Six Single Nucleotide Polymorphisms Research Articles

Genetic polymorphisms of ATG16L1 and IRGM genes in Malaysian patients with Crohn's disease.

To investigate the association between genetic polymorphisms in ATG16L1 and IRGM genes and the development of Crohn's disease (CD) in Malaysian patients. Altogether 335 participants were recruited, including 85 patients with CD and 250 unrelated healthy controls, and their informed consent was obtained. Genomic DNA was extracted via a conventional phenol-chloroform extraction method. Six single nucleotide polymorphisms (SNPs) in ATG16L1 and IRGM genes were genotyped using TaqMan SNP genotyping assays. Associations between SNP and CD were determined using Fisher's exact test, odds ratio, and 95% confidence interval. Statistical power and the Hardy-Weinberg equilibrium were also calculated. Two SNPs (rs2241880 and rs6754677) in the ATG16L1 gene were significantly associated with the onset of CD in the Malaysian population. The A allele and homozygous A/A genotype of the rs2241880 A/G polymorphism were protective against CD in the overall Malaysian and Malay population. The G allele and homozygous G/G genotype of the rs6754677 G/A polymorphism were protective in the Indian population, whereas the homozygous A/A genotype showed a risk of developing CD. The homozygous G/G genotype of IRGM rs11747270 was significantly present in the controls. However, this significance was not observed in a race-stratified analysis. All three ATG16L1 SNPs were associated with inflamed terminal ileum. IRGM rs4958847 and rs11747270 increased the risk of developing arthritis in patients with CD. We found a significant association between SNP, which are located in autophagy-related genes, and CD in a Malaysian population.

Genetic variants of VEGFR-1 gene promoter in acute myocardial infarction

BackgroundCoronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease caused by atherosclerosis. Vascular epithelial growth factor receptor-1 (VEGFR-1) stimulates angiogenesis and vascular permeability, and functions as a decoy to sequester VEGF and prevent initiation of intracellular signaling. VEGFR-1 knockout mice exhibit significantly higher mortality due to heart failure, cardiac hypertrophy, and cardiac dysfunction. An evident increase in macrophage infiltration and cardiac fibrosis are also observed after transverse aortic constriction. Therefore, VEGFR-1 gene variants may be involved in CAD. In this study, VEGFR-1 gene promoter was genetically and functionally analyzed in large cohorts of AMI patients and ethnic-matched controls.ResultsA total of 16 DNA sequence variants (DSVs) including six single-nucleotide polymorphisms (SNPs) were found in the VEGFR-1 gene promoter and 5′-untranslated region. Five novel DSVs and one SNP were only identified in AMI patients group. These DSVs and SNP significantly altered the transcriptional activity of the VEGFR-1 gene promoter in both HEK-293 and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assay indicated that the DSVs and SNPs evidently affected the binding of transcription factors.ConclusionsThe genetic variants in VEGFR-1 gene identified in AMI patients may alter the transcriptional activity of the VEGFR-1 gene promoter and change VEGFR-1 level, contributing to AMI development.

Molecular characterization in the toll-like receptor 9 gene of Cape Mountain Zebra (Equus zebra zebra) from three populations

Toll-like receptors (TLR) are a family of proteins that signal activation of the innate immune response through the recognition of a variety of pathogen molecular compounds. Here, we characterized the complete TLR9 gene in Cape mountain zebra (Equus zebra zebra) from three populations in South Africa and compared sequences to a variety of horse and donkey breeds. Overall, we identified six single nucleotide polymorpHisms (SNPs). A single SNP (G586S) was non-synonymous, whereas the remaining SNPs were synonymous. The G586S alteration was detected in Cape mountain zebra populations with varying frequency. In addition, adaptive diversity was found to be discordant with variation based on neutral markers. The mutation is unique to the Cape mountain zebra when compared to other equid species. The structure of TLR9 is relatively conserved and the resulting amino acid substitution was found to have minimal interaction with active sites in the protein. Future studies can explore the effects of this potentially functional mutation which will contribute to our understanding of genetic diversity within adaptive sites of the Cape mountain zebra genome.

A novel NR3C2 polymorphism and the increased thyroid-stimulating hormone concentration are associated with venlafaxine treatment outcome in Chinese Han MDD patients

Objective: We aimed to study the association among venlafaxine antidepressive outcome, NR3C2 gene polymorphisms and the change of two neuroendocrine hormones during treatment. Methods: 195 Chinese Han major depressive disorder (MDD) patients were recruited and received a 6-week venlafaxine treatment in this study. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) levels were measured at the beginning and at the end of treatment. Six single-nucleotide polymorphisms (SNPs) (NR3C2: rs1512325, rs1512342, rs2070951; NR3C1: rs6191, rs6196, rs10482614) were selected for high-throughput SNP genotyping. Allele and genotype frequencies of them were compared between remission and non-remission groups. Results: We found that genotype frequency of the rs1512325 located in the NR3C2 gene was significantly different between remission and non-remission groups respectively (p < 0.05). Meanwhile, the frequency of the rs1512325 C-allele was significantly lower (p < 0.05) in remission group. The TSH concentration significantly increased after venlafaxine treatment in remission group (p < 0.05). Conclusion: The rs1512325 in NR3C2 gene and TSH concentration may be related to venlafaxine treatment outcome in Chinese Han MDD patients.

Association of a CARD9 Gene Haplotype with Behcet’s Disease in a Chinese Han Population

ABSTRACT Purpose: To investigate the association of CARD9 gene polymorphisms with Behcet’s disease (BD) and acute anterior uveitis (AAU) in a Chinese Han population. Methods: We performed a case-control association study in 480 patients with BD, 1151 patients with AAU and 1440 healthy controls. Six single nucleotide polymorphisms (SNPs) of CARD9 were genotyped, including rs4077515, rs11145769, rs59902911, rs9411205, rs4073153 and rs1135314. Results: None of the individual SNPs in the CARD9 gene showed an association with either BD or AAU. Haplotype analysis revealed a significant decrease of the frequency of a CARD9 gene haplotype CGCCA (rs4077515, rs11145769, rs59902911, rs9411205, rs4073153) in BD when compared to healthy controls (Pc = 0.012, OR = 0.585, 95%CI = 0.409 ~ 0.837). Haplotype analysis did not show an association between CARD9 and AAU. Conclusions: This study shows that a five-SNP haplotype of the CARD9 gene (CGCCA) may be a protective factor for BD with ocular involvement, but not for AAU.

Gene–gene interaction and association of Wnt/Β-catenin signalling pathway gene polymorphisms with ankylosing spondylitis susceptibility in the Chinese Han population

Objectives: To explore the genetic interaction between Wnt/β-catenin signalling pathway genes and ankylosing spondylitis (AS) in the Chinese population.Methods: Six single-nucleotide polymorphisms (SNPs) in DKK1, LRP5, LRP6, and SOST genes were genotyped in 673 AS patients and 687 healthy controls by using SNPs can Technic. Single marker genetic association analysis was performed. Haplotypes were constructed after linkage disequilibrium analysis; additive, multiplicative, and higher-order interactions were analysed.Results: The DKK1 gene rs1569198 polymorphism was significantly associated with AS susceptibility in females (χ2 = 4.55, p = .03), but the association disappeared after Bonferroni correction. Moreover, a haplotype (T-G) in the DKK1 gene showed a protective role in AS susceptibility in females (p = .04). Significant additive interactions were observed between DKK1: rs1896368 and LRP5: rs3736228, relative excess risk due to interaction (RERI) = 0.40, 95% CI = 0.08 – 0.71; attributable proportion due to interaction (AP) = 51%, 95% CI = 0.07 – 0.94, DKK1: rs1569198 and LRP5: rs3736228 (RERI = 0.49, 95% CI = 0.12 – 0.86; AP = 49%, 95% CI = 0.17 – 0.82), LRP5: rs3736228 and SOST: rs4792909 (RERI = 0.33, 95% CI = 0.002 – 0.65; AP = 41%, 95% CI = 0.01 – 0.81) in the dominant model.Conclusions: Our research implies a potential gene–gene interaction, thus revealing the importance of the Wnt/β-catenin signalling pathway for understanding the genetic architecture of AS.

Clinical and Genetic Factors Impact Time to Surgical Recurrence After Ileocolectomy for Crohn's Disease.

The aim of this study was to evaluate factors associated with time to surgical recurrence after Crohn's ileocolectomy. The most common surgery performed for Crohn's disease is ileocolectomy. Identifying patients at high risk for surgical recurrence may assist with medical and surgical decision-making. Data were obtained from 409 patients with Crohn's disease (CD) who had undergone ≥1 ileocolectomies at Penn State Hershey Medical Center. Six single-nucleotide polymorphisms (SNPs) associated with CD were evaluated in these patients: rs2076756, rs2066844, and rs2066845 in NOD2, rs4958847 and rs13361189 in IRGM, and rs2241880 in ATG16L1. Genotype and clinical factors were analyzed to determine associations with time to recurrent ileocolectomy. A subgroup analysis was performed on 241 patients naïve to biologics before initial ileocolectomy to assess the effect of biologic therapy on time to recurrent surgery. There were 286 patients who underwent a single ileocolectomy, whereas 123 required multiple ileocolectomies. Ileocolonic involvement [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.21-3.00, P = 0.006] and rs2066844 in NOD2 (HR 1.8, 95% CI 1.17-2.77, P = 0.007) were associated with decreased time to surgical recurrence by multivariate analysis. In patients naïve to preoperative biologics, the initiation of postoperative biologics was associated with a 40% decreased incidence of surgical recurrence (HR 0.60, CI 0.39-0.93, P = 0.02) over time. Ileocolonic distribution of disease and the rs2066844 SNP in NOD2 are associated with shorter time to recurrent ileocolectomy. The initiation of postoperative biologics in naïve patients was associated with a reduced incidence of recurrence over time.

Association of SGK1 Polymorphisms With Susceptibility to Coronary Heart Disease in Chinese Han Patients With Comorbid Depression.

There is a strong link between heart disease and depression, both of which are closely related to lifetime stress exposure. Serum/glucocorticoid-regulated kinase 1 (SGK1) is a stress-responsive gene with a pivotal role in both the heart and brain. To determine the role of SGK1 polymorphisms (rs2758151, rs1743963, rs9493857, rs1763509, rs9376026, and rs9389154) in susceptibility to comorbid coronary heart disease (CHD) and depression, we conducted a hospital-based case–control study involving 257 CHD cases (including 69 cases with depression and 188 cases without depression) and 107 controls in a Chinese Han population. Six single-nucleotide polymorphisms (SNPs) in the SGK1 gene were successfully genotyped by polymerase chain reaction–ligase detection reaction (PCR-LDR) assay. Our results showed no significant differences in SGK1 genetic polymorphisms between CHD patients and controls, whereas significant associations were observed between SGK1 SNPs (rs1743963 and rs1763509) and the development of depression in CHD patients (P = 0.018 by genotype, P = 0.032 by allele; P = 0.017 by genotype, P = 0.003 by allele, respectively). However, none of these associations remained significant after Bonferroni correction (P = 0.054 for rs1743963; P = 0.051 for rs1763509). Interestingly, both the GG genotype of SGK1 rs1743963 and AA genotype of SGK1 rs1763509 were associated with a higher risk of depression in CHD patients; for rs1763509, the Patient Health Questionnaire-9 (PHQ-9) scores in the carriers of the risk genotype for comorbid depression, AA, were significantly higher than in GG and AG carriers (P = 0.008). Notably, haplotype analysis indicated that haplotype GGA significantly increased the risk of depression in CHD patients (P = 0.011, odds ratio (OR) = 1.717, 95% confidence interval (CI) = 1.132–2.605), whereas haplotype AAG may be a protective factor for CHD patients with comorbid depression (P = 0.038, OR = 0.546, 95% CI = 0.307–0.972). It should be noted that only the significance of haplotype GGA survived after Bonferroni adjustment (P = 0.044) and that no significant differences were found for other SGK1 SNPs (rs2758151, rs9493857, rs9376026, and rs9389154) between CHD patients with and without depression. These findings, for the first time, elucidate the important role of SGK1 variants in the comorbidity of CHD and depression.

Genetic associations of vitamin D receptor polymorphisms with advanced liver fibrosis and response to pegylated interferon-based therapy in chronic hepatitis C.

Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C > T (rs12979860) SNP and five VDR SNPs, comprising FokI T > C (rs2228570), BsmI C > T (rs1544410), Tru9I G > A (rs757343), ApaI C > A (rs7975232), and TaqI A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12–5.58], p < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04–3.91], p = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31–2.28], p < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10–2.58], p = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07–2.37], p = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p = 0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06–2.51], p = 0.03) and age ≥55 years (OR = 2.25; 95% CI [1.54–3.32], p < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the FokI rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.

Association Study of KCNH7 Polymorphisms and Individual Responses to Risperidone Treatment in Schizophrenia.

Risperidone has been used to treat the symptoms of schizophrenia and to reduce its relapse. However, the responses to treatment show great variability among patients. The potassium channel has been reported as an effective target for antipsychotics. KCNH7, a member of the voltage-gated K+ channel Kv11 family, is primarily expressed in the brain. Here, we assessed the genetic association of KCNH7 with risperidone responses in 393 schizophrenia patients. The patients were treated with risperidone for 6 weeks. The reduction rates of Positive and Negative Syndrome Scale (PANSS) scores were determined to quantify drug response. We also examined the associations between six single-nucleotide polymorphisms (SNPs) of KCNH7 and the risperidone responses for a total of 6 weeks. The SNP rs77699177 (C > T) in the KCNH7 gene intron was significantly associated with the treatment response reflected by the PANSS reduction rate (CC, 55.8 ± 23.0; TC, 70.9 ± 20.3, P = 0.000110), indicating that patients with the TC genotype have better efficacy for antipsychotic therapy. The rs2241240 SNP also showed a significant association with treatment responses after 6 weeks of treatment (P = 0.00256). The findings indicate that the voltage-gated K+ channel KCNH7 is a potential functional marker for the identification of the response to risperidone treatment in schizophrenia patients.Note: The study was registered under clinical trial number ChiCTR-RNC-09000522 (http://www.chictr.org/).

Uric acid level, gout and bone mineral density: A Mendelian randomization study.

This study aimed to examine whether the uric acid level or gout is causally associated with bone mineral density (BMD). We performed a two-sample Mendelian randomization (MR) analysis. The statistics dataset, we used was from a meta-analysis of genome-wide association studies (GWASs) on uric acid levels from 14 studies with a total of 28141 participants of European descent, and the dataset for gout from the United Kingdom (UK) Biobank (4807 cases and 332352 controls). We further used the summary statistics dataset of a GWAS on lumbar spine and femur neck (FN) BMDs of individuals of European ancestry (up to 32735). The instrumental variables (IVs) selected were six single nucleotide polymorphisms (SNPs) from the uric acid level GWAS data and 19 SNPs from the gout GWAS data. The inverse-variance weighted (IVW) method yielded no evidence to support a causal association between the uric acid level or gout and lumbar spine BMD (β=-.002, standard error (SE)=0.035, P=.951; β=-.700, SE=0.672, P=.297). MR-Egger regression revealed no causality between uric acid level, gout and lumbar spine. Similarly, the weighted median approach provided no evidence of causality between uric acid level, gout and lumbar spine BMD. The MR results on FN BMD showed similar patterns with those of the lumbar spine BMD. Mendelian randomization analysis did not support a causal association between uric acid level, gout and lumbar spine or FN BMD.

Gene polymorphism of cytochrome P450 significantly affects lung cancer susceptibility.

BackgroundCytochrome P450 (CYPs) are heme proteins involved in the metabolism of a variety of endogenous and exogenous substances and play an important role in the carcinogenesis mechanisms of environmental and hereditary factors. The objective of this study was to investigate how polymorphisms of CYPs correlate with lung cancer (LC) susceptibility.MethodsSix single nucleotide polymorphisms (SNPs) were genotyped in this study. The chi‐square test and unconditional logistic regression model were used to evaluate the correlation between SNPs and LC susceptibility. The expressions and survival data of genes in patients with LC were mined using Oncomine and Kaplan‐Meier Plotter database.ResultsFour SNPs were found to be significantly associated with the risk of LC development (P < 0.05). The most significant correlation was that the A allele and AA genotype of CYP2D6 rs1065852 were associated with increased risk of LC development (adjusted odds ratio [OR] = 1.35, 95% confidence interval [95%CI] = 1.13‐1.60, P = 9.04e‐4; OR = 1.83, 95%CI = 1.29‐2.59, P = 0.001 respectively). Similar association of this variant was also found in the subgroups of male patients, cases in III‐IV stages, positive lymph node, squamous cell carcinomas and adenocarcinomas. Whereas rs1065852 was considered as protective factor in females (adjusted OR = 0.33, 95% CI = 0.16‐0.70, P = 0.004). In stratified analyses, the association of CYP24A1 rs2762934, CYP24A1 rs6068816, CYP20A1 rs2043449 polymorphism with LC risk appeared stronger in some subgroups. CYP2D6, CYP24A1 and CYP20A1 are overexpressed in some pathological types of LC (P < 0.05), and high levels of CYP2D6 and CYP20A1 indicate poor and good prognosis of LC, respectively.ConclusionThis study revealed that rs1065852, rs2043449, rs2762s934, and rs6068816 of CYPs were associated with LC susceptibility in the Northwestern Chinese Han population; CYP2D6 and CYP20A1 were overexpressed and correlated with prognosis of LC.

Abstract 2416: Vitamin D concentration and the risks of Barrett’s esophagus and esophageal adenocarcinoma: A Mendelian randomization study

Abstract Background Epidemiological studies on circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risks of esophageal adenocarcinoma (EAC) have shown conflicting results. Here we conducted a Mendelian randomization (MR) study to determine the associations between circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risks of EAC and its precursor, Barrett’s esophagus (BE). Methods We conducted a MR study using a two-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs) (rs3755967, rs10741657, rs12785878, rs10745742, rs8018720 and rs17216707) associated with circulating 25(OH)D concentrations were used as instrumental variables. Data from 6,167 BE patients, 4,112 EAC patients and 17,159 control participants were from studies participating in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. Results Overall, we found no evidence for an association between genetically estimated 25(OH)D concentrations and the risk of BE or EAC. The odds ratio (OR) per standard deviation unit increase in genetically estimated 25(OH)D concentrations for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% confidence interval, CI, 0.77-1.92; P = 0.41). The OR for EAC risk estimated by combining the individual SNP association using inverse variance weighting was 0.68 (95% CI, 0.39-1.19; P = 0.18). Conclusions This Mendelian randomization study found that genetically estimated low 25(OH)D concentrations were not associated with increased risks of BE or EAC. Citation Format: Jing Dong, Aaron Thrift. Vitamin D concentration and the risks of Barrett’s esophagus and esophageal adenocarcinoma: A Mendelian randomization study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2416.

Functional testing of thousands of osteoarthritis-associated variants for regulatory activity

To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis but, due to linkage disequilibrium, the specific variants underlying these associations and the mechanisms by which they contribute to disease risk have yet to be pinpointed. Here, we functionally test 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identify six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that the most significant SNP, rs4730222, exhibits differential nuclear protein binding in electrophoretic mobility shift assays and drives increased expression of an alternative isoform of HBP1 in a heterozygote chondrosarcoma cell line, in a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients. This study provides a framework for prioritization of GWAS variants and highlights a role of HBP1 and Wnt signaling in osteoarthritis pathogenesis.

Genetic analysis of the relation between IL2RA/IL2RB and rheumatoid arthritis risk

BackgroundThe biological mechanisms driving disease chronicity in rheumatoid arthritis (RA) are largely unidentified. Therefore, we aimed to determine genetic risk factors for RA.MethodsIn this case–control study, which includes samples from 499 patients and 507 healthy controls, six single‐nucleotide polymorphisms (SNPs) in interleukin‐2 receptor subunit alpha (IL2RA) and IL2RB were selected. Genotyping was performed using the Agena MassARRAY platform, and the statistical analyses were performed using the chi‐squared and Fisher's exact tests, genetic model analysis, and haplotype analysis.ResultIn the allele model, using the chi‐squared test, the result showed that rs791588 in IL2RA was associated with a decreased RA risk (odds ratios [OR] = 0.74, 95% confidence intervals [CI] = 0.62–0.89, p = 0.0014) after adjusting for age and gender. In the genetic model, logistic regression analyses revealed that rs791588 was associated with a decreased risk of RA under the codominant model, dominant model, recessive model, and log‐additive model. Stratification analysis revealed that two SNPs (rs791588 and rs2281089) were significantly associated with a reduced RA risk in an allele and genetic model after stratification by gender or age (p < 0.05). In addition, the haplotypes “Crs12569923Grs791588” and “Crs12569923Trs791588” of IL2RA was associated with an increased risk of RA adjusted by age and gender (OR = 1.35, 95% CI: 1.12–1.64, p = 0.0016; OR = 1.24, 95% CI: 1.03–1.48, p = 0.021).ConclusionThis finding indicates that the inherited altered genetic constitution at IL2RA may predispose to a less destructive course of RA.

Association of glypican-6 polymorphisms with lumbar disk herniation risk in the Han Chinese population.

BackgroundLumbar disk herniation (LDH) is a degenerative disorder, which partly results from complex genetic factors. The aim of the study was to investigate the potential associations between glypican‐6 (GPC6) variants and LDH risk in Han Chinese population.MethodsA total of 508 Han Chinese LDH patients and 508 healthy controls were recruited in this study. Six single‐nucleotide polymorphisms (SNPs) in GPC6 were selected and genotyped using an Agena MassARRAY platform. We used logistic regression method to evaluate the linkage between GPC6 variants and LDH risk by calculating the odds ratio (OR) and 95% confidence intervals (CIs) in multiple genetic models. HaploReg database was used for SNP functional annotation.ResultsOur result revealed GPC6 rs4773724 was associated with a decreased risk of LDH in allele model (OR = 0.82, 95% CI: 0.68–0.98, p = 0.026), whereas rs1008993 increased the LDH risk (OR = 1.34, 95% CI: 1.05–1.71, p = 0.020). Besides, we also found rs4773724 and rs9523981 were associated with susceptibility of LDH among individuals whose age are less than 45. And rs1008993 was associated with increased LDH risk in males. Furthermore, Haplotype analysis showed that the TT (rs4773724, rs1008993) haplotype and GC (rs4773724, rs1008993) haplotype had the opposite effects on the susceptibility of LDH.ConclusionsFor the first time, we suggest that rs4773724 and rs1008993 in GPC6 were considered as a protective factor and a risk factor for LDH in Han Chinese population, respectively. These results provide new ideas for the treatment and prevention of LDH in Han Chinese population.

Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study.

While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., “depressive symptoms” (DS, n = 161,460) and “broad depression” (BD, n = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all p > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, p = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, p = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

Association of CYP19A1 single-nucleotide polymorphism with digit ratio (2D:4D) in a sample of men and women from Ningxia (China)

Objectives2D:4D is an anthropometric indicator that may reflect the level of intrauterine sexual hormone exposure before birth. The aromatase gene (CYP19A1) mainly encodes cytochrome P450 aromatase, a key enzyme that catalyzes the conversion of androgens to estrogens in vivo and affects the development of 2D:4D. Studying the association between six single-nucleotide polymorphisms (SNPs) in CYP19A1 and digit ratios in the normal population of China will provide some basis for the biological basis of digit ratio development and promote the practical application of digit ratios. MethodsIn this study, six SNPs (rs10046, rs2414095, rs4646, rs4775936, rs749292 and rs936306) in CYP19A1 were tested in 1949 students (692 males and 1247 females) by TaqMan SNP genotyping in Ningxia, China. The digit ratios (right and left 2D:4D and right-left 2D:4D [Dr-l]) of all participants were collected using a photographic record. ResultsThe frequencies of the genotypes rs2414095 (P < 0.05), rs10046 (P < 0.01) and rs4775936 (P < 0.05) in the CYP19A1 gene and their allele frequencies were significantly different between the Hui and Han populations, and the frequency of the rs2414095 genotype (P < 0.05) was significantly different between males and females in Ningxia, China. There was a sex difference in right and left 2D:4D and in Dr-l. There was no significant association between the six SNPs of the CYP19A1 gene and right and left 2D:4D, although rs4775936 showed a lower 2D:4D ratio in allele T than in allele C, in both male and female subjects. For Dr-l we found that rs4775936 associated with increased Dr-l in females (t787 = −2.441, P < 0.05). ConclusionsWe found the different frequencies of rs10046, rs2414095 and rs4775936 between Hui and Han populations in China. There was an association between rs4775936 and Dr-l. We discuss the implications of this association for links between Dr-l and rs4775936 and prenatal sex steroids and for susceptibility to breast cancer.

The Interaction of TPH2 and 5-HT2A Polymorphisms on Major Depressive Disorder Susceptibility in a Chinese Han Population: A Case-Control Study.

Purpose: TPH2 and 5-HT2A appear to play vital roles in the homeostatic regulation of serotonin levels in the brain, their genetic variations may lead to impaired homeostatic regulation of serotonin resulting in abnormal levels of serotonin in the brain, thus predisposing individuals to MDD. However, research studies have yet to confirm which gene-gene interaction effect between TPH2 and 5-HT2A polymorphisms results in increased susceptibility to MDD.Methods: A total of 565 participants, consisting of 278 MDD patients and 287 healthy controls from the Chinese Han population, were recruited for the present study. Six single nucleotide polymorphisms (SNPs) of TPH2/5-HT2A were selected to assess their interaction by use of a generalized multifactor dimensionality reduction method.Results: A-allele carriers of rs11178997 and rs120074175 were more likely to suffer from MDD than T-allele carriers of rs11178997, or G-allele carriers of rs120074175. The interaction between TPH2 (rs120074175, rs11178997) and 5-HT2A (rs7997012) was considered as the best multi-locus model upon the MDD susceptibility.Conclusions: Our data identified an important effect of TPH2 genetic variants (rs11178997 and rs120074175) upon the risk of MDD, and suggested that the interaction of TPH2/5-HT2A polymorphism variants confer a greater susceptibility to MDD in Chinese Han population.

Association of Genetic Variants of RANK, RANKL, and OPG with Ankylosing Spondylitis Clinical Features in Taiwanese.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.