CCGC and TCAC (Log-Rank P = 0.027 and P = 0.038, respectively). In the survival analyses stratified for BMI, significant survival differences between alleles were observed among overweight women (rs4986938 and rs1256031 with Log-Rank P = 0.001 and P = 0.001, respectively). The BMI-stratified survival analyses based on haplotypes showed shorter disease-free survival for overweight women with null copies of CCGC (Log-Rank P = 0.001) and for overweight women with any TCAC copy (Log-Rank P < 0.0001). Markedly impaired disease-free survival was found for genotypes in two out of four ESR2 htSNPs and for two haplotypes. ESR2 polymorphisms seem to divide patients into good and poor survivors based on BMI, stressing the need of taking host factors into consideration in the evaluation of prognostic markers.

PMID: 23274843 [PubMed - indexed for MEDLINE]

Genome, epigenome and transcriptome analyses of a pair of monozygotic twins discordant for systemic lupus erythematosus.

Hum Immunol. 2013 Feb;74(2):170-5

Authors: Furukawa H, Oka S, Matsui T, Hashimoto A, Arinuma Y, Komiya A, Fukui N, Tsuchiya N, Tohma S

Abstract
Information to distinguish genetic and environmental factors in the pathogenesis of multifactorial diseases can be obtained by investigation of disease development in monozygotic twins. Recent reports have shown that there are genomic and epigenomic differences between monozygotic twins. Genomic/epigenomic and gene expression analyses were performed in monozygotic twins discordant for systemic lupus erythematosus (SLE) to find the genes playing important roles in SLE pathogenesis. Single nucleotide polymorphism (SNP) and copy number variation (CNV) typing, CpG methylation and gene expression were analyzed. The discordances in SNPs and CNVs were not confirmed. Both CpG methylation and gene expression levels were different for 10 genes. There were no genomic differences between monozygotic twins discordant for SLE, but epigenomic and gene expression differences were detected. These findings provide information for better understanding of SLE pathogenesis.

PMID: 23200755 [PubMed - indexed for MEDLINE]

Indoleamine 2,3 dioxygenase gene polymorphisms correlate with CD8+ Treg impairment in systemic sclerosis.

Hum Immunol. 2013 Feb;74(2):166-9

Authors: Tardito S, Negrini S, Conteduca G, Ferrera F, Parodi A, Battaglia F, Kalli F, Fenoglio D, Cutolo M, Filaci G

Abstract
Systemic sclerosis (SSc) is characterized by tissue fibrosis, vasculopathy and autoimmunity. Indoleamine 2,3 dioxygenase (IDO) plays a pivotal role in immunological tolerance modulating regulatory T cell (Treg) generation and function. Single nucleotide polymorphisms (SNPs) of IDO gene could impact on Treg function and predispose to autoimmunity. Here, the existence of an association between specific IDO SNPs and SSc was analyzed. Five specific SNPs in IDO gene were searched in 31 SSc patients and 37 healthy controls by gene sequencing or restriction fragment length polymorphism. The function of both CD4+CD25+ and CD8+ Treg from SSc patients was analyzed by proliferation suppression assay. SNP rs7820268 was statistically more frequent in SSc patients than in controls. Notably, SSc patients bearing the T allelic variant of the rs7820268 SNP showed impaired CD8+ Treg function. Our unprecedented data show that a specific IDO gene SNP is associated with an autoimmune disease such as SSc.

PMID: 23200754 [PubMed - indexed for MEDLINE]