Short-term and long-term outcomes of on-pump beating-heart coronary artery bypass surgery in dialysis and non-dialysis patients: a retrospective study in a single center.

BACKGROUND: This study aimed to evaluate the short-term and long-term outcomes of dialysis and non-dialysis patients after On-pump beating-heart coronary artery bypass grafting (OPBH-CABG). METHODS: We retrospectively reviewed medical records of 659 patients underwent OPBH-CABG at our hospital from 2009 to 2019, including 549 non-dialysis patients and 110 dialysis patients. Outcomes were in-hospital mortality, length of stay, surgical complications, post-CABG reintervention, and late mortality. The median follow-up was 3.88 years in non-dialysis patients and 2.24 years in dialysis patients. Propensity matching analysis was performed. RESULTS: After 1:1 matching, dialysis patients had significantly longer length of stay (14 (11-18) vs. 12 (10-15), p = 0.016), higher rates of myocardial infarction (16.85% vs. 6.74%, p = 0.037) and late mortality (25.93% vs. 9.4%, p = 0.005) after CABG compared to non-dialysis patients. No significant differences were observed in in-hospital mortality, complications, or post-CABG reintervention rate between dialysis and non-dialysis groups. CONCLUSIONS: OPBH-CABG could achieve comparable surgical mortality, surgical complication rates, and long-term revascularization in dialysis patients as those in non-dialysis patients. The results show that OPBH-CABG is a safe and effective surgical option for dialysis patients.

Enterococcus faecalis suppresses Staphylococcus aureus-induced NETosis and promotes bacterial survival in polymicrobial infections.

Enterococcus faecalis is an opportunistic pathogen that is frequently co-isolated with other microbes in wound infections. While E. faecalis can subvert the host immune response and promote the survival of other microbes via interbacterial synergy, little is known about the impact of E. faecalis-mediated immune suppression on co-infecting microbes. We hypothesized that E. faecalis can attenuate neutrophil-mediated responses in mixed-species infection to promote survival of the co-infecting species. We found that neutrophils control E. faecalis infection via phagocytosis, ROS production, and degranulation of azurophilic granules, but it does not trigger neutrophil extracellular trap formation (NETosis). However, E. faecalis attenuates Staphylococcus aureus-induced NETosis in polymicrobial infection by interfering with citrullination of histone, suggesting E. faecalis can actively suppress NETosis in neutrophils. Residual S. aureus-induced NETs that remain during co-infection do not impact E. faecalis, further suggesting that E. faecalis possess mechanisms to evade or survive NET-associated killing mechanisms. E. faecalis-driven reduction of NETosis corresponds with higher S. aureus survival, indicating that this immunomodulating effect could be a risk factor in promoting the virulence polymicrobial infection. These findings highlight the complexity of the immune response to polymicrobial infections and suggest that attenuated pathogen-specific immune responses contribute to pathogenesis in the mammalian host.

Robust flight navigation out of distribution with liquid neural networks.

Autonomous robots can learn to perform visual navigation tasks from offline human demonstrations and generalize well to online and unseen scenarios within the same environment they have been trained on. It is challenging for these agents to take a step further and robustly generalize to new environments with drastic scenery changes that they have never encountered. Here, we present a method to create robust flight navigation agents that successfully perform vision-based fly-to-target tasks beyond their training environment under drastic distribution shifts. To this end, we designed an imitation learning framework using liquid neural networks, a brain-inspired class of continuous-time neural models that are causal and adapt to changing conditions. We observed that liquid agents learn to distill the task they are given from visual inputs and drop irrelevant features. Thus, their learned navigation skills transferred to new environments. When compared with several other state-of-the-art deep agents, experiments showed that this level of robustness in decision-making is exclusive to liquid networks, both in their differential equation and closed-form representations.

Zone 0 thoracic endovascular aortic repair in high risk patients: A retrospective case series.

To report our experience applying endovascular stent graft repair to treat ascending aortic diseases in high-risk patients and to evaluate the safety and feasibility of this approach. Patients with comorbid conditions or older age are not suitable for open procedures but may be considered suitable for ascending endovascular repair. Eleven high-risk patients received zone 0 thoracic endovascular aortic repair from September 2014 to May 2020. All patients were followed up until death or December 2021. Primary outcomes were in-hospital and long-term all-cause mortality as well as in-hospital and long-term aorta-related mortality. The mean follow-up duration of all patients was 35.78 months. The cohort comprised of three pathology subgroups: penetrating atherosclerotic ulcer (PAU) (n =6), acute dissection (AD) (n = 3), and chronic dissecting aneurysm (CDA) (n = 2). The in-hospital all-cause mortality rates were 0%, 33.33% and 0% for PAU, AD, and CDA groups, respectively. Long-term all-cause mortality were 33.33%, 33.33%, and 50% for PAU, AD, and CDA groups, respectively. There was only one in-hospital death related to acute aortic dissection, and no long-term aorta-related deaths occurred during the study period. During the follow-up time, the majority of patients had good remodeling of ascending aorta, slow progression in cases with endoleak, and no aorta-related mortality. Ascending endovascular aortic repair appears to be a safe and feasible procedure for emergent aortic repair in carefully selected patients with prohibitive surgical risk who are not candidates for open procedures.

Relationship between Energy Dosage and Apoptotic Cell Death by Modulated Electro-Hyperthermia.

Modulated electro-hyperthermia (mEHT) is a form of mild hyperthermia (HT) used for cancer treatment. The principle utility of HT is the ability not only to increase cell temperature, but also to increase blood flow and associated pO2 to the microenvironment. While investigational evidence has shown the unique ability of mEHT to elicit apoptosis in cancer cells, in vivo and in vitro, the same trait has not been observed with conventional HT. There is dissension as to what allows mEHT to elicit apoptosis despite heating to only mild temperatures, with the predominant opinion in favor of increased temperature at a cellular level as the driving force. For this study, we hypothesized that in addition to temperature, the amount of electrical energy delivered is a major factor in induction of apoptosis by mEHT. To evaluate the impact of electrical energy on apoptosis, we divided generally practiced mEHT treatment into 3 phases: Phase I (treatment start to 10 min. mark): escalation from 25 °C to 37 °C Phase II (10 min. mark to 15 min. mark): escalation from 37 °C to 42 °C Phase III (15 min. mark to 45 min. mark): maintenance at 42 °C Combinations of mEHT at 18 W power, mEHT at 7.5 W power, water bath, and incubator were applied to each of the three phases. Power output was recorded per second and calculated as average power per second. Total number of corresponding Joules emitted per each experiment was also recorded. The biological effect of apoptotic cell death was assayed by annexin-V assay. In group where mEHT was applied for all three phases, apoptosis rate was measured at 31.18 ± 1.47%. In group where mEHT was only applied in Phases II and III, apoptosis rate dropped to 20.2 ± 2.1%. Where mEHT was only applied in Phase III, apoptosis was 6.4 ± 1.7%. Interestingly, when mEHT was applied in Phases I and II, whether Phase III was conducted in either water bath at 42 °C or incubator at 37 °C, resulted in nearly identical apoptosis rates, 26 ± 4.4% and 25.9 ± 3.1%, respectively. These results showed that accumulation of mEHT at high-powered setting (18 W/sec) during temperature escalation (Phase I and Phase II), significantly increased apoptosis of tested cancer cells. The data also showed that whereas apoptosis rate was significantly increased during temperature escalation by higher power (18 W/sec), apoptosis was limited during temperature maintenance with lower power (7.5 W/sec). This presents that neither maintenance of 42 °C nor accumulation of Joules by mEHT has immediate correlating effect on apoptosis rate. These findings may offer a basis for direction of clinical application of mEHT treatment.

Dr. Jekyll and Mr. Hide: How Enterococcus faecalis Subverts the Host Immune Response to Cause Infection.

Enterococcus faecalis, a ubiquitous member of the healthy human gut microbiota, is also a common opportunistic pathogen and leading cause of nosocomial infections. This tenacious microbe is well adapted to infect and persist in multiple niches within the mammalian host and can rapidly tune its metabolism to respond to new environments, enabling infection in sites including the gastrointestinal tract, urinary tract, wounded epithelium, heart, and blood. In order to withstand and persist in the face of host immune responses, E. faecalis has an arsenal of strategies to suppress, evade, or inactivate innate and adaptive immune mechanisms. In this review, we present the variety of ways E. faecalis modulates the immune response, enabling this otherwise innocuous gut commensal to transition and persist as a pathogen.

Etiology of developmental spinal stenosis: A genome-wide association study.

Our study aimed to identify possible single nucleotide polymorphisms (SNPs) via a genome-wide association study (GWAS) approach and a candidate gene platform that were associated with lumbar developmental spinal stenosis (DSS). Southern Chinese population-based study volunteers were assessed (age range: 18-55 years). DSS was defined as the anteroposterior bony spinal canal diameter on T1-weighted axial MRI of L1 to S1. Genotyping was performed using the Illumina HumanOmniZhongHua-8 BeadChip. Using the canal diameter as the quantitative trait, genomic statistical analyses was performed. A total of 469 subjects were recruited. The mean axial AP measurements noted were: L1: 21.8 mm, L2: 21.9 mm, L3: 22.4 mm, L4: 20.2 mm, L5: 19.6 mm, and S1: 17.3 mm. Q-Q plots of genome-wide associations found significant differences in L4 and L5 measurements. More significant SNPs were found on chromosomes 8, 11, and 18. Low-density lipoprotein receptor-related protein 5 on chromosome 11 was found to be an important functional gene in canal bony development via candidate gene approach. We found two clusters in the findings with one including the upper levels (L1-L4) and the other the lower levels (L5 and S1). This is the first GWAS addressing DSS. The presence of multiple SNPs suggests a multi-factorial origin of DSS. Further analyses noted region-specific genetic predisposition, delineating distinct upper to lower lumbar regions of DSS. With better understanding of the DSS phenotype and genetic markers, the at-risk population can be identified early, preventative measures can be initiated, lifestyle/activity modification can be implemented, and more novel and precision-based therapeutics can be developed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1262-1268, 2018.

Prevalence, Patterns, and Genetic Association Analysis of Modic Vertebral Endplate Changes.

STUDY DESIGN: A prospective genetic association study. PURPOSE: The etiology of Modic changes (MCs) is unclear. Recently, the role of genetic factors in the etiology of MCs has been evaluated. However, studies with a larger patient subset are lacking, and candidate genes involved in other disc degeneration phenotypes have not been evaluated. We studied the prevalence of MCs and genetic association of 41 candidate genes in a large Indian cohort. OVERVIEW OF LITERATURE: MCs are vertebral endplate signal changes predominantly observed in the lumbar spine. A significant association between MCs and lumbar disc degeneration and nonspecific low back pain has been described, with the etiopathogenesis implicating various mechanical, infective, and biochemical factors. METHODS: We studied 809 patients using 1.5-T magnetic resonance imaging to determine the prevalence, patterns, distribution, and type of lumbar MCs. Genetic association analysis of 71 single nucleotide polymorphisms (SNPs) of 41 candidate genes was performed based on the presence or absence of MCs. SNPs were genotyped using the Sequenome platform, and an association test was performed using PLINK software. RESULTS: The mean age of the study population (n=809) was 36.7±10.8 years. Based on the presence of MCs, the cohort was divided into 702 controls and 107 cases (prevalence, 13%). MCs were more commonly present in the lower (149/251, 59.4%) than in the upper (102/251, 40.6%) endplates. L4-5 endplates were the most commonly affected levels (30.7%). Type 2 MCs were the most commonly observed pattern (n=206, 82%). The rs2228570 SNP of VDR (p=0.02) and rs17099008 SNP of MMP20 (p=0.03) were significantly associated with MCs. CONCLUSIONS: Genetic polymorphisms of SNPs of VDR and MMP20 were significantly associated with MCs. Understanding the etiopathogenetic mechanisms of MCs is important for planning preventive and therapeutic strategies.

Genetic Association Study of KCNQ5 Polymorphisms with High Myopia.

Identification of genetic variations related to high myopia may advance our knowledge of the etiopathogenesis of refractive error. This study investigated the role of potassium channel gene (KCNQ5) polymorphisms in high myopia. We performed a case-control study of 1563 unrelated Han Chinese subjects (809 cases of high myopia and 754 emmetropic controls). Five tag single-nucleotide polymorphisms (SNPs) of KCNQ5 were genotyped, and association testing with high myopia was conducted using logistic regression analysis adjusted for sex and age to give Pasym values, and multiple comparisons were corrected by permutation test to give Pemp values. All five noncoding SNPs were associated with high myopia. The SNP rs7744813, previously shown to be associated with refractive error and myopia in two GWAS, showed an odds ratio of 0.75 (95% CI 0.63-0.90; Pemp = 0.0058) for the minor allele. The top SNP rs9342979 showed an odds ratio of 0.75 (95% CI 0.64-0.89; Pemp = 0.0045) for the minor allele. Both SNPs are located within enhancer histone marks and DNase-hypersensitive sites. Our data support the involvement of KCNQ5 gene polymorphisms in the genetic susceptibility to high myopia and further exploration of KCNQ5 as a risk factor for high myopia.

Genetic Polymorphisms in Estrogen Metabolic Pathway Associated with Risks of Alzheimer's Disease: Evidence from a Southern Chinese Population.

OBJECTIVES: To investigate whether genetic variations on the estrogen metabolic pathway would be associated with risk of Alzheimer's disease (AD). DESIGN: Cross-sectional study. SETTING: Individuals were recruited at the Memory Clinic, Queen Mary Hospital, Hong Kong. PARTICIPANTS: Chinese individuals with (n = 426) and without (n = 350) AD. MEASUREMENTS: All subjects underwent a standardized cognitive assessment and genotyping of four candidate genes on the estrogen metabolic pathway (estrogen receptor α gene (ESR1), estrogen receptor ß gene (ESR2), cytochrome P450 19A1 gene (CYP19A1), cytochrome P450 11A1 gene (CYP11A1)). RESULTS: Apart from consistent results showing an association between apolipoprotein (APO)E and AD, strong evidence of disease associations were found for polymorphisms in ESR2 and CYP11A1 based on the entire data set. For ESR2, significant protective effects were found for A alleles of rs4986938 (permuted P = .02) and rs867443 (permuted P = .02). For CYP11A1, significant risk effects were found for G alleles of rs11638442 (permuted P = .03) and rs11632698 (permuted P = .03). Stratifying subjects according to APOE ε4 status, their genetic effects continued to be significant in the APOE ε4-negative subgroup. Associations between CYP11A1 polymorphisms (rs2279357, rs2073475) and risk of AD were detected in women but not men. Further gene-level analysis confirmed the above association between ESR2 and CYP11A1, and pathway-level analysis highlighted the genetic effect of the estrogen metabolic pathway on disease susceptibility (permuted pathway-level P = .03). CONCLUSION: Consistent with previous biological findings for sex steroid hormones in the central nervous system, genetic alterations on the estrogen metabolic pathway were revealed in the Chinese population. Confirmation of these present findings in an independent population is warranted to elucidate disease pathogenesis and to explore the potential of hormone therapy in the treatment of AD.

Pathway analysis of complex diseases for GWAS, extending to consider rare variants, multi-omics and interactions.

BACKGROUND: Genome-wide association studies (GWAS) is a major method for studying the genetics of complex diseases. Finding all sequence variants to explain fully the aetiology of a disease is difficult because of their small effect sizes. To better explain disease mechanisms, pathway analysis is used to consolidate the effects of multiple variants, and hence increase the power of the study. While pathway analysis has previously been performed within GWAS only, it can now be extended to examining rare variants, other "-omics" and interaction data. SCOPE OF REVIEW: 1. Factors to consider in the choice of software for GWAS pathway analysis. 2. Examples of how pathway analysis is used to analyse rare variants, other "-omics" and interaction data. MAJOR CONCLUSIONS: To choose appropriate software tools, factors for consideration include covariate compatibility, null hypothesis, one- or two-step analysis required, curation method of gene sets, size of pathways, and size of flanking regions to define gene boundaries. For rare variants, analysis performance depends on consistency between assumed and actual effect distribution of variants. Integration of other "-omics" data and interaction can better explain gene functions. GENERAL SIGNIFICANCE: Pathway analysis methods will be more readily used for integration of multiple sources of data, and enable more accurate prediction of phenotypes.

How Reliable Are the Reported Genetic Associations in Disc Degeneration?: The Influence of Phenotypes, Age, Population Size, and Inclusion Sequence in 809 Patients.

STUDY DESIGN: Prospective genetic association study. OBJECTIVE: The aim of this study was to document the variations in the genetic associations, when different magnetic resonance imaging (MRI) phenotypes, age stratification, cohort size, and sequence of cohort inclusion are varied in the same study population. SUMMARY OF BACKGROUND DATA: Genetic associations with disc degeneration have shown high inconsistency, generally attributed to hereditary factors and ethnic variations. However, the effect of different phenotypes, size of the study population, age of the cohort, etc have not been documented clearly. METHODS: Seventy-one single-nucleotide polymorphisms (SNPs) of 41 candidate genes were correlated to six MRI markers of disc degeneration (annular tears, Pfirmann grading, Schmorl nodes, Modic changes, Total Endplate Damage score, and disc bulge) in 809 patients with back pain and/or sciatica. In the same study group, the correlations were then retested for different age groups, different sample, size and sequence of subject inclusion (first 404 and the second 405) and the differences documented. RESULTS: The mean age of population (M: 455, F: 354) was 36.7 ±â€Š10.8 years. Different genetic associations were found with different phenotypes: disc bulge with three SNPs of CILP; annular tears with rs2249350 of ADAMTS5 and rs11247361 IGF1R; modic changes with VDR and MMP20; Pfirmann grading with three SNPs of MMP20 and Schmorl node with SNPs of CALM1 and FN1 and none with Total End Plate Score.Subgroup analysis based on three age groups and dividing the total population into two groups also completely changed the associations for all the six radiographic parameters. CONCLUSION: In the same study population, SNP associations completely change with different phenotypes. Variations in age, inclusion sequence, and sample size resulted in change of genetic associations. Our study questions the validity of previous studies and necessitates the need for standardizing the description of disc degeneration, phenotype selection, study sample size, age, and other variables in future studies. LEVEL OF EVIDENCE: 4.

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia.

Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.

Genetic susceptibility of lumbar degenerative disc disease in young Indian adults.

PURPOSE: Although the exact mechanisms that lead to degenerative disc disease (DDD) are not well understood, a significant genetic influence has been found. Focusing on DDD that occurs in young adults can be valuable in determining the exact role of genetic predisposition to DDD. METHODS: Patients (<40 years) with lumbar disc degeneration were evaluated with MRI imaging (1.5 Tesla) and genetic association analysis for 58 single nucleotide polymorphism (SNP) of 35 candidate genes was performed. Disc degeneration of individual discs of lumbar spine from L1 to S1 was graded by Pfirrmann's grading. The subjects were stratified into two groups based on Total Disc Degenerative Score (TDDS). Based on TDDS, the severity of DDD was classified as mild (Group A: TDDS <10) and severe (Group B: TDDS >10). RESULTS: 695 Indian subjects including 308 with mild TDDS and 387 with severe TDDS were studied. The mean age of the patients was 29.6 ± 6.9 years in group A and 31.7 ± 6.1 in group B (p < 0.05). Five of the 35 candidate genes viz., rs1337185 of COL11A (p = 0.02), rs5275 (p = 0.03) and rs5277 (p = 0.05) of COX2, rs7575934 of IL1F5 (p = 0.04), rs3213718 of CALM1 (p = 0.04) and rs162509 of ADAMTS5 (p = 0.04) were found to be significantly associated with severe TDDS. CONCLUSION: The study identifies specific SNP associations of five genes in young adults with severe lumbar disc degeneration. These five genes (COL11A1, ADAMTS5, CALM1, IL1F5 and COX2) have different functions in the matrix metabolism, intracellular signalling and inflammatory cascade. This shows that disc degeneration is a complex disease with an intricate interplay of multiple genetic polymorphisms.

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant.

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family­based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population.

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (-) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations.

Genetic susceptibility of intervertebral disc degeneration among young Finnish adults.

BACKGROUND: Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD. METHODS: We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging. RESULTS: Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89). CONCLUSION: Our results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.

Genetics of lumbar disk degeneration: technology, study designs, and risk factors.

Lumbar disk degeneration (LDD) is a common musculoskeletal condition. Genetic risk factors have been suggested to play a major role in its cause. This article reviews the main research strategies that have been used to study the genetics of LDD, and the genes that thus far have been identified to influence susceptibility to LDD. With the rapid progress in genomic technologies, further advances in the genetics of LDD are expected in the next few years.

IGG3: a tool to rapidly integrate large genotype datasets for whole-genome imputation and individual-level meta-analysis.

SUMMARY: There is an urgent and increasing demand for integrating large genotype datasets across genome-wide association studies and HapMap project for whole-genome imputation and individual-level meta-analysis. A new algorithm was developed to efficiently merge raw genotypes across large datasets and implemented in the latest version of IGG, IGG3. In addition, IGG3 can integrate the latest phased and unphased HapMap genotypes and can flexibly generate complete sets of input files for six popular genotype imputation tools. We demonstrated the efficiency of IGG3 by simulation tests, which could rapidly merge genotypes in tens of thousands of large genotype chips (e.g. Affymetrix Genome-Wide Human SNP Array 6.0 and Illumina Human1m-duo) and in HapMap III project on an ordinary desktop computer. AVAILABILITY: (http://bioinfo.hku.hk/iggweb) (version 3.0).

Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.