Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients

AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor(TNF)therapy and evaluate for any serologic and genetic associations.METHODS This study was a retrospective review of patients attending the inflammatory bowel disease(IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure.RESULTS Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients(21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the antiTNF agent. In total: n = 66(5%) infusion reactions; n = 49(4%) allergic/serum sickness reactions; n = 19(1.5%) lupus-like reactions, n = 52(4%) rash, n = 18(1.4%) infections. In Crohn's disease, Ig A ASCA(P = 0.04) and Ig G-ASCA(P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions(P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT(Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic, and pathways associations.

SHEsis,a powerful software platform for analyses of linkage disequi-librium,haplotype construction,and genetic association at polymor-phism loci

The authors want to changed the web link of the software platform in this Briefing.Page 97,section 'INTRODUCTION',the web link of SHEsis is changed from http://www.nhgg.org/analysis tohttp://analysis.bio-x.

Genetic association of rs7754840 and rs7756992 polymorphisms in the CDKAL1 gene and gestational diabetes mellitus in selected Filipino pregnant women

Objective:To investigate the possible association between rs7754840 and rs7756992 polymorphisms of CDKAL1 gene and susceptibility to gestational diabetes mellitus(GDM)in a Filipino pregnant population.Methods:A total of 101 patients with GDM and 99 women without GDM were included.Two CDKAL1 gene single nucleotide polymorphisms(SNPs),namely rs7754840 and rs7756992,were genotyped by using TaqMan allelic discrimination assays.Mann-Whitney U test,median and interquartile range were used to describe physical and biochemical characteristics.The differences in the genotype and allele distribution of the target genetic variants among the two groups of participants were assessed by using Chi-square test.Conformity to Hardy-Weinberg equilibrium was tested prior to conducting further analysis.Multiple logistic regression model was used to investigate the effects of the genotype models on GDM development.Results:There was no observed correlation between the genotypes of the rs7754840 SNP and oral glucose tolerance test parameters.Consequently,there was no significant association between genetic models of the rs7754840 SNP and GDM risk(additive OR 1.43,95%CI 0.82-2.50,P=0.21;dominant OR 1.21,95%CI 0.57-2.59,P=0.62;recessive OR 1.63,95%CI 0.86-3.09,P=0.13).Conclusions:The results of this study suggest no association between CDKAL1 gene variant rs7754840 and GDM development in Filipino pregnant women.Further studies with a larger population should be performed to validate our findings.

Differences in clinical and genetic characteristics between early-and late-onset narcolepsy in a Han Chinese cohort

Early-and late-onset narcolepsy constitutes two distinct diagnostic subgroups.However,it is not clear whether symptomology and genetic risk factors differ between early-and late-onset narcoleptics.This study compared clinical data and single-nucleotide polymorphisms(SNPs)between early-and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients.Blood,cerebrospinal fluid,and clinical data were prospectively collected from patients,and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs.Genetic risk scores(GRSs),associations of five different sets of SNPs(GRS1–GRS5)with early-and late-onset narcolepsy,were evaluated using logistic regression and receiver operating characteristic curves.Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases.Symptom severity was greater among late-onset patients,with higher rates of sleep paralysis,hypnagogic hallucinations,health-related quality of life impairment,and concurrent presentation with four or more symptoms.Hypocretin levels did not differ significantly between early-and late-onset cases.Only rs3181077(CCR1/CCR3)and rs9274477(HLA-DQB1)were more prevalent among early-onset cases.Only GRS1(26 SNPs;OR=1.513,95%CI:0.893–2.585;P<0.05)and GRS5(6 SNPs;OR=1.893,95%CI:1.204–2.993;P<0.05)were associated with early-onset narcolepsy,with areas under the receiver operating characteristic curves of 0.731 and 0.732,respectively.Neither GRS1 nor GRS5 included SNPs in HLA regions.Our results indicate that symptomology and genetic risk factors differ between early-and late-onset narcolepsy.This protocol was approved by the Institutional Review Board(IRB)Panels on Medical Human Subjects at Peking University People’s Hospital,China(approval No.Yuanlunshenlinyi 86)in October 2011.

Genetic epidemiology of diabetic retinopathy

The disease burden of diabetic retinopathy(DR)is tremendous around the world.While DR is correlated with hemoglobin A1c(HbA1c)and duration of diabetes,genetic differences likely account for variation in susceptibility to DR.DR is a polygenic disorder with demonstrated heritability.However,linkage and admixture analyses,candidate gene association studies,and genome-wide association studies(GWAS)have not identified many loci for DR that can be consistently replicated.Larger,collaborative,multi-ethnic GWAS are needed to identify common variants with small effects.Rigorous defining of controls groups as patients with a long duration of diabetes without DR,and case groups as patients with severe DR will also aid in finding genes associated with DR.Replication in independent cohorts will be key to establishing associated loci for DR.Investigations of mitochondrial DNA and epigenetics in DR are ongoing.Whole exome sequencing presents new opportunities to identify rare variants that might be implicated in DR development.Continued research in the genetic epidemiology of DR is needed,with the potential to elucidate pathogenesis and treatment of an important disease.

An Adaptive Weighted Sum Test for Family-Based Multi-Marker Association Studies

Backgrounds: Although many disease-associated common variants have been discovered through genome-wide association studies, much of the genetic effects of complex diseases have not been explained. Population-based association studies are vulnerable to population stratification. A possible solution is to use family-based tests. However, if tests only estimate the genetic effect from the within-family variation to avoid population stratification, they may ignore the useful genetic information from between-family variation and lose power. Methods: We have developed an adaptive weighted sum test for family-based association studies. The new test uses data driven weights to combine two test statistics, and the weights measure the strength of population stratification. When population stratification is strong, the proposed test will automatically put more weight on one statistic derived from within-family variation to maintain robustness against spurious positives. On the other hand, when the effect of population stratification is relatively weak, the proposed test will automatically put more weight on the other statistic derived from both within-family and between-family variation to make use of both sources of genetic variation;and at the same time, the degrees of freedom of the test will be reduced and power of the test will be increased. Results: In our study, the proposed method achieves a higher power in most scenarios of linkage disequilibrium structure as well as Hap Map data from different genes under different population structures while still keeping its robustness against population stratification.

Implicit Hypotheses Are Hidden Power Droppers in Family-Based Association Studies of Secondary Outcomes

Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform such studies. However, researchers are also often interested in the genetic contribution to a more specific manifestation of the phenotype (e.g. severe vs. non-severe form) known as a secondary outcome. Here, what we demonstrate is the limited power of the classical formulation of the FBAT statistic to detect the effect of genetic variants that influence a secondary outcome, in particular when these variants also impact on the onset of the disease, the primary outcome. We prove that this loss of power is driven by an implicit hypothesis, and we propose a derivation of the original FBAT statistic, free from this implicit hypothesis. Finally, we demonstrate analytically that our new statistic is robust and more powerful than FBAT for the detection of association between a genetic variant and a secondary outcome.

The glutamate metabotropic receptor 5(GRM5)gene is associated with beef cattle home range and movement tortuosity

Background:The grazing behaviour of herbivores and their grazing personalities might in part be determined genetically,but there are few studies in beef cattle illustrating this.In this study,we investigated for first time the genetic variation within a candidate‘grazing gene',the glutamate metabotropic receptor 5 gene(GRM5),and tested associations between variation in that gene and variation in grazing personality behaviours(GP-behaviours)displayed by free-ranging cows during winter grazing in the steep and rugged rangelands of New Zealand.Mature beef cows(n=303,from 3 to 10 years of age)were tracked with global positioning system(GPS)and,with 5-minutes(min)relocation frequency,various GP-behaviours were calculated.These included horizontal and vertical distances travelled,mean elevation,elevation range,elevation gain,slope,home range and movement tortuosity,variously calculated using daily relocation trajectories with repeated measurements(i.e.,7 to 24 days(d))and satellite-derived digital elevation models(DEM).The different GP-behaviours were fitted into mixed models to ascertain their associations with variant sequences and genotypes of GRM5.Results:We discovered three GRM5 variants(A,B and C)and identified the six possible genotypes in the cattle studied.The mixed models revealed that A was significantly associated with elevation range,home range and movement tortuosity.Similarly,GRM5 genotypes were associated(P<0.05)to home range and movement tortuosity,while trends suggesting association(P<0.1)were also revealed for elevation range and horizontal distance travelled.Most GP-behaviour models were improved by correcting for cow age-class as a fixed factor.The analysis of GP-behaviours averaged per cow age-class suggests that grazing personality is fully established as beef cows reached 4 years of age.Home range and movement tortuosity were not only associated with GRM5 variation,but also negatively correlated with each other(r=-0.27,P<0.001).Conclusions:There seems to be a genetically determined trade-off between home range and movement tortuosity that may be useful in beef cattle breeding programmes aiming to improve the grazing distribution and utilisation of steep and rugged rangelands.

Malocclusion May Be Attributed to Variation among 10 Genes

Introduction: The goal of this study was to utilize physical characteristics instead of placing subjects in arbitrary diagnostic categories to test for associations with genetic variants. Methods: Forty-four single nucleotide polymorphisms were tested for association with specific cephalometric measurements in thirty-nine University of Pittsburgh Dental Registry and DNA Repository orthodontic subjects. Cephalometric measurements included an evaluation of FMA, a Wits appraisal, and a Steiner’s ANB analysis. Genetic markers were genotyped using polymerase chain reaction and Taqman chemistry. Chi-square and Fischer’s exact tests (α = 0.05) were used in investigation of overrepresentation of marker alleles. Samples were divided into groups based upon having an FMA, Wits, or ANB measurement above or below the mean of the cohort studied. Secondary analysis was done for sex and ethnicity to determine their effect on FMA, Wits, or ANB. Results: An association between FMA measurements was discovered in the following genes: ACTN3, CASP4, ESR1, FGF13, KRT7, and PITX2. An association between Wits measurements was discovered in the following genes: ACTN2, BTBD11, CASP4, FGF3, and FGF10. No associations were found with ANB. Conclusions: Genetic markers in several genes at different loci may contribute to craniofacial deformities in humans. This approach of using physical measurements may be an advantage to placing patients in arbitrary diagnostic categories.

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

Age-related macular degeneration(AMD)is the leading cause of irreversible blindness in adults over 50 years old.Genetic,epidemiological,and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease,which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and progression.Many of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age,including cardiovascular disease(CVD).In this review,we present epidemiological findings associating AMD with a variety of lipid pathway genes,cardiovascular phenotypes,and relevant environmental exposures.Despite a number of studies showing significant associations between AMD and these lipid/cardiovascular factors,results have been mixed and as such the relationships among these factors and AMD remain controversial.It is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

Fine genetic mapping of the chromosome 11q23.3 region in a Han Chinese population:insights into the apolipoprotein genes underlying the blood lipid-lipoprotein variances

The unusual chromosome 11q23.3 harboring the apolipoprotein(APO)gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases.However,its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed.We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing,association analyses,genetic fine mapping,and functional interpretation.The present study identified new meaningful genetic associations that were not simply determined by statistical significance.In addition to the APOA5 gene,we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids.Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses.rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility.Similarly,multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol.Our findings provided novel insights into this genomic locus in the Chinese population.

Genetics in Keratoconus: where are we?

Keratoconus(KC)is a non-inflammatory thinning and protrusion of the cornea in which the cornea assumes a conical shape.Complex etiology of this condition at present remains an enigma.Although environmental factors have been involved in KC pathogenesis,strong underlining genetic susceptibility has been proven.The lack of consistent findings among early genetic studies suggested a heterogeneity and complex nature of the genetic contribution to the development of KC.Recently,genome-wide linkage studies(GWLS)and genome-wide association studies(GWAS)were undertaken.Next-generation sequencing(NGS)-based genomic screens are also currently being carried out.Application of these recently developed comprehensive genetic tools led to a much greater success and increased reproducibility of genetic findings in KC.Involvement of the LOX gene identified through GWLS has been confirmed in multiple cohorts of KC patients around the world.KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated.Rare variants in the ZNF469 gene(mutated in corneal dystrophy Brittle Cornea Syndrome)and in the TGFBI gene(mutated in multiple corneal epithelial–stromal TGFBI dystrophies)have been repeatedly identified in familial and sporadic KC patients of different ethnicities.Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC.Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness.These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.

Evaluation of the association of C5 with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

Background:Neovascular age-related macular degeneration(AMD)and polypoidal choroidal vasculopathy(PCV)are sight-threatening maculopathies with both environmental and genetic risk factors.We have previously shown relative risks posed by genes of the complement pathways to neovascular AMD and PCV.Methods:In this study,we investigated the haplotype-tagging single nucleotide polymorphisms(SNPs)in the complement component 5(C5)gene in 708 unrelated Chinese individuals:200 neovascular AMD patients,233 PCV patients and 275 controls.Six tagging SNPs in C5 were genotyped.Univariate single SNP association analysis,haplotype-based association analysis and gene-gene interaction analysis between C5 and other AMD-associated genes were performed.Results:The results revealed none of the six tagging SNPs of the C5 gene had a significant association with neovascular AMD or PCV(P>0.05).We also found insignificant haplotype-based association,and no significant SNPSNP interaction between C5 and other genes(including C2-CFB-RDBP-SKIV2L,SERPING1,CETP,ABCG1,PGF,ANGPT2,CFH and HTRA1)for neovascular AMD and PCV.Conclusions:This study showed no statistical significance in the genetic association of C5 with neovascular AMD or PCV in a Hong Kong Chinese population.Further studies in large samples from different populations are warranted to elucidate the role of C5 in the genetic susceptibility of AMD and PCV.

Multi-omics analyses of 398 foxtail millet accessions reveal genomic regions associated with domestication,metabolite traits,and antiinflammatory effects

Foxtail millet(Setaria italica),which was domesticatedfromthewild speciesgreenfoxtail(Setaria viridis),isa richsource of phytonutrientsfor humans.To evaluate how breeding changed themetabolome offoxtail millet grains,we generated and analyzed the datasets encompassing the genomes,transcriptomes,metabolomes,and anti-inflammatory indices from 398 foxtail millet accessions.We identified hundreds of common variants that influence numerous secondary metabolites.We observed tremendous differences in natural variations of the metabolites and their underlying genetic architectures between distinct sub-groups of foxtail millet.Furthermore,we found that the selection of the gene alleles associated with yellow grains led to altered profiles of metabolites such as carotenoids and endogenous phytohormones.Using CRiSPR-mediated genome editing wevalidated the function of PHYTOENE SYNTHASE1(PSY1)gene in affecting milletgrain colorand quality.Interestingly,our in vitro cell inflammation assays showed that 83 metabolites in millet grains have anti-inflammatory effects.Taken together,ourmulti-omics study illustrates how the breeding history of foxtail millet has shaped its metabolite profile.The datasets we generated in this study also provide important resources for further understanding how millet grain quality is affected by different metabolites,laying the foundations for future millet genetic research and metabolome-assisted improvement.

Creation and judicious application of a wheat resistance gene atlas

Disease-resistance(R)gene cloning in wheat(Triticum aestivum)has been accelerated by the recent surge of genomic resources,facilitated by advances in sequencing technologies and bioinformatics.However,with the challenges of population growth and climate change,it is vital not only to clone and functionally characterize a few handfuls of R genes,but also to do so at a scale that would facilitate the breeding and deployment of crops that can recognize the wide range of pathogen effectors that threaten agroecosystems.Pathogen populations are continually changing,and breeders must have tools and resources available to rapidly respond to those changes if we are to safeguard our daily bread.To meet this challenge,we propose the creation of a wheat R-gene atlas by an international community of researchers and breeders.The atlas would consist of an online directory from which sources of resistance could be identified and deployed to achieve more durable resistance to the major wheat pathogens,such as wheat rusts,blotch diseases,powdery mildew,and wheat blast.We present a costed proposal detailing how the inter-acting molecular components governing disease resistance could be captured from both the host and the pathogen through biparental mapping,mutational genomics,and whole-genome association genetics.We explore options for the configuration and genotyping of diversity panels of hexaploid and tetraploid wheat,as well as their wild relatives and major pathogens,and discuss how the atlas could inform a dynamic,durable approach to R-gene deployment.Set against the current magnitude of wheat yield losses worldwide,recently estimated at 21%,this endeavor presents one route for bringing R genes from the lab to the field at a considerable speed and quantity.