CGG Haplotype Research Articles

Association Study of CACNA1D, KCNJ11, KCNQ1, and CACNA1E Single-Nucleotide Polymorphisms with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in CACNA1D, KCNQ1, KCNJ11, and CACNA1E genes and the increased probability of developing T2DM. In this work, we performed a case-control study in 301 Mexican adults, including 201 cases with diabetes and 100 controls without diabetes. Our findings indicate a moderate association between T2DM and the C allele, and the C/C genotype of rs312480 within CACNA1D. The CAG haplotype surprisingly showed a protective effect, whereas the CAC and CGG haplotypes have a strong association with T2DM. The C allele and C/C genotype of rs5219 were significantly associated with diabetes. Also, an association was observed between diabetes and the A allele and the A/A genotype of rs3753737 and rs175338 in CACNA1E. The TGG and CGA haplotypes were also found to be significantly associated. The findings of this study indicate that the SNPs examined could serve as a potential diagnostic tool and contribute to the susceptibility of the Mexican population to this disease.

Association of IL-10–592 C > A /-1082 A > G and the TNFα -308 G > A with susceptibility to COVID-19 and clinical outcomes

BackgroundVariation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and − 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome.MethodsGenotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt.ResultsA significant association between the − 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the − 1082. The − 592 /-1082 CG and the − 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with − 592, while positive association was observed with − 1082. Higher D-dimer levels were strongly associated with the − 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes.ConclusionIL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients.

Single Nucleotide Variants in the TLR1, TLR2 and TLR6 Genes: A Case-Control Study in a Colombian Population.

Single nucleotide variants in toll-like receptor genes play a crucial role in leprosy susceptibility or resistance. With an epidemiology case-control study, associations between SNVs rs5743618 in TLR1, rs5743708 in TLR2, and rs5743810 in TLR6 and overall susceptibility for leprosy were estimated in 114 cases and 456 controls. Following that, stratified analysis was performed. DNA was extracted from peripheral blood. Genotyping was performed using predesigned TaqMan probes. The A/G genotype of rs5743810 behaved as a protective factor for the development of leprosy in the codominant (OR= 0.37; 95% CI = 016-0.86, p = 0.049) and over-dominant (OR = 0.38; 95% CI = 0.16-0.88, p = 0.019) inheritance models. The A/G and A/A genotypes behaved as a protective factor (OR = 0.39; 95% CI = 0.17-0.87, p = 0.016) in the dominant model. The SNVs rs5743618 and rs5743708 showed no association with any of the models. The CGG haplotype (rs5743618-rs5743708-rs5743810) behaved as a susceptibility factor for developing leprosy (OR = 1.86; 95% CI = 1.11-3.10, p = 0.019). The latter haplotype behaved as a susceptibility factor for leprosy development in women (OR = 2.39; 95% CI = 1.21-4.82, p = 0.013). The identified variants in the genes encoding TLRs, specifically rs5743810 in TLR6 and CGG (rs5743618-rs5743708-rs5743810) haplotypes, may somehow explain leprosy susceptibility in the studied population in a leprosy endemic region in Colombia.

Adiponectin Gene Polymorphisms and Possible Susceptibility to Metabolic Syndrome among the Sudanese Population: A Case-Control Study.

There is a significant difference in genotypic frequencies of the rs266729, rs2241766, and rs1501299 SNPs and allele frequencies (P < 0.05) between the MetS patients and non-MetS group. MetS patients had a significantly higher serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) in the GG genotype of rs2241766 (P < 0.05). Additionally; the TT genotype of rs1501299 had higher SBP, serum TG, TC, and LDL-C (P < 0.05). Multivariate logistic regression analysis showed hypertension, hyperglycemia, BMI, WC, serum TG, ADIPOQ rs2241766 (TG allele), and ADIPOQ rs1501299 (GT allele) had independently predicted the incidence of metabolic syndrome in the Sudanese population. The three investigated SNPs of ADIPOQ were in a moderate linkage disequilibrium (LD) connection according to the LD measures (D' = 0.54, 0.62, and 0.69, respectively). The CTT, CGG, and GTG haplotypes, which consist of three alleles of -11377C > G, +45T > G, and +276G > T, were shown to report 1.788-, 1.622,- and 1.641-fold risks toward MetS susceptibility in Sudanese's population, respectively. Along with clinical and biochemical signs, the ADIPOQ gene's genetic variants (rs266729, rs2241766, and rs1501299), CTT, CGG, and GTG haplotypes are connected to the MetS risk among the Sudanese population.

The association between abusive supervision and anxiety in female employees is stronger in carriers of the CRHR1 TAT haplotype

• In the general working population men report less anxiety than women. • The score of anxiety is associated with the exposure to abusive supervision. • Anxiety induced by abusive supervision is influenced by the CRHR1 genotype. • CRHR1 TAT/TAT in women increases the risk of anxiety induced by abusive supervision. Previous findings suggest that exposure to social stress in the form of abusive supervision may increase the risk of anxiety disorders. In the present study, we examined the link between abusive supervision, the CRHR1 genotype and anxiety. The data was collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1225 individuals returned both the questionnaire and the saliva kit. Abusive supervision was assessed with 5 items from the Tepper's “Abusive Supervision Scale”. Anxiety was measured by 5 items of the “Hopkins Symptom checklist”. Genotyping with regard to CRHR1 rs7209436 C/T, rs110402 G/A and rs242924 G/T was carried out using Taqman assay, and Phase v.2.1.1 was used to define the CRHR1 haplotype TAT versus CGG. The analyses revealed that abusive supervision was associated with anxiety. In particular, we observed a strong effect of abusive supervision on anxiety in female TAT/TAT carriers ( p = 0.000). Moreover, using TAT/TAT as a reference, TAT/CGG and CGG/CGG both showed protective effects ( p = 0.015, p = 0.001, respectively). Thus, the association between abusive supervision and anxiety was strong among female TAT/TAT carriers was stronger than among female TAT/CGG and female CGG/CGG carriers. No such gene-environment interaction was seen in men. Our data demonstrated that the CRHR1 TAT haplotype may exacerbate, whereas the CRHR1 CGG haplotype may reduce, the effect of abusive supervision on anxiety in female employees. Hence, the present study supports the theory that both gender and the CRHR1 genotype, moderate the responses to social stressors.

Association of the MYH6 Gene Polymorphism with the Risk of Atrial Fibrillation and Warfarin Anticoagulation Therapy.

Objective: To study the associations of single nucleotide polymorphisms (SNP) of the myosin heavy chain 6 (MYH6) gene with the risk of atrial fibrillation (AF) and warfarin anticoagulation therapy. Methods: Sanger sequencing was employed to analyze the genotypes of the MYH6 gene's rs28730771, rs365990, and rs2277473 loci in 243 AF patients and 243 non-AF patients (control group) selected according to the age and sex of AF patients at a 1:1 ratio. A multiple logistic regression analysis was used to analyze the risk factors in AF. SHEsis was adopted to analyze the association between rs28730771, rs365990, rs2277473 haplotypes and susceptibility to AF. The average weekly doses of warfarin administered to AF patients with different genotypes were compared. Results: The T allele at rs28730771 of the MYH6 gene (odds ratio [OR] = 2.82, 95% confidence interval [CI]: 1.73-4.59, p < 0.01), the G allele at rs365990 (OR = 1.65, 95% CI: 1.22-2.24, p < 0.01) and the T allele at rs2277473 (OR = 1.91, 95% CI: 1.25-2.91, p < 0.01) were significantly associated with an elevated risk of AF. The results of a logistic regression analysis demonstrated that hypertension, smoking, drinking, family history of stroke, as well as the genotypes at the rs28730771, rs365990, and rs2277473 loci were all risk factors in AF (p < 0.05). The CAG haplotype for the three SNPs was associated with a reduced risk of AF susceptibility (OR = 0.61, 95% CI: 0.46-0.81, p < 0.01), and the CGG haplotype was related to an increased risk of AF (OR = 1.49, 95% CI: 1.07-2.06, p = 0.02). The doses of warfarin used in AF patients with different genotypes at the MYH6 rs28730771, rs365990, and rs2277473 loci were significantly different (p < 0.05). Conclusion: The three SNPs (rs28730771, rs365990, and rs2277473) of the MYH6 gene loci were significantly associated with the risk of AF susceptibility and the dose of warfarin anticoagulant therapy.

Relationship between onset of eclampsia and AGTR1 gene polymorphisms.

We aimed to study the correlations of angiotensin II receptor type 1 (AGTR1) gene polymorphisms with the occurrence and development of eclampsia. A total of 200 pregnant women with eclampsia admitted to our hospital from January 1, 2017 to September 30, 2019 were collected as observation group and 200 normal pregnant women during the same period were recruited in the control group. Genome sequencing was performed to detect the AGTR1 gene polymorphisms in the two groups. Expression level of AGTR1 in both groups was detected. The influences of AGTR1 on clinical data of pregnant women with eclampsia were analyzed. There were no significant differences in age (p=0.545), height (p=0.738), weight (p=0.695) and hypertension (p=0.372) between observation group and control group. However, significant differences were found in the distributions of alleles at AGTR1 rs1799870 (p=0.002) and AGTR1 rs52936049 (p=0.047) between groups. The frequencies of T allele at rs1799870 and rs52936044 in observation group were higher than those in the control group. In addition, the distributions of AGTR1 gene genotypes at rs1799870 (p=0.012), rs144520513 (p=0.008) and rs529360494 (p p =0.036) in observation group differed from those in control group. Observation group had higher frequencies of TT genotype at rs1799870, GG genotype at rs144520513 and TG genotype at rs529360494 than those in control group. Besides, the frequency of CGG haplotype (p=0.008) of AGTR1 gene in observation group was notably lower than that in the control group, while the frequency of TGT haplotype (p=0.012) of AGTR1 gene in the former was remarkably higher than that in the latter. Moreover, the linkage disequilibrium between rs529360494 and rs144520513 of AGTR1 gene was relatively high (D'=0.623). AGTR1 gene polymorphism rs529360494 showed an evident relationship with the expression of AGTR1 gene, and the expression of AGTR1 in pregnant women with eclampsia who carried TG genotype was markedly reduced (p<0.05). Furthermore, AGTR1 gene polymorphism rs1799870 was associated with prothrombin time (PT) in pregnant women with eclampsia (p=0.046), and PT in those carrying genotype TC was shorter. Rs144520513 was related to the levels of triglyceride (TG) (p<0.001) and low-density lipoprotein (LDL) (p<0.001) in pregnant women with eclampsia, and TG and LDL levels were significantly lower. AGTR1 gene polymorphisms are closely associated with the onset and progression of eclampsia.

Transforming Growth Factor Beta Receptor 3 Haplotypes in Sickle Cell Disease Are Associated with Lipid Profile and Clinical Manifestations.

Individuals with sickle cell disease (SCD) present both chronic and acute inflammatory events. The TGF-β pathway is known to play a role in immune response, angiogenesis, inflammation, hematopoiesis, vascular inflammation, and cell proliferation. Polymorphisms in the transforming growth factor-beta receptor 3 (TGFBR3) gene have been linked to several inflammatory diseases. This study investigated associations between two TGFBR3 haplotypes and classical laboratory parameters, as well as clinical manifestations, in SCD. We found that individuals with the GG haplotype presented higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, non-HDL cholesterol, total proteins, and globulin than individuals with non-GG haplotypes. In addition, the GG haplotype was associated with a previous history of pneumonia. Individuals with the CGG haplotype presented increased plateletcrit, TC, LDL-C levels, and non-HDL cholesterol. The CCG haplotype was also associated with a previous history of pneumonia. Our findings suggest that individuals with the GG and CGG haplotypes of TGFBR3 present important alterations in lipid profile.

IGF2BP2 polymorphisms as genetic biomarkers for either schizophrenia or type 2 diabetes mellitus: A case-control study

The link between schizophrenia (SCZ) and type 2 diabetes mellitus (T2DM) has been known for many years. Recent investigations suggested the contribution of insulin resistance to both disorders. Hence, the present investigation is aimed to determine the possible link between three IGF2BP2 polymorphisms and the susceptibility to either SCZ or T2DM in the Iranian population. In this case-control study, 878 subjects were recruited. Genotyping of rs1470579, rs4402960, and rs11705701 polymorphisms was performed using the tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS–PCR) method. We found a significant link between dominant and recessive inheritance patterns of the two intronic IGF2BP2 variants (rs1470579, rs11705701) and SCZ or T2DM (P < .05). Strong linkage disequilibrium (LD) was noticed between rs1470579 vs. rs11705701 variants. We found that AGA, AGG, ATA, and CTG haplotypes were more frequent in patients with T2DM as compared with controls (P < .001). Regarding the CGG and CTA haplotypes, significant differences were found with 4.3 and 3.5 fold increase in SCZ patients compared to controls (P < .001). Besides, interactions between these variants influenced T2DM or SCZ susceptibility. These results recommend that rs11705701 and rs1470579 gene polymorphisms are associated to either SCZ or T2DM. Haplotypes of IGF2BP2 non-coding SNPs and their interactions may influence susceptibility to both diseases. Examining the co-existence of the disorders in different ethnicities with a larger population is encouraged for further investigations.

Association of polymorphisms in MALAT1 with the risk of endometrial cancer in Southern Chinese women.

BackgroundEndometrial cancer is the most common gynecologic malignancy worldwide. Polymorphisms in MALAT1 have been demonstrated to play critical roles in cancer. However, the roles of MALAT1 polymorphisms in the etiology of endometrial cancer have not been well documented.MethodsWe genotyped three MALAT1 polymorphisms in 249 endometrial cancer cases and 446 cancer‐free female controls using quantitative polymerase chain reaction with TaqMan probes. To estimate the association between MALAT1 polymorphisms (rs591291 C>T, rs664589 C>G, and rs4102217 G>C) and the risk of endometrial cancer, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) and the 95% confidence interval (CI), adjusting for surgery history, menopause, number of deliveries, BMI, and FIGO stage.ResultsWe found that the MALAT1 rs664589 C>G polymorphism was significantly associated with endometrial cancer risk (heterogeneous: adjusted OR = 0.57, 95% CI = 0.34‐0.93, P = .026; homogenous: adjusted OR = 3.74, 95% CI = 1.12‐12.45, P = .032; and recessive: adjusted OR = 4.06, 95% CI = 1.22‐13.48, P = .022). Stratified analysis further demonstrated that the MALAT1 rs664589 C>G polymorphism significantly increased the risk of endometrial cancer susceptibility in patients with no history of surgery, more deliveries, BMI between 25 and 29.9, and FIGO stages II‐III. Compared with the wild‐type GCG haplotype carriers, individuals with CGG haplotypes had a higher risk of developing endometrial cancer.ConclusionThe MALAT1 rs664589 C>G polymorphism was associated with a significant increase in endometrial cancer risk.

Relationship between CYP1B1 polymorphisms (c.142C > G, c.355G > T, c.1294C > G) and lung cancer risk in Polish smokers.

To determine whether three of CYP1B1 single nucleotide polymorphisms, c.142C>G, c.355G>T and c.1294C>G are associated with a lung cancer risk. A total of112 lung cancer patients and 100 controls were genotyped using the RFLP-PCR. In the c.142C>G polymorphisms, G allele was more frequent in lung cancer patients than in controls (p<0.001), while in the c.1294C>G polymorphisms, C allele was more frequent in lung cancer patients, than in controls (p=0.012). In the c.355G>T polymorphism, the distribution of alleles in both analyzed groups was similar. The GTC haplotype turned out to be correlated with the increased lung cancer risk, compared with the most common CGG haplotype (OR: 2.38; p=0.001). CYP1B1 gene polymorphisms appear to influence lung cancer susceptibility.

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms with Psoriasis Vulgaris: A Case-Control Study in Turkish Population.

Psoriasis is a common, chronic, and autoimmune skin disease in which dysregulation of immune cells, particularly T cells, is thought to play an important role in the pathogenesis. Cytotoxic T lymphocyte antigen-4 (CTLA-4) expressed only on activated T cells is an immunoregulatory molecule and plays a role in the pathogenesis of autoimmune disorders. We aimed to determine whether CTLA-4 gene polymorphisms are associated with development and/or clinical features of psoriasis vulgaris (Pv). Genotyping of SNPs (−318C>T, +49A>G, and CT60A>G) in CTLA-4 gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 103 Pv patients and 102 controls. No statistically significant associations were detected in any of the investigated genetic models for the −318C>T polymorphism. The genotype distributions of +49A>G and CT60A>G were associated with Pv development. In haplotype analysis, while frequency of CAA haplotype was significantly higher in the control group, frequencies of CGG and CAG haplotype were significantly higher among the patients. However, all of CTLA-4 polymorphisms and haplotypes do not have an effect on severity and onset age of Pv. In conclusion, the +49A>G and CT60A>G polymorphisms may be risk factors for Pv development. Furthermore, CGG and CAG haplotypes may contribute to Pv development, while CAA haplotype may be protective against Pv.

Genetic Polymorphisms ofIL1B, IL6,andTNFαin a Chinese Han Population with Pulmonary Tuberculosis

Background The factors that predispose to pulmonary tuberculosis (PTB) are not fully understood. Previous studies have shown that cytokine gene polymorphisms were associated with PTB. Objectives In this study, we have investigated the relationship between ILB, IL6, and TNFα polymorphisms and a predisposition to Mycobacterium tuberculosis (MTB) infection and PTB. Methods A total of 209 cases of PTB, 201 subjects with latent TB infection (LTBI), and 204 healthy controls (HCS) were included in this study. Logistic regression analyses under allelic, homozygous, and heterozygous models were used to calculate P values, odds ratios (ORs), and 95% confidence intervals (CIs) for assessing the association between single nucleotide polymorphisms (SNPs) and disease risk, adjusting for sex and age. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. Results When comparing PTB patients with LTBI subjects, significant associations with disease development were observed for SNPs of IL6 and TNFα. When comparing LTBI subjects with HCS, IL1B polymorphisms were significantly associated with LIBI. Haplotype analyses suggested that the CGG haplotype of IL1B was associated with an increased risk of PTB (P = 0.039, OR = 1.34, 95% CI: 1.01–1.76), while the TTGCG haplotype of TNFα was a protective factor against PTB (P = 0.039, OR = 0.66, 95% CI: 0.44–0.98). Conclusion Our study demonstrated that IL1B variants were related to LTBI and IL6 and TNFα variants were associated with PTB.

Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells

BackgroundGenome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094.MethodsWe used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies.ResultsThe ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver.ConclusionsOur results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.

Variant of the clock circadian regulator (CLOCK) gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population.

Circadian rhythm disruptions can cause various health disorders. The present study evaluated associations between single nucleotide polymorphisms in the core circadian gene clock circadian regulator (CLOCK) and the prevalence of type 2 diabetes (T2D) in the Japanese population. Cross-sectional data were analyzed from 2485 subjects (1243 men, 1242 women; age 35-69 years) enrolled in the baseline surveys of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Associations between three CLOCK gene polymorphisms (rs1801260, rs3736544, and rs4864548) and the prevalence of obesity (body mass index [BMI] ≥25 kg/m(2) ), overweight (BMI ≥23 kg/m(2) ), and T2D were evaluated by logistic regression analyses; haplotype analysis and stratified analyses for the prevalence of diabetes were also conducted. Compared with those who were homozygous for the respective major alleles, subjects with the rs1801260 minor allele C had a significantly higher odds ratio (1.5; 95% confidence interval 1.1-2.1) for the prevalence of diabetes after adjustment for potential confounding factors, including BMI. When stratified by overweight, the associations between rs1801260 and the prevalence of diabetes were marked and significant in non-overweight subjects, but not in overweight subjects. The TGA (rs1801260-rs3736544-rs4864548) haplotype was associated with a lower prevalence of diabetes, whereas the CGG haplotype was associated with a higher prevalence of diabetes. Variant of the CLOCK gene and related haplotypes are associated with the prevalence of T2D in the Japanese population, in which obesity is less common, and the association between CLOCK gene variant at rs1801260 and the prevalence of diabetes is enhanced in normal-weight subjects.

The ADAM33 S2 polymorphism is associated with susceptibility to pediatric asthma in the Chinese Han population.

The disintegrin and metalloprotease domain containing protein 33 (ADAM33) is a novel susceptibility gene for asthma and airway hyperresponsiveness, particularly in the Asian population. We investigated the influence of ADAM33 polymorphisms on the serum levels of ADAM33 and the susceptibility to pediatric asthma in the Chinese Han population. Polymerase chain reaction-restriction fragment length polymorphism analysis was employed to study the genotypic distribution of F+1, T1, and S2 in ADAM33 in a cohort of 120 pediatric asthma patients and 105 healthy controls. The serum levels of secreted ADAM33 protein were measured in all the study subjects using the enzyme-linked immunosorbent assay (ELISA). This case-control study showed that the distribution of F+1 and T1 genotypes of ADAM33 was not significantly different between pediatric asthma patients and healthy controls (p > 0.05); however, the genotype and allele frequencies of the S2 polymorphism were significantly different between asthmatic patients and healthy controls (both p < 0.05). In addition, the frequency of CGC and CGG haplotypes exhibited statistically significant differences, with lower CGC and higher CGG frequencies found in the case group compared to the control group. Finally, in comparison to healthy controls, the serum levels of ADAM33 protein were significantly lower in patients carrying the S2 polymorphism. Our results provide evidence that the ADAM33 S2 polymorphism is associated with increased susceptibility to pediatric asthma and that the CGG haplotype for the F+1, T1, and S2 polymorphisms is associated with an elevated risk of pediatric asthma in the Han population, whereas the CGC haplotype appears to confer a protective effect. Our results may prove useful for population-based screening to affect early intervention.

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.

Is there any relationship between polymorphism of Heat Shock Protein 70 genes and Pemphigus foliaceus?

The human Heat Shock Proteins (HSP70) family plays a key role in up-regulating stress responses. Some studies reported possible associations of single nucleotide polymorphisms in the HSP70 genes with some autoimmune diseases. However, whether HSP70 polymorphisms represent a risk factor for pemphigus foliaceus (PF) is still unkown.We analyzed by PCR-RFLP polymorphisms of HSP70 genes HSA1A, HSPA1B and HSPA1L in 80 Tunisian patients with PF, 160 matched healthy controls and 147 related healthy subjects.There were significant differences between PF patients and controls in the allelic (pc=5.91×10−12, pc=1.14×10−5 and pc=0.0089, respectively) and homozygous genotypic frequencies of HSPA1L>T, HSPA1A>C and HSPA1B>G (p=2.617×10−12, p=1.017×10−5 and p=0.0058, respectively). Haplotype analysis showed significant differences between PF patients and controls: the CCA, CGA, CCG and CGG haplotypes were significantly over-represented in controls whereas the TCG haplotype was significantly over-represented in patients. However, the significant LD found between the HSP70 and the HLA class II susceptibility alleles together with the multivariant regression analysis data between the two loci could argue against a direct role of the HSP70 polymorphism in the occurrence of PF.

PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile.

Type 1 diabetes (T1D) has a complex etiology in which genetic and environmental factors are involved, whose interactions have not yet been completely clarified. In this context, the role in PD-1 pathway and its ligands 1 and 2 (PD-L1 and PD-L2) have been proposed as candidates in several autoimmune diseases. The aim of this work was to determine the allele and haplotype frequency of six gene polymorphisms of PD-ligands (PD-L1 and PD-L2) in Chilean T1D patients and their effect on serum levels of PD-L1 and autoantibody profile (GAD65 and IA2). This study cohort comprised 205 T1D patients and 205 normal children. We performed genotypic analysis of PD-L1 and PD-L2 genes by TaqMan method. Determination of anti-GAD65 and anti-IA-2 autoantibodies was performed by ELISA. The PD-L1 serum levels were measured. The allelic distribution of PD-L1 variants (rs2297137 and rs4143815) showed differences between T1D patients and controls (p = 0.035 and p = 0.022, respectively). No differences were detected among the PD-L2 polymorphisms, and only the rs16923189 showed genetic variation. T1D patients showed decreased serum levels of PD-L1 compared to controls: 1.42 [0.23-7.45] ng/mL versus 3.35 [0.49-5.89] ng/mL (p < 0.025). In addition, the CGG haplotype in PD-L1 associated with T1D (constructed from rs822342, rs2297137 and rs4143815 polymorphisms) showed an OR = 1.44 [1.08 to 1.93]. Finally, no association of these genetic variants was observed with serum concentrations of PD ligands or auto-antibody profile, although a correlation between PD-L1 ligand serum concentration and the age at disease onset was detected. Two polymorphism of PD-L1 are presented in different allelic variants between T1D and healthy subjects, also PDL-1 serum levels are significantly lowered in diabetics patients. Moreover, the age of onset of the disease determine differences between serum ligand levels in diabetics, being lower in younger. These results points to a possible establishment of PDL-1 as a genetic and biochemical marker for T1D onset, at least in Chilean population.

Equivocal Association of RAD51 Polymorphisms with Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population

To study the contribution of genetic variation in RAD51 to risk of esophageal squamous cell carcinoma (ESCC). Three single nucleotide polymorphisms (SNPs) in RAD51 (rs1801320, rs4144242 and rs4417527) were genotyped in 316 ESCC patients and 316 healthy controls in Anyang area of China using PCR- RFLP (polymerase chain reaction-restriction fragment length polymorphism). Demographic variables between cases and controls were statistically compared by T test and Chi-square test. Hardy-Weinberg equilibrium was evaluated by the Chi-square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure any association with ESCC. Haplotype frequencies were estimated by Phase 2.1. The genotype frequencies of rs1801320, rs4144242 and rs4417527 in patients with ESCC demonstrated no significant differences from those in control group (P>0.05). When the haplotypes of these three SNPs were constructed and their relationships with ESCC risk investigated, however, CGG was observed to increase the risk (P=0.020, OR=2. 289). There was no association between the three SNPs of RAD51 and ESCC susceptibility in our Chinese population. However, the CGG haplotype might be a risk factor.