We’ve had another busy few weeks for Golden Helix customers who have been hard at work publishing in all sorts of journals on all sorts of topics. (All abstracts below.)

First off, from the Cedars-Sinai Medical Center in LA, “Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome” was recently in Fertility and Sterility with contributing authors Michelle Jones and Kent Taylor.

In the bovine world, congrats to Gonzalo Rincon at University of California Davis for his work on “Variants in the pregnancy-associated plasma protein-A2 gene on Bos taurus autosome 16 are associated with daughter calving ease and productive life in Holstein cattle” currently featured in the Journal of Dairy Science.

Over at UC San Francisco, Kim Taylor published “Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes” in PLoS ONE with help from Peter Gregersen at Feinstein.

Close by at the Albert Einstein College of Medicine, Tingwei Guo contributed to “Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome” in the American Journal of Medical Genetics.

BMC Medical Genetics recently posted an article by Nancy Lange at Harvard entitled, “Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.” Props to other authors, Jessica Lasky-Su, Bianca Himes, Benjamin Raby, and Augusto Litonjua at the Channing Lab.

Also asthma related, “Possible Association of SLC22A2 Polymorphisms with Aspirin-Intolerant Asthma” in the International Archives of Allergy and Immunology was worked on by Hyun Sub Cheong at SNP Genetics and In Song Koh at Han Yang University both in Seoul, Korea.

At Kyung Hee University, Joo-Ho Chung helped write, “Association between polymorphisms of TAL1 gene and schizophrenia in a Korean population” in Psychatric Genetics in February.

PLoS ONE just came out with “Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels” by the Guangxi Medical University in China.

Over in Germany, Joern Loetsuch at the University of Frankfurt contributed to “Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy: protection against anemia in patients with chronic hepatitis C” in Pharmacogenetics and Genomics.

At the Hannover Medical School also in Germany, Thilo Dork received an author spot on “Apoptosis gene polymorphisms and risk of prostate cancer: A hospital-based study of German patients treated with brachytherapy” in Urologic Oncology.

Ronald Adkins received top billing for “Racial differences in gene-specific DNA methylation levels are present at birth” in Birth Defects Research Part A: Clinical and Molecular Teratology. Also helping was Julia Krushkal from University of Tennessee.

And finally, plaudits to Ney Alliey-Rodriguez and Elliot Gershon at University of Chicago for putting together “Genome-wide association study of personality traits in bipolar patients” featured in Psychiatric Genetics.

Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome
Objective: To evaluate association with polycystic ovary syndrome (PCOS) of 295 variants in 39 genes central to metabolic insulin signaling and glycogen synthase kinase 3β (GSK-3β) regulation, followed by replication efforts.

Design: Case-control association study, with discovery and replication cohorts.

Setting: Subjects were recruited from reproductive endocrinology clinics, and controls were recruited from communities surrounding the University of Alabama at Birmingham and Erasmus Medical Center, Rotterdam.

Patient(s): A total of 273 cases with PCOS and 173 control subjects in the discovery cohort; and 526 cases and 3,585 control subjects in the replication cohort. All subjects were caucasian.

Intervention(s): Phenotypic and genotypic assessment.

Main Outcome Measure(s): Detection of 295 single-nucleotide polymorphisms (SNPs), PCOS status.

Result(s): Several SNPs were associated with PCOS in the discovery cohort. Four insulin receptor (INSR) SNPs and three insulin receptor substrate 2 (IRS2) SNPs associated with PCOS were genotyped in the replication cohort. One INSR SNP (rs2252673) replicated association with PCOS. The minor allele conferred increased odds of PCOS in both cohorts, independent of body mass index.

Conclusion(s): A pathway-based tagging SNP approach allowed us to identify novel INSR SNPs associated with PCOS, one of which confirmed association in a large replication cohort. Access this article

Variants in the pregnancy-associated plasma protein-A2 gene on Bos taurus autosome 16 are associated with daughter calving ease and productive life in Holstein cattle
Reproductive disorders in dairy herds have a negative effect on farm profitability and sustainability of milk production. Given the substantial evidence of the role of the pregnancy-associated plasma protein (PAPP) gene family in the regulation of reproduction in humans and mice, its role in insulin-like growth factor metabolism, quantitative trait loci effects in the mouse, and location of a calving ease QTL on bovine chromosome 16, the PAPP-A2 gene was chosen as a candidate gene to perform an association study for reproductive health in cattle. Single nucleotide polymorphisms (SNP) were identified in coding and conserved noncoding regions of the PAPP-A2 gene in 3 dairy breeds. A total of 7 tag SNP were genotyped in 662 Holstein bulls (UCD-bulls) to perform marker trait association analysis. Three SNP (SNP 13, 15, and 16) were in strong linkage disequilibrium in Holsteins, showing significant positive associations with daughter calving ease, productive life, milk yield, and protein yield. These results were validated by genotyping SNP15 in a larger population of 992 bulls from the cooperative dairy DNA repository (CDDR-bulls). Our results demonstrate that the PAPP-A2 gene is associated with reproductive health in Holstein cattle and that the identified SNP can be used as genetic markers in dairy breeding due to their positive association with reproductive and productive traits. Functional studies need to be conducted to identify the mechanisms for the association of SNP with these traits. Access this article

Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10−8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10−128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e−9), the immunologic criterion (ORhigh-low = 2.23, p = 3e−7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci. Access this article

Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome
Cytogenetic studies of a male child carrying the 22q11.2 deletion common in patients with velo-cardio-facial/DiGeorge syndrome showed an unexpected rearrangement of the 22q11.2 region in his normal appearing mother. The mother carried a 3 Mb deletion on one copy and a reciprocal, similar sized duplication on the other copy of chromosome 22q11.2 as shown by fluorescence in situ hybridization and array comparative genome hybridization analyses. The most parsimonious mechanism for the rearrangement is a mitotic non-allelic homologous recombination event in a cell in the early embryo soon after fertilization. The normal phenotype of the mother can be explained by the theory of genetic dosage compensation. This is the second documented case of such an event for this or any genomic disorder. This finding helps to reinforce this phenomenon in a human model, and has significant implications for recurrence risks for the dose-compensated mother. Access this article

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes
Background: Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.

Methods: rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.

Results: Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV1 and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.

Conclusion: Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus. Access this article

Possible Association of SLC22A2 Polymorphisms with Aspirin-Intolerant Asthma
Background: Aspirin-intolerant asthma (AIA) is a clinical syndrome characterized by acute bronchoconstriction following the ingestion of aspirin. Solute carrier family 22, member 2 (SLC22A2), also known as organic cation transporter 2 (OCT2), is predominantly expressed in the luminal membrane of airway epithelial cells and has been shown to mediate the transport of prostaglandins on the cyclooxygenase pathway which is regulated by aspirin blockage. Recently, SLC22A2-mediated uptake inhibition by several nonsteroidal anti-inflammatory drugs and decreased SLC22A2 transport activity by its genetic variants have been elucidated in asthma.

Methods: To investigate the associations between AIA and genetic polymorphisms of the SLC22A2 gene, 18 variants were genotyped in 163 AIA subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate p values for the associations of SLC22A2 polymorphisms with AIA. R

esults: One common polymorphism in intron 5, i.e. rs316021, was significantly associated with susceptibility to AIA (p = 0.004, Pcorr = 0.05, OR = 0.60, 95% CI = 0.43–0.85 in a codominant model). The minor allele frequency of rs316021 in the AIA group was significantly lower than that in the ATA controls. In addition, a polymorphism in intron 4 (rs3912161) and a haplotype (SLC22A2-ht3) showed significantly stronger association signals with the FEV1 fall rate induced by aspirin provocation in AIA subjects compared with ATA controls (p = 0.004, Pcorr = 0.05).

Conclusion: Our findings suggest that SLC22A2 could be a susceptibility gene for aspirin intolerance in asthmatics. Access this article

Association between polymorphisms of TAL1 gene and schizophrenia in a Korean population
Numerous studies have found that patients with schizophrenia have a reduced or increased risk of developing cancer. Hippisley-Cox et al. (2007) reported that patients with schizophrenia had a 190% increased risk of colon cancer and a 47% decreased risk of respiratory cancer. Park
et al. (2004) have explained the lower incidence of lung cancer among persons with schizophrenia, resulting from the role of a protective gene. T-cell acute lymphocytic leukemia 1 (TAL1) is the most common gene known to be associated with T-cell acute lymphoblastic leukemia. Muroyama et al. (2005) showed that mouse TAL1 had multiple functions in the regulation of astrocyte versus oligodendrocyte cell fate acquisition. Here, we investigated the association between single nucleotide polymorphisms (SNPs) of the TAL1 gene, one of the candidate genes of leukemia and schizophrenia. Access this article

Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels
Background: Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5–1131T.C, c.553G.T and c.457G.A polymorphisms and alcohol consumption on serum lipid levels.

Methodology/Principal Findings: A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDLC), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P,0.05–0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between –1131T.C genotypes and alcohol consumption on ApoB levels (P,0.05) and the ApoA1/ApoB ratio (P,0.01), between c.553G.T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P,0.05) and the ApoA1/ApoB ratio (P,0.05), and between c.457G.A genotypes and alcohol consumption on TG levels (P,0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The –1131T.C genotypes were correlated with TG, and c.553G.T and c.457G.A genotypes were associated with HDL-C levels in nondrinkers (P,0.05 for all). For drinkers, the –1131T.C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P,0.01 for all); c.553G.T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P,0.05–0.01); and c.457G.A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P,0.05–0.01).

Conclusions: The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption. Access this article

Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy: protection against anemia in patients with chronic hepatitis C
Background and aim: The standard of hepatitis C antiviral therapy combines pegylated interferon-[alpha] with ribavirin. This polar guanosine analog improves the sustained virological response (SVR) rates, but may induce hemolytic anemia. As its pharmacokinetics depend on facilitated transmembrane transport, we assessed whether variants in genes that code for concentrative (concentrative nucleoside transporters 2 and 3 coded by SLC28A2 and SLC28A3, respectively) and equilibrative nucleoside transporters (equilibrative nucleoside transporters 1 and 2 coded by SLC29A1 and SLC29A2, respectively) are associated with the therapy response and side effects.

Methods: Patients (n=169) chronically infected with the hepatitis C virus genotype 1, treated with standard doses of pegylated interferon-[alpha] and weight-based doses of ribavirin for up to 48 weeks, were genotyped for 21 variants in nucleoside transporter genes SLC28A2, SLC28A3, SLC29A1, and SLC29A2, selected to include reported functional variants and to span the complete gene loci. The presence or absence of a SVR (n=169) and a relevant decrease (>3 g/dl, n=115) in blood hemoglobin were associated with the genotypes.

Results: The variant SLC28A3 haplotype rs10868138G/rs56350726T (allelic frequency 0.074) was associated with a lower incidence (35.5%) of relevant decreases (>3 g/dl) in blood hemoglobin than in noncarriers (64.3%; P=0.024, n=115). This protection against hemolytic anemia was not associated with decreased SVR rates (n=169).

Conclusion: A genetic variant in SCL28A3 coding for the concentrative nucleoside transporter 3 protects patients with chronic hepatitis C against hemolytic anemia without affecting SVR in hepatitis C virus genotype Access this article

Apoptosis gene polymorphisms and risk of prostate cancer: A hospital-based study of German patients treated with brachytherapy
Background and objectives: Prostate cancer has a genetic component, and single nucleotide polymorphisms (SNPs) can contribute to the risk. We aimed to investigate the role of polymorphisms in 10 candidate genes with a key function in apoptosis.

Methods and materials: Eight coding SNPs were chosen in ATM (Ser49Cys), BID (Ser56Cys), CASP8 (Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1 (Ser133Ala), TP53 (Arg72Pro), and TP53AIP1 (Ala7Val), and two non-coding SNPs were selected in BCL2 (-938C/A) and HDM2 (SNP309). A hospital-based case-control series of 510 prostate cancer patients and 490 healthy males from Northern Germany were genotyped for these polymorphisms.

Results: SNP rs4644 in LGALS3 showed evidence for a protective effect of the minor allele, encoding the His64 variant (OR 0.82, 95% CI 0.69;0.99, P = 0.04). Carriers were underrepresented among cases under a dominant model (OR 0.71; 95% CI 0.54;0.92; P = 0.01), and the effect appeared more pronounced in patients diagnosed before the age of 60 years (OR 0.52; 95% CI 0.31;0.85, P = 0.01). The other nine polymorphisms did not vary significantly between cases and controls, though subtle trends were noted for BCL2 (P = 0.07) and CASP10 (P = 0.08). The Asp302His variant of CASP8 tended to associate with a protective effect in the group with higher Gleason score under a dominant model (P = 0.03). Carriers of either the CASP8 or the CASP10 variants were underrepresented in the prostate cancer series (P = 0.02).

Conclusions: These results provide first evidence to implicate the functional Pro64His variant of galectin-3 (LGALS3) in the genetic susceptibility towards prostate cancer. The potential role of polymorphisms in BCL2, CASP8, and CASP10 merits further investigation. Access this article

Racial differences in gene-specific DNA methylation levels are present at birth
BACKGROUND: DNA methylation patterns differ among children and adults and play an unambiguous role in several disease processes, particularly cancers. The origin of these differences is inadequately understood, and this is a question of specific relevance to childhood and adult cancer.

METHODS: DNA methylation levels at 26,485 autosomal CpGs were assayed in 201 newborns (107 African American and 94 Caucasian). Nonparametric analyses were performed to examine the relation between these methylation levels and maternal parity, maternal age, newborn gestational age, newborn gender, and newborn race. To identify the possible influences of confounding, stratification was performed by a second and third variable. For genes containing CpGs with significant differences in DNA methylation levels between races, analyses were performed to identify highly represented gene ontological terms and functional pathways.

RESULTS: 13.7% (3623) of the autosomal CpGs exhibited significantly different levels of DNA methylation between African Americans and Caucasians; 2% of autosomal CpGs had significantly different DNA methylation levels between male and female newborns. Cancer pathways, including four (pancreatic, prostate, bladder, and melanoma) with substantial differences in incidence between the races, were highly represented among the genes containing significant race-divergent CpGs.

CONCLUSIONS: At birth, there are significantly different DNA methylation levels between African Americans and Caucasians at a subset of CpG dinucleotides. It is possible that some of the epigenetic precursors to cancer exist at birth and that these differences partially explain the different incidence rates of specific cancers between the races. Access this article

Genome-wide association study of personality traits in bipolar patients
Objective: Genome-wide association study was carried out on personality traits among bipolar patients as possible endophenotypes for gene discovery in bipolar disorder.

Methods: The subscales of Cloninger’s Temperament and Character Inventory (TCI) and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) were used as quantitative phenotypes. The genotyping platform was the Affymetrix 6.0 SNP array. The sample consisted of 944 individuals for TCI and 1007 for ZKPQ, all of European ancestry, diagnosed with bipolar disorder by Diagnostic and Statistical Manual of Mental Disorders-IV criteria.

Results: Genome-wide significant association was found for two subscales of the TCI, rs10479334 with the ‘Social Acceptance versus Social Intolerance’ subscale (Bonferroni P=0.014) in an intergenic region, and rs9419788 with the ‘Spiritual Acceptance versus Rational Materialism’ subscale (Bonferroni P=0.036) in PLCE1 gene. Although genome-wide significance was not reached for ZKPQ scales, lowest P values pinpointed to genes, RXRG for Sensation Seeking, GRM7 and ITK for Neuroticism Anxiety, and SPTLC3 gene for Aggression Hostility.

Conclusion: After correction for the 25 subscales in TCI and four scales plus two subscales in ZKPQ, phenotype-wide significance was not reached. Access this article