Determination of the Relationship Between rs4986790 and rs4986791 Variants of TLR4 Gene and Lung Cancer

Chronic inflammation triggers DNA damage and oncogenic mutations and causes tumor formation and tumor progression. One of the important components of the inflammatory response is Toll-like receptor (TLR) family. The objective of our study is to determine the relationship between rs4986790(+896A/G) and rs4986791(+1196C/T) gene polymorphisms and lung cancer risk. PCR-RFLP technique was carried out to identify the genotypes in 100 control individuals and 160 lung cancer patients. DNA extracted from peripheral blood samples were amplified and digested with NcoI and HinfI then visualized. We did not find any difference between genotype frequencies between controls and patients (p?>?0.05) in rs4986790. But a significant difference between control group and patients with lung cancer as for genotype frequencies (χ ²?=?4.19, p?=?0.041) in rs4986791 variants was found. Our data indicate that any correlation was not found between rs4986790 polymorphism and lung cancer, while a correlation between rs4986791 and lung cancer has been determined and found to be associated with lung cancer risk.     

Interleukin-28B TT genotype is frequently found in patients with hepatitis C virus cirrhosis but does not influence hepatocarcinogenesis

Persistent hepatitis C virus (HCV) infection is associated with progressive hepatic fibrosis and ultimately hepatocellular carcinoma. The interleukin-28B (IL28B) rs12979860 polymorphism is associated with fibrosis progression in chronic HCV infection. IL28B encodes interferon-λ, which has both antiviral and anti-proliferative properties. This study aimed to determine whether IL28B rs12979860 polymorphism is also associated with development of hepatocellular carcinoma both in chronic HCV infection and in non-viral-related cirrhosis. Real-time polymerase chain reaction and melting curve analyses were used to genotype 311 patients who underwent liver transplantation for HCV cirrhosis (n = 202) or alcoholic cirrhosis (n = 109). HCV patients were older (p = 0.012) and less likely males (p < 0.001) than patients with alcoholic cirrhosis. IL28B rs12979860 TT genotype [OR 6.08, 95 % CI 2.11–17.53; p < 0.001] and T allele carriage (CT + TT; OR 2.3, CI 95 % 1.42–3.72; p = 0.001) were more frequent among HCV patients and, among them, more common in patients infected with HCV genotype 1 (CT + TT; OR 1.79, CI 95 % 1.03–3.09; p = 0.009). Incidence of hepatocellular carcinoma was higher in HCV cirrhosis (OR 2.7, CI 95 % 1.5–4.7; p < 0.001), with no differences according to HCV genotype. IL28B genotype distribution was similar among patients with or without hepatocellular carcinoma, in both HCV patients regardless viral genotype (p = 0.84) and alcoholic patients (p = 0.91). Multivariate analysis showed that older age (OR 1.06, CI 95 % 1.02–1.1; p = 0.003) and male gender (OR 2.49, CI 95 % 1.24–5; p = 0.01) were independent risk factors for hepatocellular carcinoma in HCV patients. In summary, the current study did not find a significant association between IL28B rs12979860 polymorphism and hepatocarcinogenesis.     

Relationship between transforming growth factor-β1 and type 2 diabetic nephropathy risk in Chinese population

Background

Diabetes mellitus (DM) is divided into four different etiological categories: type 1 DM (T1DM), type 2 DM (T2DM), other specific types, and gestational DM. One severe complication of T2DM is type 2 diabetic nephropathy (T2DN). The possible association of serum transforming growth factor-β1 (TGF-β1) levels and the TGF-β1 T869C gene polymorphism with patient susceptibility to T2DN in Chinese population is unclear at present. This study was conducted to assess these relationships in Chinese population by a meta-analysis.

Methods

Association reports were searched and pulled from the Cochrane Library, the China Biological Medicine Database (CBM), and PubMed on March 1, 2018, and eligible studies were selected and used for calculations. The results were expressed as weighted mean differences (MD) for continuous data. Odds ratios (OR) were used to express the results for dichotomous data. Additionally, 95% confidence intervals (CI) were calculated.

Results

Forty-eight reports for the relationship between serum TGF-β1 levels and the risk of T2DN and 13 studies on the association of the TGF-β1 T869C gene polymorphism with susceptibility to T2DN in Chinese population were retrieved from this study. Serum TGF-β1 levels in the T2DM group were higher than those in the normal control group (MD?=?17.30, 95% CI: 12.69–21.92, P?<?0.00001). The serum TGF-β1 level in the T2DN group was significantly higher than that in the normal control group (MD?=?70.03, 95% CI: 60.81–79.26, P?< 0.00001;). The serum TGF-β1 level in the T2DN group was significantly higher than that in the T2DM group (MD?=?56.18, 95% CI: 46.96–65.39, P?< 0.00001). Serum TGF-β1 levels in T2DM patients with microalbuminuria were increased when compared with those in T2DM patients with normoalbuminuria. Furthermore, serum TGF-β1 levels in T2DM patients with macroalbuminuria were increased when compared with those in T2DM patients with microalbuminuria. The TGF-β1 T allele, TT allele and CC genotype were associated with T2DN susceptibility in Chinese population (T: OR?=?0.74, 95% CI: 0.59–0.92, P?=?0.007; TT: OR?=?0.55, 95% CI: 0.31–0.96, P?=?0.04; CC: OR?=?1.38, 95% CI: 1.14–1.67, P?=?0.001).

Conclusions

High levels of TGF-β1 are associated with susceptibility to T2DM, T2DN and the progression of proteinuria in T2DN patients in Chinese population. Further, the TGF-β1 T allele, and TT genotype were protective factors against the onset of T2DN and CC genotype was a risk factor for the susceptibility of T2DN in Chinese populations.

     

Polymorphism rs547984 on human chromosome 1q43 is not associated with primary open angle glaucoma in a Saudi cohort

Background

To investigate the association between polymorphism rs547984, located in close proximity to the Zona Pellucida Glycoprotein 4 (ZP4) gene on human chromosome 1q43 and primary open angle glaucoma (POAG).

Method

Polymorphism rs547984 was genotyped using Taq-Man® assay in 185 subjects comprising of 90 unrelated POAG cases and 95 controls of Saudi origin.

Results

Association analysis between cases and controls revealed no significant genotype distribution under additive (p = 0.356), dominant (p = 0.517) and recessive (p = 0.309) models. Besides, the allele frequency distribution was also found to be non-significant (p = 0.70). The minor “A” allele frequency was found to be 0.49 and 0.50 among POAG cases and controls, respectively. In addition, specific clinical indices used to assess severity of glaucoma such as intraocular pressure (IOP), cup/disc ratio and number of anti-glaucoma medication also did not show any significant genotype distribution in POAG cases.

Conclusion

Polymorphism rs547984 is neither associated with any clinical indices important for POAG such as IOP and cup/disc ratio nor is a risk factor for POAG in the Saudi cohort.

     

Individualized significance of the −251 A/T single nucleotide polymorphism of interleukin-8 in severe infections

Based on the concept of the individualized nature of sepsis, we investigated the significance of the ?251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n?=?146), community-acquired pneumonia (CAP, n?=?109), intra-abdominal infections (IAI, n?=?119), and primary bacteremia (BSI, n?=?105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8.     

Polymorphism rs7555523 in <Emphasis Type="Italic">transmembrane and coiled-coil domain 1</Emphasis> (<Emphasis Type="Italic">TMCO1</Emphasis>) is not a risk factor for primary open angle glaucoma in a Saudi cohort

Background

We investigated whether polymorphism rs7555523 (A?>?C) in human transmembrane and coiled-coil domain 1 (TMCO1) gene is a risk factor for primary open angle glaucoma (POAG) in a Saudi cohort.

Methods

A cohort of 87 unrelated POAG cases and 94 control subjects from Saudi Arabia were genotyped using Taq-Man® assay. The association of genotypes with POAG and other glaucoma specific clinical indices was investigated.

Results

The genotype and allele frequency of polymorphism rs7555523 at TMCO1 did not show any statistically significant association with POAG as compared to controls. The minor allele frequency was 0.103 in cases and 0.085 in controls. Except for awareness of glaucoma (p?=?0.036), no significant association of genotypes were seen with glaucoma specific clinical indices such as intraocular pressure (IOP), cup/disc ratio and number of anti-glaucoma medications used. Binary logistic regression analysis (adjusted for age and gender) showed that age was a significant indicator for the development of glaucoma in this group (adjusted odds ratio?=?1.2; 95 % confidence interval?=?1.078–1.157; p?<?0.001).

Conclusion

Our study was unable to replicate the findings of previously reported association for polymorphism rs7555523 in TMCO1 with POAG and related clinical indices such as IOP and cup/disc ratio indicating that this variant is not a risk factor for POAG in the Saudi cohort.

     

The relationship between polymorphism of four serotonic genes (<Emphasis Type="Italic">5-HTTL, 5-HT1A, 5-HT2A</Emphasis>, and <Emphasis Type="Italic">MAOA</Emphasis>) and personality traits in wrestlers and control group

The molecular genetic analysis of serotonin system genes (5-HTTL, 5-HT1A, 5-HT2A, and MAOA) in male and female wrestlers and in a control group has been performed. Comparative population genetics analysis of the 5-HTTL gene showed the highest frequency of the SS genotype 5-HTTLPR in athletes (p = 0.04), as well as a trend to higher frequencies of united genotypes of the locus 5-HTTLPR VNTR and SNP rs25531—S _A S _A (p = 0.06) compared to the control group. As for the markers of 5-HT1A (rs6295), 5-HT2A (rs6311), and MAOA (VNTR), we found no significant differences between the groups tested. Using an NEO PI-R questionnaire, possible correlations between the genotypes and psychological traits were analyzed in the studied samples. It was demonstrated that the athletic achievements of upper-tier athletes are associated with their lower openness to experience and higher conscientiousness. It was revealed that the factors of gender and 5-HT1A genotype should influence the self-rating for openness to experience. Furthermore, a combined effect of the level of sports achievements and 5-HT2A genotypes was found, as well as gender and 5-HT1A genotypes, on the self-rating for conscientiousness.     

Polymorphisms in DNA repair genes and breast cancer risk in Russian population: a case–control study

Genetic variation in DNA repair genes can alter an individual’s capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians.     

Tumor necrosis factor gene polymorphisms are associated with systemic lupus erythematosus susceptibility or lupus nephritis in Mexican patients

The TNF -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms have consistently been associated with systemic lupus erythematosus (SLE) in several populations; however, these findings have not been verified in all populations. Here, we aimed to examine whether the TNF -238G/A, -308G/A, -376G/A (rs1800750), and -1031T/C (rs1799964) polymorphisms confer SLE or lupus nephritis (LN) susceptibility in a Mexican population. Our study included 442 patients with SLE and 495 controls. For genotyping, we used the TaqMan 5′ allele discrimination assay. The TNF -238G/A and -1031T/C polymorphisms were associated with SLE susceptibility (odds ratio (OR) 2.1, p?=?0.0005 and OR 1.4, p?=?0.003, respectively). Gender stratification showed a strong association between TNF -238G/A and SLE in women (OR 2.2, p?=?0.00006), while TNF -1031T/C had an OR of 1.5 (p?=?0.007). With regard to the TNF -376G/A polymorphism, this also showed association with SLE susceptibility (OR 1.95, p?=?0.036) and LN (OR 3.5, p?=?0.01). In conclusion, our study provides the first demonstration of association between the TNF -376G/A polymorphism and SLE and LN susceptibility. In addition, our study is the second documenting an association of TNF -1031T/C with SLE susceptibility. We also observed a strong association between TNF -238G/A and SLE susceptibility. The TNF 308G/A polymorphism was not associated with SLE or LN.     

Association of genetic variants in the promoter region of genes encoding p22phox (<Emphasis Type="Italic">CYBA</Emphasis>) and glutamate cysteine ligase catalytic subunit (<Emphasis Type="Italic">GCLC</Emphasis>) and renal disease in patients with type 1 diabetes mellitus

Background

Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O₂^?- (-675 T → A in CYBA, unregistered) and in glutathione metabolism (-129 C → T in GCLC [rs17883901] and -65 T → C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients.

Methods

401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m² (n = 136) and were genotyped.

Results

No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068).

Conclusions

The functional SNPs CYBA -675 T → A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.

     

Emerging Role of SIGIRR rs7396562(T/G) Polymorphism in Systemic Lupus Erythematosus in a Chinese Population

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with heterogeneous presentation. The aim of this study was to examine the association of a single-nucleotide polymorphism, rs7396562, of the interferon induced with single immunoglobulin IL-1-related receptor (SIGIRR) gene with SLE in a Chinese population. A total of 741 SLE patients and 731 healthy control subjects were enrolled in the present study. The genotyping of polymorphism (rs7396562) was determined by TaqMan allele discrimination assay on the 7,300 real-time polymerase chain reaction system. The frequency of T allele for rs7396562 in patients was significantly higher than in controls (T versus G, OR?=?1.318, 95 % confidence interval (CI)?=?1.139–1.525, P?P?versus GG, P?=?0.002; TT versus TG?+?GG, P?=?0.002). We also analyzed the association of the SIGIRR rs7396562 T allele with clinical features; luckily, photosensitivity and malar rash had some significant signal with the SNP. In conclusion, our study represents the first report demonstrating an association of the SIGIRR rs7396562 polymorphism with SLE susceptibility in a Chinese population.     

Lack of association between polymorphism rs540782 and primary open angle glaucoma in Saudi patients

Background

To investigate whether polymorphism rs540782 on chromsome 1, in close proximity to the Zona Pellucida Glycoprotein 4 (ZP4) gene, is a risk factor for primary open angle glaucoma (POAG).

Method

The study genotyped 92 unrelated POAG cases and 95 control subjects from Saudi Arabia using Taq-Man® assay.

Results

The genotype frequency distribution did not deviate significantly from the Hardy-Weinberg equilibrium (p?>?0.05). Overall, both the genotype and allele frequencies were not significantly different between cases and controls. The minor ‘C’ allele frequency was 49.4%, which was comparable to the Japanese population and higher than the Indian and Afro-Caribbean populations. Similarly, no significant association was found between genotypes and systemic diseases and health awareness/behavior domain variables. Importantly, glaucoma specific indices, such as intraocular pressure, cup/disc ratio and number of anti-glaucoma medication, also showed no statistically significant effect of genotypes within POAG cases.

Conclusion

Polymorphism rs540782 is not a risk factor for POAG in the Saudi cohort.

     

Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients

Objectives

The study investigated the association between plasma homocysteine, folate and vitamin B12 with 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TYMS 2R → 3R) and methionine synthase (MTR A2756G) polymorphisms and methotrexate (MTX) treatment and toxicity in Tunisian Rheumatoid arthritis (RA) patients.

Methods

A total of 185 patients with RA were included. Homocysteine (Hcy) was assessed by fluorescence polarization immunoassay, and folate and vitamin B12 were measured by chemiluminescence immunoassays. The genetic polymorphisms were analyzed by PCR or PCR-RFLP. Hyperhomocysteinemia (HHC) was considered for Hcy?>?15 µmol/L.

Results

MTHFR C677T polymorphism was associated with HHC in RA patients (multi-adjusted OR, 95% CI 2.18, [1.07–4.57]; p?=?0.031). No association was detected with the remaining polymorphisms. Plasma Hcy, folate, and vitamin B12 did not differ according to each polymorphism, or with MTX treatment or toxicity. However, HHC was more prevalent in patients with than those without MTX toxicity (32.7 vs. 16.7%; p?=?0.035).

Conclusions

The MTHFR 677TT genotype is an independent risk factor for HHC in Tunisians RA patients. HHC could be a useful marker of MTX toxicity in RA patients.

     

Low density lipoprotein receptor-related protein 5 gene polymorphisms and osteoporosis in Thai menopausal women

Background

Osteoporosis, characterized by low bone mineral density (BMD) and high bone fracture risk, is prevalent in Thai menopausal women. Genetic factors are known to play a key role in BMD. Low density lipoprotein receptor-related protein 5 (LRP5), a co-receptor in the Wnt/beta-catenin pathway, is involved in many aspects of bone biology. As coding single nucleotide polymorphisms (cSNPs) of LRP5, including A1330V (rs3736228), and Asian-related Q89R (rs41494349) and N740N (rs2306862), are associated with lowered BMD, this study aimed to determine the relationship between these LRP5 polymorphisms and BMD in 277 Thai menopausal women.

Results

Only rs3736228 deviated from the Hardy–Weinberg equilibrium of allele frequency (p = 0.022). The median, range and p value for the BMD related to each SNP parameter were compared (Mann–Whitney U test). Significant differences were observed between wild-type and risk alleles for both rs3736228 (total radial, p = 0.011; and radial 33, p = 0.001) and rs2306862 (radial 33: p = 0.015) SNPs, with no significant difference for rs41494349 SNP. Linkage disequilibrium was strong for both rs3736228 and rs2306862 SNPs. Haplotype analysis identified high CC frequency in both normal and osteopenia/osteoporosis groups, with a significant odds ratio for carrying the TT haplotype; however, this was non-significant after adjusting for age. Multivariate binary logistic regression analysis performed for rs3736228 showed that individuals with a body mass index <25 kg/m² had an increased risk of osteoporosis for each decade, but the polymorphism had no effect.

Conclusions

This study did not identify LRP5 polymorphisms as a risk factor for osteoporosis in Thai menopausal women. Further studies with larger sample sizes are needed to further clarify the role of LRP5 as a genetic determinant of osteoporosis.

     

The effects of <Emphasis Type="Italic">SP110</Emphasis>’s associated genes on fresh cavitary pulmonary tuberculosis in Han Chinese population

SP110 is a promising anti-Mycobacterium tuberculosis (MTB) gene. To investigate the effects of SP110 and its associated genes, i.e., MYBBP1A and RELA, on pathological progression of MTB infection, an association study with 424 patients of fresh pulmonary tuberculosis (PTB) and 424 healthy controls was performed. Moreover, classification and regression tree and multifactor dimensionality reduction were employed to explore the effects of gene–gene interactions on cavitary PTB. The results indicated that both the heterozygous genotype GC and homozygous genotype CC in rs3809849 had significant effects on the risk of PTB (OR 1.42, 95 % CI 1.06–1.92, p 0.019; OR 1.55, 95 % CI 1.04–2.33, p = 0.033, respectively), and heterozygous genotype CT in rs9061 also had similar effects (OR 1.43, 95 % CI 1.07–1.90, p = 0.014). The rs3809849 and rs9905742 in MYBBP1A were also significantly associated with cavitary PTB (p = 0.00046 and 0.039, respectively), while rs9061 in SP110 had no such association (p = 0.06931) except its significant association with non-cavitary PTB (p = 0.0093). The interaction of MYBBP1A and RELA had significant effect on cavitary PTB (OR 4.24, 95 % CI 1.44–12.49, p = 0.005). These suggest that MYBBP1A instead of SP110 may be a genetic risk factor for cavitary PTB and play important effects on its whole progress.     

Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C

Single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 genes are prognostic factors of treatment response in chronic hepatitis C (CHC). Iron overload, frequently diagnosed in CHC, is associated with unfavorable disease course and a risk of carcinogenesis. Its etiology and relationship with the immune response in CHC are not fully explained. Our aim was to determine whether IFNL polymorphisms in CHC patients associate with body iron indices, and whether they are linked with hepatic expression of genes involved in iron homeostasis and IFN signaling. For 192 CHC patients, four SNPs within IFNL3-IFNL4 region (rs12979860, rs368234815, rs8099917, rs12980275) were genotyped. In 185 liver biopsies, histopathological analyses were performed. Expression of five mRNAs and three long non-coding RNAs (lncRNAs) was determined with qRT-PCR in 105 liver samples. Rs12979860 TT or rs8099917 GG genotypes as well as markers of serum and hepatocyte iron overload associated with higher activity of gamma-glutamyl transpeptidase and liver steatosis. The presence of two minor alleles in any of the tested SNPs predisposed to abnormally high serum iron concentration and correlated with higher hepatic expression of lncRNA NRIR. On the other hand, homozygosity in any major allele associated with higher viral load. Patients bearing rs12979860 CC genotype had lower hepatic expression of hepcidin (HAMP; P = 0.03). HAMP mRNA level positively correlated with serum iron indices and degree of hepatocyte iron deposits. IFNL polymorphisms influence regulatory pathways of cellular response to IFN and affect body iron balance in chronic hepatitis C virus infection.     

<Emphasis Type="Italic">HIF-1A</Emphasis> gene polymorphisms and its protein level in patients with rheumatoid arthritis: a case–control study

Objectives

The aim of the study was to identify HIF-1A genetic variants and their possible association with HIF-1α, VEGF, KDR, RORc and Foxp3 protein levels, and susceptibility to and severity of RA.

Methods

The HIF-1A gene polymorphisms were genotyped for 587 RA patients and 341 healthy individuals. The HIF-1α, VEGF, KDR, RORc and Foxp3serum levels were evaluated.

Results

Under the codominant model, the frequency of the rs12434438 GG genotype was lower in RA patients than in controls (P?=?0.02). Under the recessive model (AA?+?AG vs GG), the association was also significant (OR 3.32; CI 1.19–9.24; P?=?0.02). Overall, rs12434438 A/G and rs1951795 A/C are in almost completed linkage disequilibrium with D′?=?0.96 and r²?=?0.85. The HIF-1A rs1951795 A allele was associated with rheumatoid factor (P?=?0.02) and mean value of erythrocyte sedimentation rate (ESR) (P?=?0.05). In RA patients with HIF-1A rs12434439 GG genotype, the parameters of disease activity such as DAS-28, VAS score, Larsen score or HAQ score were lower compared to RA patients with the HIF-1A rs12434439 AA genotype. Moreover, we also observed that Foxp3 serum levels were higher, and RORc2 serum levels were lower in RA patients with rs12434439 GG.

Conclusion

The polymorphic HIF-1A rs12434439 GG genotype may play a protective role for RA development.

     

Association of Uncoupling Protein 1 (<Emphasis Type="Italic">UCP1</Emphasis>) gene polymorphism with obesity: a case-control study

Background

Obesity is one of the main causes of morbidity and mortality worldwide. More than 120 genes have been shown to be associated with obesity related phenotypes. The aim of this study was to determine the effect of selected genetic polymorphisms in Uncoupling protein 1 (UCP1) and Niemann-Pick C1 (NPC1) genes in an obese population in Saudi Arabia.

Methods

The genotypes of rs1800592, rs10011540 and rs3811791 (UCP1 gene) and rs1805081 and rs1805082 (NPC1 gene) were determined in a total of 492 subjects using TaqMan chemistry by Real-time PCR. In addition, capillary sequencing assay was performed to identify two specific polymorphisms viz., rs45539933 (exon 2) and rs2270565 (exon 5) of UCP1 gene.

Results

A significant association of UCP1 polymorphisms rs1800592 [OR, 1.52 (1.10–2.08); p?=?0.009] was observed in the obese cohort after adjusting with age, sex and type 2 diabetes. Further BMI based stratification revealed that this association was inconsistent with both moderate and extreme obese cohort. A significant association of UCP1 polymorphisms rs3811791 was observed only in the moderate-obese cohort [OR?=?2.89 (1.33–6.25); p?=?0.007] but not in the extreme-obese cohort indicating an overlying genetic complexity between moderate-obesity and extreme-obesity. The risk allele frequencies, which were higher in moderate-obese cohort, had abnormal HDL, LDL and triglyceride levels.

Conclusion

The rs1800592 and rs3811791 of UCP1 gene are associated with obesity in general and in the moderate-obese group in particular. The associated UCP1 polymorphisms in the moderate-obese group may regulate the impaired energy metabolism which plays a significant role in the initial stages of obesity.

     

Polymorphisms in inflammation-related genes and the risk of primary varicose veins in ethnic Russians

Inflammation was shown to be activated in varicose veins, although its role in the development of vein wall transformation remains inconclusive. We aimed to investigate the influence of 13 inflammation-related single nucleotide polymorphisms (SNPs) TNF rs1800629 and rs3093661, IL1A rs1800587, IL1RN rs4251961, IL6 rs1800795 and rs1800796, IFNG rs2430561, IL10 rs1800896, TGFB1 rs1800469, HIF1A rs11549465, NFKB1 rs28362491, and rs4648068 on the risk of primary varicose veins (PVVs) in ethnic Russians. We genotyped 709 patients with PVVs and 278 individuals without a history of chronic venous disease and performed a single SNP and a haplotype analysis. Several associations with P?<?0.05 were revealed in our study. Variant allele HIF1A rs11549465 T, TNF rs3093661 A, and NFKB1 rs28362491 ATTG deletion showed the reverse association with PVV risk, and allele IL6 rs1800795 C was associated with the increased risk of the studied pathology. Haplotype analysis revealed associations of TNF haplotypes rs3093661 A-rs1800629 G and IL6 rs1800795 C-rs1800796 G with the decreased and the increased risk of PVVs, correspondingly. However, all the observed associations failed to reach statistical significance after the correction for multiple testing, which was set at a level of 10^?3 due to many tests performed. Our study therefore provides evidence that investigated polymorphisms do not play a major role in susceptibility to PVVs.