Susceptibility Single Nucleotide Polymorphisms Research Articles

Association between MMP-3 polymorphisms among Chinese patients with osteonecrosis of the femoral head.

Many potential causative factors are related to the initiation and progression of osteonecrosis of the femoral head (ONFH). The matrix metalloproteinase/tissue inhibitor of metalloproteinases (MMPs/TIMPs) system was found to play a significant role in the development of ONFH. The aim of this study is to investigate the association between polymorphisms of MMP-3 and ONFH in the Chinese population. We selected 8 single-nucleotide polymorphisms (SNPs) in 2 genes selected from the MMPs/TIMPs system in a case–control study with 585 cases of ONFH and 507 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using the chi-squared test, genetic model analysis, haplotype analysis, and stratification analysis. We found that the minor allele of rs650108 and rs522616 (p<0.05) was assumed a risk allele compared to the wild-type allele. In the genetic model analysis, We observed two susceptibility SNPs additionally: rs650108, dominant model analyses (with adjustment: OR=0.73; 95%CI 0.56-0.95; p=0.017) and additive model analyses (with adjustment: OR=0.83; 95%CI 0.70-0.99; p=0.044); and rs522616 recessive model analyses (with adjustment: OR=1.52; 95%CI 1.07-2.14; p=0.018) and additive model analyses (with adjustment: OR=1.21; 95% CI 1.02-1.44; p=0.033). Our results verify that genetic variants of MMP3 contribute to ONFH susceptibility in the population of northern China. In addition, we found that gender differences might interact with MMP3 polymorphisms to contribute to the overall susceptibility to ONFH.

The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults

BackgroundWhile common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. MethodsGenotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. ResultsFor pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18–2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05–3.03, p = 0.026). ConclusionsOur results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.

Association between SNPs in microRNA machinery genes and gastric cancer susceptibility, invasion, and metastasis in Chinese Han population.

ObjectiveThe present study investigates the influence of genetic variants in miRNA machinery genes (DROSHA, DICER, AGO1, and GEMIN4) on gastric cancer in Chinese Han population, further revealing the genetic mechanisms of gastric cancer occurrence and development.MethodsGenotyping of single nucleotide polymorphisms (SNPs) was performed in 628 patients with GC and 502 frequency-matched (age and gender) controls by the high resolution melting (HRM) method.ResultsThe SNPs rs3742330 (DICER) and rs7813 (GEMIN4) were associated with susceptibility to gastric cancer (P = 0.002 and 0.010, respectively). Stratified analysis showed that the G allele of rs3742330 and genotype TT as well as T allele of rs7813 were associated with a later stage of gastric cancer (P=0.027, 0.032 and 0.018, respectively). Furthermore, the genotype TT and T allele of rs7813 appeared to be associated with a higher level of lymphatic metastasis of gastric cancer (P=0.021 and 0.030, respectively), while the genotype AA and A allele of rs636832 (AGO1) were correlated with a lower level of lymphatic metastasis of gastric cancer (P=0.016 and 0.041, respectively). There was no significant association between rs10719 (DROSHA) and gastric cancer.ConclusionThe present data demonstrated that genetic variants in miRNA machinery genes had a significant association with GC susceptibility (DICER and GEMIN4) and malignant behavior such as tumor stage (DICER and GEMIN4) and lymphatic metastasis of GC (GEMIN4 and AGO1) in Chinese Han population.

Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability. Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence. Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p-value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions. Results: We identified 486 MS-associated (p < 1 × 10–4) and 18,426 MS-linked (p < 0.05) SNPs. A total of 111 loci were both linked and associated with MS, 18 of them pointing to 14 non-major histocompatibility complex (MHC) genes, and 93 of them located in the MHC region. Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS.

Comparison of the role of HHIP SNPs in susceptibility to chronic obstructive pulmonary disease between Chinese Han and Mongolian populations

The contribution of risk alleles to chronic obstructive pulmonary disease (COPD) may vary between populations. This study aimed to investigate the role of single nucleotide polymorphisms (SNPs) in HHIP on COPD susceptibility in the Chinese Mongolian and Han populations from Inner Mongolia autonomous region. In this case-control study, five SNPs in HHIP gene were detected in 700 COPD patients (350 Chinese Han and 350 Chinese Mongolian) and 700 healthy controls (350 Chinese Han and 350 Chinese Mongolian). The genotype, the association with COPD, and the differences between Chinese Han and Mongolian populations were evaluated using the chi-squared (χ2) test, genetic models, and logistic analysis. The minor allele C in SNP rs10519717 was associated with COPD in Mongolian (Odds ration (OR)=1.401, 95% confidence interval (CI): 1.110–1.769, P=0.044); however, not in the Han. The CC genotype in SNP rs10519717 was a risk factor for COPD in Mongolian (OR=2.667, 95% CI: 1.479–4.809, P=0.044); however, the TC genotype in Han played the same role (OR=1.396, 95% CI: 1.018–1.915, P=0.044). The GG genotype in SNP rs13147758 was protective in the Han (OR=0.546, 95% CI: 0.332–0.897, P=0.017). The homozygote of the minor alleles in SNPs rs12504628, rs1828591, and rs13118928 had a protective role in the both of COPD populations. For the minor allele distribution, the differences between the Han and Mongolian were presented only in the case group for rs12504628 (P=0.003), rs13147758 (P=0.002), rs1828591 (P=0.001), and rs13118928 (P=0.002); for the genotypes, differences was presented at the frequency of the minor allele homozygote in rs13147758 (P=0.048), rs10519717 (P=0.027), rs1828591 (P=0.041), and rs13118928 (P=0.044) in Mongolian. Our findings suggested that HHIP rs10519717 might be associated with susceptibility of Mongolian COPD. For the other SNPs, the differences between the two populations were represented by minor allele distribution and frequency of the minor allele homozygotes.

Integrating regulatory features data for prediction of functional disease-associated SNPs.

Genome-wide association studies (GWASs) are an effective strategy to identify susceptibility loci for human complex diseases. However, missing heritability is still a big problem. Most GWASs single-nucleotide polymorphisms (SNPs) are located in noncoding regions, which has been considered to be the unexplored territory of the genome. Recently, data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomics projects have shown that many GWASs SNPs in the noncoding regions fall within regulatory elements. In this study, we developed a pipeline named functional disease-associated SNPs prediction (FDSP), to identify novel susceptibility loci for complex diseases based on the interpretation of the functional features for known disease-associated variants with machine learning. We applied our pipeline to predict novel susceptibility SNPs for type 2 diabetes (T2D) and hypertension. The predicted SNPs could explain heritability beyond that explained by GWAS-associated SNPs. Functional annotation by expression quantitative trait loci analyses showed that the target genes of the predicted SNPs were significantly enriched in T2D or hypertension-related pathways in multiple tissues. Our results suggest that combining GWASs and regulatory features data could identify additional functional susceptibility SNPs for complex diseases. We hope FDSP could help to identify novel susceptibility loci for complex diseases and solve the missing heritability problem.

The SNP-set based association study identifies ITGA1 as a susceptibility gene of attention-deficit/hyperactivity disorder in Han Chinese

Genome-wide association studies, which detect the association between single-nucleotide polymorphisms (SNPs) and disease susceptibility, have been extensively applied to study attention-deficit/hyperactivity disorder (ADHD), but genome-wide significant associations have not been found yet. Genetic heterogeneity and insufficient genomic coverage may account for the missing heritability. We performed a two-stage association study for ADHD in the Han Chinese population. In the discovery stage, 1033 ADHD patients and 950 healthy controls were genotyped using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Infinium HumanExome BeadChip. The genotyped SNPs were combined to generate a powerful SNP set with better genomic coverage especially for the nonsynonymous variants. In addition to the association of single SNPs, we collected adjacent SNPs as SNP sets, which were determined by either genes or successive sliding windows, to evaluate their synergetic effect. The candidate susceptibility SNPs were further replicated in an independent cohort of 1441 ADHD patients and 1447 healthy controls. No genome-wide significant SNPs or gene-based SNP sets were found to be associated with ADHD. However, two continuous sliding windows located in ITGA1 (P-value=8.33E−7 and P-value=8.43E−7) were genome-wide significant. The quantitative trait analyses also demonstrated their association with ADHD core symptoms and executive functions. The association was further validated by follow-up replications for four selected SNPs: rs1979398 (P-value=2.64E−6), rs16880453 (P-value=3.58E−4), rs1531545 (P-value=7.62E−4) and rs4074793 (P-value=2.03E−4). Our results suggest that genetic variants in ITGA1 may be involved in the etiology of ADHD and the SNP-set based analysis is a promising strategy for the detection of underlying genetic risk factors.

Age at diagnosis and gender modify the risk of 9q22 and 14q13 polymorphisms for papillary thyroid carcinoma.

Papillary thyroid cancer (PTC) shows familial occurrence, and some susceptibility single nucleotide polymorphisms (SNPs) have been identified in FOXE1 and near the NKX2-1 locus. The aim of our study was to analyse the association of PTC risk with SNPs in FOXE1 (rs965513, rs1867277, rs1443434) and near the NKX2-1 locus (rs944289) in a Polish population, and, in the second step, the interac-tion between SNPs and patient-related factors (age at diagnosis and gender). A total of 2243 DNA samples from PTC patients and 1160 controls were included in the study. The SNP analysis was performed with the allelic discrimination technique. There were significant associations of all SNPs with PTC (rs965513 odds ratio [OR] = 1.72, p = 8 × 10-7; rs1867277 OR = 1.59, p = 1 × 10-6; rs1443434 OR = 1.53, p = 1 × 10-5; rs944289 OR = 1.52, p = 4 × 10-5). Logistic regression analysis revealed an increased PTC risk in the interaction of rs944289 with age at diagnosis (OR = 1.01 per year, p = 6 × 10-4) and a decreased PTC risk in the interaction of male gender with the GGT FOXE1 protective haplotype (OR = 0.69, p = 0.01). the association between PTC and all analysed SNPs was confirmed. It was also shown that patient-related factors modify the predisposition to PTC by increasing the risk for rs944289 per year of age, and by enhancing the protective effect of the FOXE1 GGT haplotype in men.

Detecting genetic association through shortest paths in a bidirected graph.

Genome-wide association studies (GWASs) commonly use marginal association tests for each single-nucleotide polymorphism (SNP). Because these tests treat SNPs as independent, their power will be suboptimal for detecting SNPs hidden by linkage disequilibrium (LD). One way to improve power is to use a multiple regression model. However, the large number of SNPs preclude simultaneous fitting with multiple regression, and subset regression is infeasible because of an exorbitant number of candidate subsets. We therefore propose a new method for detecting hidden SNPs having significant yet weak marginal association in a multiple regression model. Our method begins by constructing a bidirected graph locally around each SNP that demonstrates a moderately sized marginal association signal, the focal SNPs. Vertexes correspond to SNPs, and adjacency between vertexes is defined by an LD measure. Subsequently, the method collects from each graph all shortest paths to the focal SNP. Finally, for each shortest path the method fits a multiple regression model to all the SNPs lying in the path and tests the significance of the regression coefficient corresponding to the terminal SNP in the path. Simulation studies show that the proposed method can detect susceptibility SNPs hidden by LD that go undetected with marginal association testing or with existing multivariate methods. When applied to real GWAS data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), our method detected two groups of SNPs: one in a region containing the apolipoprotein E (APOE) gene, and another in a region close to the semaphorin 5A (SEMA5A) gene.

Chromosome 4q25 variants and recurrence after second-generation cryoballoon ablation in patients with paroxysmal atrial fibrillation

BackgroundChromosome 4q25 single-nucleotide polymorphisms (SNPs) are associated with atrial fibrillation (AF) recurrence after radiofrequency catheter ablation, however the underlying mechanism is unknown. Pulmonary vein (PV) reconnections are common post-radiofrequency ablation. We explored the pre-procedural parameters, including AF susceptibility SNPs, predicting the response to PV isolation (PVI) using second-generation cryoballoons. MethodsOne hundred fifty-seven paroxysmal AF patients undergoing PVI using second-generation cryoballoons and genetic testing were enrolled. The top 6 AF-associated Japanese ancestry SNPs were evaluated. Fourteen-day consecutive monitoring was performed to detect AF recurrences. ResultsEarly recurrence of AF (ERAF) was detected in 74(47.1%) patients, and the AF-free survival at 12-months after single procedures was 72.1%. Cox's proportional models determined that higher pro-BNP values (hazard ratio [HR]=1.001; 95% confidence interval [CI]=1.000–1.001; p=0.003) and the rs1906617 risk allele (HR=2.440; 95% CI=1.062–5.605; p=0.035) were independently associated with ERAFs, and the rs1906617 risk allele (HR=4.339; 95% CI=1.044–18.028; p=0.043) was the sole factor significantly associated with AF recurrence. Second procedures were performed in 41 patients a median of 6.0[5.0–9.5] months later, and 42/162(25.9%) PVs were reconnected. Reconnections were similarly observed in rs1906617 risk allele carriers and wild-type patients. Risk allele carriers at rs1906617 were more likely to have non-PV foci, but did not reach statistical significance (10/35 vs. 0/6, p=0.132). ConclusionsAF risk alleles on chromosome 4q25 modulated the risk of AF recurrence after PVI using second-generation cryoballoons in patients with paroxysmal AF. Our study results suggested that non-PV foci might be the more likely mechanism of a high AF recurrence in chromosome 4q25 variant carriers.

Colonic Phenotypes Are Associated with Poorer Response to Anti-TNF Therapies in Patients with IBD.

Although anti-tumor necrosis factor (TNF) agents are effective in patients with inflammatory bowel disease (IBD), many patients either do not respond to anti-TNF treatment or lose response over time. The aim of this study was to determine factors associated with response to anti-TNF therapy in IBD. Patients with Crohn's disease (CD) or ulcerative colitis who had consented to participate in a genetics registry and been treated with anti-TNF agents were evaluated retrospectively and categorized as primary nonresponders or secondary nonresponders. We evaluated clinical, serological, and genetic characteristics associated with primary nonresponse or time to loss of response to anti-TNF agents. We included 314 CD (51 [16.2%] primary nonresponders and 179 [57.0%] secondary nonresponders) and 145 subjects with ulcerative colitis (43 [29.7%] primary nonresponders and 74 [51.0%] secondary nonresponders). Colonic involvement (P = 0.017; odds ratio = 8.0) and anti-TNF monotherapy (P = 0.017; odds ratio = 4.9) were associated in a multivariate analysis with primary nonresponse to anti-TNF agents in CD. In addition, higher anti-nuclear cytoplasmic antibody levels (P = 0.019; hazard ratio = 1.01) in CD, anti-nuclear cytoplasmic antibody positivity (P = 0.038; hazard ratio = 1.6) in ulcerative colitis, and a positive family history of IBD (P = 0.044; hazard ratio = 1.3) in all patients with IBD were associated with time to loss of response to anti-TNF agents. Furthermore, various known IBD susceptibility single-nucleotide polymorphisms and additional variants in immune-mediated genes were shown to be associated with primary nonresponse or time to loss of response. Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD.

Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management.

Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

Association of ARHGAP22 gene polymorphisms with the risk of type 2 diabetic retinopathy.

Little is known about the contribution of ARHGAP22 polymorphism to diabetic retinopathy (DR) risk. We performed a case-control study to investigate the associations between ARHGAP22 and the risk of DR in a Chinese Han population. A total of 341 patients with type 2 diabetes mellitus (T2DM) were selected. All patients underwent a complete eye examination. Based on this, the patients with T2DM were divided into two subgroups: 188 patients with DR and 153 patients without DR. Five single nucleotide polymorphism (SNPs) were selected and genotyped using the MassARRAY method (Sequenom, San Diego, CA, USA). The odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age and sex. Two susceptibility SNPs in ARHGAP22 were found to be associated with an increased risk of DR both before and after the adjustment: rs10491034 under the dominant model (adjusted OR=0.51, 95% CI=0.27-0.95, p=0.032) and additive model (adjusted OR=0.47, 95% CI=0.26-0.84, p=0.0098) and rs3844492 under the codominant model (adjusted OR=3.14, 95% CI=1.10-9.01, p=0.023) and recessive model (adjusted OR=3.52, 95% CI=1.26-9.85, p=0.011). Our findings reveal a significant association between SNPs in the ARHGAP22 gene and DR risk in a Han Chinese population.

Shared susceptibility loci at 2q33 region for lung and esophageal cancers in high-incidence areas of esophageal cancer in northern China.

BackgroundCancers from lung and esophagus are the leading causes of cancer-related deaths in China and share many similarities in terms of histological type, risk factors and genetic variants. Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs). Thus, the present study aimed to determine the risk of these SNPs predisposing to lung cancer in Chinese population.MethodsA total of 1170 lung cancer patients and 1530 normal subjects were enrolled in this study from high-incidence areas for esophageal cancer in Henan, northern China. Five milliliters of blood were collected from all subjects for genotyping. Genotyping of 20 high-risk SNP loci identified from genome-wide association studies (GWAS) on esophageal, lung and gastric cancers was performed using TaqMan allelic discrimination assays. Polymorphisms were examined for deviation from Hardy-Weinberg equilibrium (HWE) using Х2 test. Bonferroni correction was performed to correct the statistical significance of 20 SNPs with the risk of lung cancer. The Pearson’s Х2 test was used to compare the distributions of gender, TNM stage, histopathological type, smoking and family history by lung susceptibility genotypes. Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.ResultsFour of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107–1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100–1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098–1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089–1.447; P = 0.04). All these SNPs were located at 2q33 region harboringgenes of CASP8, ALS2CR12 and TRAK2. However, none of these susceptibility SNPs was observed to be significantly associated with gender, TNM stage, histopathological type, smoking, family history and overall survival.ConclusionsThe present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.

Cytokine gene polymorphism associations with congenital cytomegalovirus infection and sensorineural hearing loss

Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11–4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25–3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).

Polymorphisms in the Glucocorticoid Receptor Gene and Associations with Glucocorticoid-Induced Avascular Osteonecrosis of the Femoral Head.

Individual sensitivity to glucocorticoid (GC) therapy might play a pivotal role in the development of GC-induced avascular necrosis of the femoral head (GANFH). In a growing number of studies, common polymorphisms of the glucocorticoid receptor gene (nuclear receptor subfamily 3 group C member 1 [NR3C1]) have been associated with variability in the individual sensitivity to GCs. However, whether the NR3C1 gene polymorphisms actually influence the susceptibility of GANFH remains unknown. In this study, we report the findings of a case-control study to investigate the role of the NR3C1 gene single-nucleotide polymorphisms (SNPs) in GANFH susceptibility among 78 GANFH patients (GCs sensitive) and 115 GC-resistant controls. Our results found no significant associations between the SNPs N363S, Tth111I, BclI, ER22/23EK, and A3669G with GANFH susceptibility. The G allele frequency, both homozygous and heterozygous, of SNP BclI was significantly different between control and GANFH combined with osteopenia subgroups (odds ratios [OR] = 1.81; 95% confidence intervals [CI] = 1.05-3.10; OR = 2.04; 95% CI = 1.03-4.07, respectively). Most of these common SNPs in the NR3C1 gene likely do not play critical roles in the susceptibility of GANFH. However, the G allele at the SNP Bcll, irrespective of dosage, may increase risk for the development of GANFH combined with osteopenia in the Chinese population.

Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Coronary Artery Calcification and Rheumatoid Arthritis: Lack of Relationship to Risk Alleles for Coronary Artery Disease in the General Population.

Coronary artery disease (CAD) in the general population is characterized by an increased frequency of particular susceptibility single-nucleotide polymorphisms (SNPs). Because the frequency of CAD is increased among patients with rheumatoid arthritis (RA), we sought to determine whether the frequency of these SNPs is increased in RA patients with CAD, hypothesizing that RA could enhance CAD risk by acting through established genetic pathways predisposing to CAD. Coronary artery calcification (CAC) as detected by computed tomography was used as a measure of CAD in 561 patients with RA. One hundred SNPs associated with CAD in the general population were genotyped or imputed, and their relationship to CAC was established through multiple regression analysis for individual SNPs and a genetic risk score representing their cumulative effect. Ninety-one CAD-related SNPs were genotyped successfully; of these, 81 exhibited no association with CAC (Agatston units) or different CAC categorizations, either individually or collectively, in the genetic risk score. Only rs579459 (ABO) and rs17676451 (HAL) had a consistent positive association between genotype and CAC, with a significant increase in the frequency of the effect allele in both homozygous and heterozygous genotype distributions. Five were variably negatively associated. Furthermore, a positive association between the Disease Activity Score in 28 joints and CAC was observed, and after adjustment for traditional cardiovascular risk factors, it was not modified by correcting for the CAD-related SNP genetic risk score. The increased risk of CAC in patients with RA does not appear to operate primarily through established genetically regulated atherogenic mechanisms that are preponderant in the general population.

Risk Model for Colorectal Cancer in Spanish Population Using Environmental and Genetic Factors: Results from the MCC-Spain study

Colorectal cancer (CRC) screening of the average risk population is only indicated according to age. We aim to elaborate a model to stratify the risk of CRC by incorporating environmental data and single nucleotide polymorphisms (SNP). The MCC-Spain case-control study included 1336 CRC cases and 2744 controls. Subjects were interviewed on lifestyle factors, family and medical history. Twenty-one CRC susceptibility SNPs were genotyped. The environmental risk model, which included alcohol consumption, obesity, physical activity, red meat and vegetable consumption, and nonsteroidal anti-inflammatory drug use, contributed to CRC with an average per factor OR of 1.36 (95% CI 1.27 to 1.45). Family history of CRC contributed an OR of 2.25 (95% CI 1.87 to 2.72), and each additional SNP contributed an OR of 1.07 (95% CI 1.04 to 1.10). The risk of subjects with more than 25 risk alleles (5th quintile) was 82% higher (OR 1.82, 95% CI 1.11 to 2.98) than subjects with less than 19 alleles (1st quintile). This risk model, with an AUROC curve of 0.63 (95% CI 0.60 to 0.66), could be useful to stratify individuals. Environmental factors had more weight than the genetic score, which should be considered to encourage patients to achieve a healthier lifestyle.

Cancer risk associated single nucleotide polymorphisms of mitochondrial D-loop and 8-hydroxy-2'-deoxyguanosine levels in gastric cancer

ABSTRACTThe accumulation of mutations and single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) is related to gastric carcinogenesis. To evaluate the potential relationships between DNA damage and D-loop SNPs, we measured the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the gastric cancer tissue by immmunostaining. Our data showed that the gastric cancer susceptibility SNP of 16519C was associated with higher 8-OHdG levels. Taken together, the cancer-risk associated D-loop SNPs might initiate carcinogenesis through increasing oxidative damage.