Association of rs11801299 and rs1380576 polymorphisms at MDM4 with risk,clinicopathological features and prognosis in patients with retinoblastoma

Backgroundrs11801299 and rs1380576, two novel polymorphisms in MDM4 gene, have been investigated in several different cancer types. However, the role of these two polymorphisms in retinoblastoma (RB) remains unclear.MethodsA total of 126 patients with primary RB and 148 age-/gender-matched controls were included in this retrospective study. The frequency of rs11801299 and rs1380576 were determined between RB patients and controls. The association of these two polymorphisms with clinicopathological characteristics, prognosis were further evaluated.ResultsAA genotype at rs11801299 was significantly associated with an increased risk of developing RB (OR = 2.06, 95%CI 1.09–3.90). The possibility of developing RB was also significantly increased in individuals with A allele at rs11801299 (OR = 1.49, 95%CI 1.06–2.08). RB patients carrying AA genotype and A allele at rs11801299 were more likely to have tumor invasion and poor differentiation. As for rs1380576, a significantly lower risk of developing RB was observed in patients with G allele (CG + GG) compared with wild-type CC genotype (OR = 0.59, 95%CI 0.36–3.95). RB patients with GG genotype or G allele had a lower risk of developing highly aggressive cancer. Kaplan-Meier curves and log-rank results revealed that RB patients carrying AA genotype or A allele (AA + GA) at rs11801299 had significantly poorer prognosis. Multivariate COX analysis showed that the rs11801299 G allele was associated with decreased survival but was not an independent prognostic factor.Conclusionrs11801299 was significantly associated with RB risk, pathological differentiation, tumor aggressiveness and poor prognosis.     

Association of vitamin D receptor BsmI (rs1544410) gene polymorphism with the chronic kidney disease susceptibility

Abstract

Association of vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism with the chronic kidney disease (CKD) susceptibility from the published reports are still conflicting. This meta-analysis was performed to evaluate the relationship between VDR BsmI (rs1544410) gene polymorphism and the risk of CKD. The association studies were identified from PubMed, Cochrane Library and China Biological Medicine Database on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Nine reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with CKD susceptibility. In this meta-analysis for overall populations, the BsmI B allele BB genotype and bb genotype were not associated with the risk of CKD (B allele: OR?=?1.12, 95% CI: 0.88–1.44, p?=?0.36; BB genotype: OR?=?1.15, 95% CI: 0.81–1.62, p?=?0.43; bb genotype: OR?=?0.86, 95% CI: 0.61–1.20, p?=?0.36). Furthermore, VDR BsmI gene polymorphism was not associated with CKD susceptibility in Asians and in Caucasians. In conclusion, the BsmI gene polymorphism was not associated with CKD susceptibility in overall populations, in Asians and in Caucasians. However, more studies should be conducted to confirm it.     

Genetic polymorphisms in MMP 2, 3 and 9 genes and the susceptibility of osteosarcoma in a Chinese Han population

Background: There are no data about the role of MMPs polymorphism in development of osteosarcoma.

Patients and methods: Two-hundred fifty-one patients with osteosarcoma and 251 healthy controls were included to investigate the association between the MMP2, 3, 9 polymorphisms and the risk of osteosarcoma.

Results: Compared with the MMP2 SNP rs243865 homozygote CC, The heterozygous CT genotype was associated with significantly increased risk for osteosarcoma (OR?=?1.86, 95% CI?=?1.18–4.22, p?=?0.014); the TT genotype was associated with increased risk for osteosarcoma (OR?=?1.92, 95% CI?=?1.21–3.52, p?=?0.028). However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms were not significantly different.

Conclusion: MMP2 rs243865 genotype was associated with increased risk for development of osteosarcoma in Chinese Han population.     

Gelsolin rs1078305 and rs10818524 polymorphisms were associated with risk of oral squamous cell carcinoma in a Chinese Han population

Background: Gelsolin (GSN) is one of the most abundant actin-binding proteins, and is involved in cancer development and progression.

Patients and methods: A hospital-based case-control study including 201 patients with OSCC and 199 healthy controls was conducted. Seventeen single-nucleotide polymorphisms (SNPs) of GSN were investigated by Sequenom Mass ARRAY and iPLEX-MALDI-TOF technology.

Results: Through comparison of the 17 SNPs on GSN gene between the two groups, SNP rs1078305 and rs10818524 were verified to be significantly associated with an increased risk of OSCC. For GSN rs1078305, the TT genotype was associated with increased risk for OSCC (OR?=?1.92, 95% CI?=?1.11–3.32, p?=?0.028). CT/TT variants were also associated with increased risk for OSCC compared to the CC genotype (OR?=?1.83, 95% CI?=?1.25–3.84, p?=?0.032).

Conclusion: The rs1078305 and rs10818524 SNPs of GSN were associated with increased risk for OSCC development in a Chinese Han population.     

The HHEX rs1111875A/G gene polymorphism is associated with susceptibility to type 2 diabetes in the iranian population

The illuminating picture of genetic mechanisms underlying the development of type 2 diabetes (T2DM) includes differently accumulated genetic polymorphisms that increase the risk along with environmental factors. A number of single nucleotide polymorphisms (SNPs) are indicated to be linked with T2DM, but also conflicting results have been found. To examine the contribution of these polymorphisms in conferring susceptibility to T2DM, the association of HHEX rs1111875A/G and CDKN2A/B rs10811661C/T common gene polymorphisms with the risk of T2DM in an Iranian population was evaluated. In this study participated 140 patients and 140 controls. Genomic DNA was extracted from samples and genotyping of the polymorphisms was performed by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique. A significant association was found with the G allele (OR = 1.729, CI = 1.184–2.523, P = 0.004) and GG genotype (OR = 2.921, 95% CI = 1.789–4.771, P< 0.001) of the rs1111875A/G SNP for susceptibility to T2DM in the recessive model. Furthermore, compared with the GG genotype, individuals with the GA genotype had a lower risk to develop T2DM (OR = 0.237, 95% CI = 0.137–0.408, P< 0.001) in the additive model. In addition, an association between the polymorphism and BMI in regard to the risk of T2DM was identified. The genotype and allele frequencies of the rs10811661C/T polymorphism did not show a statistically significant association with T2DM in any genetic model. Our results show that the rs1111875A/G polymorphism is an important susceptibility polymorphism for the development of T2DM in the Iranian population. Also, these findings support that this polymorphism is a key genetic risk factor for the development of T2DM in multiple ethnic populations.

     

Pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in early T cell development

Background

Mature miRNAs can often be classified into large families, consisting of members with identical seeds (nucleotides 2 through 7 of the mature miRNAs) and highly homologous ∼21-nucleotide (nt) mature miRNA sequences. However, it is unclear whether members of a miRNA gene family, which encode identical or nearly identical mature miRNAs, are functionally interchangeable in vivo.

Methods and Findings

We show that mir-181a-1, but not mir-181c, can promote CD4 and CD8 double-positive (DP) T cell development when ectopically expressed in thymic progenitor cells. The distinct activities of mir-181a-1 and mir-181c are largely determined by their unique pre-miRNA loop nucleotides—not by the one-nucleotide difference in their mature miRNA sequences. Moreover, the activity of mir-181a-1 on DP cell development can be quantitatively influenced by nucleotide changes in its pre-miRNA loop region. We find that both the strength and the functional specificity of miRNA genes can be controlled by the pre-miRNA loop nucleotides. Intriguingly, we note that mutations in the pre-miRNA loop regions affect pre-miRNA and mature miRNA processing, but find no consistent correlation between the effects of pre-miRNA loop mutations on the levels of mature miRNAs and the activities of the mir-181a-1/c genes.

Conclusions

These results demonstrate that pre-miRNA loop nucleotides play a critical role in controlling the activity of miRNA genes and that members of the same miRNA gene families could have evolved to achieve different activities via alterations in their pre-miRNA loop sequences, while maintaining identical or nearly identical mature miRNA sequences.     

Vitamin D receptor gene polymorphisms and susceptibility of hand osteoarthritis in Finnish women

We examined whether polymorphisms of the vitamin D receptor (VDR) gene was associated with individual risk of hand osteoarthritis (OA). Radiographs of both hands of 295 dentists and of 248 teachers were examined and classified for the presence of OA using reference images. The VDR ApaI and TaqI genotypes were determined by PCR-based methods. No association was observed between the VDR polymorphisms and the odds of overall hand OA. However, the carriers of the VDR t allele or At haplotype were at almost half the odds of symmetrical hand OA (odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38–0.94 and OR = 0.59, 95% CI = 0.38–0.93, respectively) compared with the carriers of the T allele and of the non-At haplotype, respectively. Increased odds of this disease, on the contrary, was observed for women with two copies of the VDR a allele (OR = 1.93, 95% CI = 1.99–3.70) compared with women with the AA genotype. Conversely, the VDR a allele carriage was associated with a tendency of lowered odds of osteophyte (OR = 0.51, 95% CI = 0.25–1.03). When the genotype data were used to construct haplotypes, the VDR AaTt joint genotype appeared to pose a remarkably lower odds (OR = 0.26, 95% CI = 0.08–0.91) of osteophyte compared with the AAtt joint genotype. As a novel finding we observed a joint effect of a low calcium intake and VDR polymorphisms on symmetrical OA; the OR was 2.64 (95% CI = 1.29–5.40) for carriers of the aT haplotype with low daily calcium intake compared with non-carriers of the haplotype with high daily calcium intake. Our results suggest that VDR gene polymorphisms play a role in the etiology of symmetrical hand OA. Moreover, the association between the VDR gene and OA may be modified by calcium intake.     

Multiple In Vivo Biological Processes Are Mediated by Functionally Redundant Activities of Drosophila mir-279 and mir-996

While most miRNA knockouts exhibit only subtle defects, a handful of miRNAs are profoundly required for development or physiology. A particularly compelling locus is Drosophila mir-279, which was reported as essential to restrict the emergence of CO₂-sensing neurons, to maintain circadian rhythm, and to regulate ovarian border cells. The mir-996 locus is located near mir-279 and bears a similar seed, but they otherwise have distinct, conserved, non-seed sequences, suggesting their evolutionary maintenance for separate functions. We generated single and double deletion mutants of the mir-279 and mir-996 hairpins, and cursory analysis suggested that miR-996 was dispensable. However, discrepancies in the strength of individual mir-279 deletion alleles led us to uncover that all extant mir-279 mutants are deficient for mature miR-996, even though they retain its genomic locus. We therefore engineered a panel of genomic rescue transgenes into the double deletion background, allowing a pure assessment of miR-279 and miR-996 requirements. Surprisingly, detailed analyses of viability, olfactory neuron specification, and circadian rhythm indicate that miR-279 is completely dispensable. Instead, an endogenous supply of either mir-279 or mir-996 suffices for normal development and behavior. Sensor tests of nine key miR-279/996 targets showed their similar regulatory capacities, although transgenic gain-of-function experiments indicate partially distinct activities of these miRNAs that may underlie that co-maintenance in genomes. Altogether, we elucidate the unexpected genetics of this critical miRNA operon, and provide a foundation for their further study. More importantly, these studies demonstrate that multiple, vital, loss-of-function phenotypes can be rescued by endogenous expression of divergent seed family members, highlighting the importance of this miRNA region for in vivo function.     

Association between vitamin D receptor (FokI) genetic variant rs2228570 and iron profile in hemodialysis patients

Iron deficiency is a common etiology of anemia that causes suboptimal response to erythropoietin therapy in hemodialysis (HD) patients. This study investigated the association between vitamin D receptor (VDR) genetic variant (FokI) rs2228570 with iron indices (serum iron, transferrin, transferrin saturation, and ferritin). Sixty adequately hemodialyzed patients subdivided into two groups; 31 patients with transferrin saturation (TSAT)?<?20% and 29 with TSAT?>?20% who received I.V sodium ferric gluconate, calcium, and vitamin D. Sixty normal healthy were selected as the control group.. VDR genetic variant (SNP rs2228570) was genotyped in all subjects using PCR/RFLP. HD patients showed a higher frequency of rs2228570 FF genotype (38.3%) than controls (31.7%). The frequency of ff genotype and f allele in patients (8.4 and 35% respectively) were significantly lower than controls (25 and 46.7% respectively). Allele model (f vs. F): OR 0.721, 95% CI 0.521–0.998, P?=?0.049. While (ff vs. FF): OR 0.452, 95% CI 0.223–0.917, P = 0.028. The distribution of Ff?+?ff genotypes in HD cases with TSAT?>?20% was higher than in HD cases with TSAT?<?20%, Dominant model (Ff +ff vs FF): OR 2.753, 95% CI 1.902–3.409, P?=?0.048. f allele showed lower frequency in low TSAT group than high TSAT group (27.4 vs. 43.1%) with significant P value (P?=?0.042) with allele model (f vs. F): OR 2.012, 95% CI 1.923–4.226, P?=?0.042. Fok-1 ff, Ff?+?ff genotypes were significantly associated with TSAT?>?20% with a protective effect against low TSAT in HD patients.

     

The genetic association between osteoprotegerin gene polymorphisms and fracture risk in Chinese Han population

This article put the genetic association exploration of osteoprotegerin (OPG) gene polymorphisms in promoter region (A-163G, T-245G) and fracture risk first and hoped to explain the ethology of fracture. The genotyping of OPG gene polymorphisms was conducted with the method of polymerase chain reaction-restriction fragment length polymorphism in 125 fracture patients and 138 relative controls. The genotype frequencies of selected controls based on OPG gene polymorphisms were checked by the χ² test whether conformed to Hardy–Weinberg equilibrium (HWE). The relative risk was represented with odds ratio (OR) and 95% confidence interval (95% CI) between gene polymorphism and disease. The linkage disequilibrium (LD) and haplotype were also analyzed. The genotypes distributions of selected controls in OPG polymorphisms conformed to HWE. The G allele of A-163G polymorphism carriers had the tendency to suffer from fracture in the same condition, compared with A allele carriers (OR = 1.63, 95% CI = 1.04–2.55). TG and TG/GG genotypes of OPG T-245G polymorphism also showed the increased risk of fracture development, but not TT genotype (OR = 2.22, 95% CI = 1.15–4.28; OR = 2.45, 95% CI = 1.28–4.68). Likely, the mutant allele G had an abnormally higher frequency in cases than controls (14.00% and 6.16%). These two polymorphisms existed the LD and the haplotype G _-163–G _-245 obviously increased the risk of fracture. OPG A-163G, T-245G polymorphisms were associated with the onset of fracture and both the independent risk factors.     

Association between circadian genes,bipolar disorders and chronotypes

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR?=?1.49 95%CI[1.18–1.88]; p?=?0.0008) and rs782931 in RORA (OR?=?1.31 95%CI[1.12–1.54]; p?=?0.0006) and BD. Then we used a “reverse phenotyping approach” to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p?=?0.04) and languid circadian type (p?=?0.01), whereas rs782931 was associated with rigid circadian type (p?=?0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.     

The role of FOXP3 rs3761548 and rs2294021 polymorphisms in pediatrics acute lymphoblastic leukemia: association with risk and response to therapy

FOXP3 X-linked gene has crucial roles in the development and function of regulatory T cells. We investigated the association of FOXP3 rs3761548, rs3761549 and rs2294021 single nucleotide polymorphisms (SNPs) with acute lymphoblastic leukemia (ALL) susceptibility and response to therapy. Genotyping was performed in 247 patients and 210 healthy subjects. We observed a higher frequency of rs3761548 A carriers and rs2294021 C carriers (p?<?0.04) in male patients, and lower frequencies of rs3761548 AC genotype (p?=?0.04) and rs2294021 CT genotype (p?=?0.01) in female patients compared to controls. ACC (p?=?0.04) and ATC haplotypes (p?=?0.002) were associated with susceptibility to ALL. There was a significant correlation between the genotypes of rs3761548 and rs2294021 SNPs with event-free survival (EFS) and overall survival (OS). The rs3761548 A genotype in male patients was associated with increased risk of relapse (p?<?0.0001), shorter EFS, increased death rate (p?=?0.002) and shorter OS compared to C genotype (p?=?0.001). Similar significant results were observed for the relation of rs2294021 C genotype with response to therapy in male patients. In females, patients with rs3761548 AC genotype had longer EFS (p?=?0.02) and those with rs2294021 CT had longer EFS and OS (p?<?0.005). According to haplotype analysis, patients carrying ACC or ATC haplotypes had the highest number of WBCs and shorter EFS or OS, and patients with CCT haplotype had the lowest number of WBCs and longer EFS or OS. These results provided evidence for the impact of these polymorphisms on susceptibility and response to therapy in children with ALL.

     

GST,CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83–2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88–2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74–3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85–2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92–3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72–10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.     

A systematic review and meta-analysis of the association of transforming growth factor β receptor I 6A/9A gene polymorphism with ovarian cancer risk

Abstract

Ovarian cancer is the leading cause of cancer-related death in women. This meta-analysis was conducted to evaluate the association of transforming growth factor β receptor I (TβR-I) 6A/9A gene polymorphism with ovarian cancer risk. The association literatures were identified from PubMed and Cochrane Library on 1 October 2013, and eligible reports were recruited and synthesized. Four reports were recruited into this meta-analysis for the association of TβR-I 6A/9A gene polymorphism with ovarian cancer risk. 6A allele and 6A/6A genotype of TβR-I were associated with the ovarian cancer risk (6A: OR?=?1.24, 95% CI: 1.02–1.51, p?=?0.03; 6A/6A: OR?=?2.30, 95% CI: 1.01–5.22, p?=?0.05). However, TβR-I 9A/9A genotype was not associated with the risk of ovarian cancer (OR?=?0.82, 95% CI: 0.66–1.02, p?=?0.08). In conclusion, TβR-I 6A allele and 6A/6A genotype are associated with the ovarian cancer risk. However, more studies should be performed to confirm this relationship in the future.     

Association of the genetic polymorphisms in immunoinflammatory microRNAs with risk of ischemic stroke and subtypes in an Iranian population

Stroke is one of the most common type of cerebrovascular disease threatening human health and life with high mortality, disability, and morbidity. Ischemic stroke (IS) is determined to be a complex disease containing a group of heterogeneous disorders with various environmental and genetic risk factors. This study evaluated the polymorphisms of microRNAs involved in inflammatory routes leading to stroke in an Iranian population. This study evaluated the associations of hsa-mir-608 C/G rs4919510, hsa-mir-499 A/G rs3746444, and hsa-mir-145 C/T rs190323149 polymorphisms in precursor miRNAs with the risk of IS. These microRNA polymorphisms were analyzed in 470 patients with IS and 489 control subjects. The TOAST criteria was applied for IS subtypes classification. The frequency of the allele G of hsa-mir-499/rs3746444 A/G revealed significant association with IS in comparison with controls ( p < 0.0001, OR = 1.838, 95% CI = 1.406–2.401). Increased IS risks were associated with hsa-mir-499/ rs3746444 A/G genotypes in diverse genetic model (homozygote comparison: p = 0.004, OR = 2.136, 95% CI = 1.269–3.597; heterozygote comparison: p = 0.029, OR = 1.373, 95% CI = 1.033–1.825). Statistical analysis in IS subtypes showed that cardio-embolic patients compared with other subtypes (large artery atherosclerosis and lacunar) had higher frequency of G allele (LAA vs. CEI, p = 0.017; LAC vs. CEI, p = 0.009), AG genotype (LAA vs. CEI, p = 0.016; LAC vs. CEI, p = 0.013). Nevertheless, this study did not find any association between the alleles and genotypes of mir-608 C/G rs4919510 SNP and IS, respectively ( p > 0.05). The current investigation provided verification that hsa-mir-499 rs3746444 A/G polymorphism may be associated with a significantly increased risk of IS in an Iranian population.