VDR Gene Polymorphisms,Interaction with Smoking and Risk of Periodontal Disease in Japanese Women: the Kyushu Okinawa Maternal and Child Health Study

Epidemiological evidence on the relationship between vitamin D receptor (VDR) polymorphisms and periodontal disease is inconsistent. We investigated associations between four VDR single‐nucleotide polymorphisms (SNPs) including rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI) and rs2228570 (FokI), and the risk of periodontal disease among young Japanese women. Cases included 131 women who had at least one tooth with a probing depth of 3.5 mm or deeper. Controls included 1019 women without periodontal disease. Adjustment was made for age, region of residence, education, toothbrushing frequency and use of an interdental brush. Compared with the AA genotype of SNP rs731236, the GG genotype had a significantly increased risk of periodontal disease: the adjusted OR was 3.68 (95% confidence interval: 1.06–12.78). There were no significant relationships between SNPs rs7975232, rs1544410 or rs2228570 and periodontal disease. None of the haplotypes were significantly related to periodontal disease. Compared with subjects with the AA or AG genotype of SNP rs731236 who had never smoked, those with the GG genotype who had ever smoked had a significantly increased risk of periodontal disease; nevertheless, neither multiplicative nor additive interaction was significant. The additive interaction between SNP rs7975232 and smoking was significant, although the multiplicative interaction was not statistically significant. No multiplicative or additive interactions were observed between the other SNPs and smoking. Our results indicated that VDR SNP rs731236 might be associated with periodontal disease. In addition, we present new evidence for a biological interaction between VDR SNP rs7975232 and smoking that affects periodontal disease.     

Estrogen receptor alpha gene (ESR1) polymorphism and its interaction with smoking and drinking contribute to susceptibility of systemic lupus erythematosus

The aim of this study is to investigate the association of estrogen receptor alpha gene (ESR1) polymorphisms, additional gene–gene, and gene–environment interaction with systemic lupus erythematosus (SLE) risk. SNPStats (available online at http://bioinfo.iconcologia.net/SNPstats) was used to investigate the Hardy–Weinberg equilibrium (HWE) in controls and association between SNP and SLE risk. Generalized multifactor dimensionality reduction (GMDR) was used to screen the interactions among SNPs and environmental risk factors; SLE risk was significantly higher in carriers of rs2234693 C allele than those with TT (TC + CC versus TT), adjusted OR (95%CI) = 1.57 (1.21–2.06), and was also higher in carriers of rs9340799 G allele than those with AA (AG + GG versus AA), adjusted OR (95%CI) = 1.68 (1.24–2.13). However, we also find no association between rs2228480 and SLE risk after covariates adjustment. We found a significant two-locus model (p = 0.0010) involving rs2234693 and smoking; the cross-validation consistency of this model was 10/10, and the testing accuracy was 62.70%. Smokers with TC or CC of rs2234693 genotype have the highest SLE risk, compared to never-smokers with TT of rs2234693 genotype, OR (95%CI) was 2.50 (1.65–3.42), after covariates adjustment for gender, age, alcohol drinking, and BMI. We found that C allele of rs2234693 and G allele of rs9340799 within ESR1 gene, their interaction between rs2234693 and current smoking were all associated with increased SLE risk.     

Associations of VCAM-1 gene polymorphisms with obesity and inflammation markers

Objective

Among the inflammatory mediators involved in the pathogenesis of obesity, cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) stand out. The aim of this study was to investigate the associations of ICAM-1 and VCAM-1 gene variants with obesity and to investigate the associations between these genetic polymorphisms and CRP, UA, and WBC count.

Method

Four SNPs of the VCAM-1 gene (rs3176860, rs2392221, rs3917010 and rs3176879) and two SNPs of the ICAM-1 gene (rs281432 and rs5498) were analyzed in 181 control (18 < BMI < 23) and 144 obese (BMI ≥ 25) subjects. The SNPs were genotyped by direct sequencing.

Results

In allele frequency analysis, the G allelic frequency of rs3176860 in the VCAM-1 gene was lower in the obese group (30.9%) than in the controls (41.2%) (P = 0.007). The C allelic frequency of rs3917010 was lower in the obese group (18.1%) than in the control (25.1%) (P = 0.03). In the haplotype analysis of VCAM-1 gene, the ht1 (ACA) was higher and ht2 (GCC) was lower in the obese subjects than in the controls (P = 0.0057 and P = 0.037, respectively). In the obese group, participants carrying the G allele of rs3176860 of the VCAM-1 gene showed a higher percentage of segmented neutrophils and CRP levels than those carrying only the A allele (P = 0.028 and P = 0.042, respectively).

Conclusions

The results of this study suggest that VCAM-1 gene variants may be related to obesity and inflammatory markers in the Korean population.

     

Interaction of MTHFR gene with smoking and alcohol use and haplotype combination susceptibility to psoriasis in Chinese population

To investigate the association of MTHFR gene polymorphism and additional gene–gene interaction with psoriasis risk. GMDR model was used to screen the best gene–smoking and gene–drinking interaction combinations. Logistic regression was performed to investigate association between two SNPs and psoriasis. For psoriasis patient-control haplotype analyses, the SHEsis online haplotype analysis software (http://analysis.bio-x.cn) was employed. We found that carriers of homozygous mutant of rs1801133 polymorphism and heterozygous of rs1801131 are associated with increased psoriasis risk than those with wild-type homozygotes, OR (95%CI) were 2.01 (1.48–2.79), and 2.08 (1.56–2.86), respectively. We also found a significant gene–environment interaction between C677T and alcohol drinking. In all samples, the haplotype 1298A-677C was observed most frequently in two groups, with 49.43 and 55.71% for the patients and controls, respectively. The results also indicated that the haplotype containing 1298C and 677T alleles were associated with a statistically increased psoriasis risk, OR (95%CI)?=?1.73 (1.12–2.46), P?=?0.0002. Our study found that rs1801133, rs1801131 within MTHFR gene, and interaction between C677T and alcohol drinking and haplotype containing the 1298C and 677T alleles were all associated with increased psoriasis risk.     

Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection

Vitamin D is known to affect pathogenesis of dengue through modulation of immune responses. Vitamin D exerts its effects through vitamin D receptor (VDR). The functioning of VDR is affected by the gene polymorphisms in the coding (rs2228570) and 3′untranslated region (UTR) (rs1544410, rs7975232 and rs731236). In the present study, VDR gene polymorphisms were investigated in 112 dengue infected patients (83 dengue fever (DF) and 29 dengue hemorrhagic fever cases (DHF)) and 105 apparently healthy controls (HCs) using polymerase chain reaction based restriction fragment length polymorphisms methods. HCs had no documented evidence of symptomatic dengue. Results revealed significantly lower frequency of ‘C’ allele of rs7975232 in all dengue patients (DEN) as compared to HCs [(P corrected (Pc) = 0.014, Odds ratio (OR) 0.51]. The frequency of C/C genotype of rs7975232 was significantly lower in DEN and DF cases compared to HCs (DEN vs. HCs: Pc = 0.0184, OR 0.24; DF cases vs. HCs: Pc = 0.028, OR 0.21). The frequency of T allele of rs2228570 in a dominant mode was significantly higher in DHF cases as compared to DF cases (P = 0.034 OR 2.58). A significantly lower frequency of the haplotype G-C-T (Pc = 0.0135) and higher frequency of the haplotype G-A-T (Pc = 0.000085) was observed in DEN and DF cases as compared to HCs. The results suggest that the 3′UTR haplotypes of VDR gene are differentially associated with risk of symptomatic dengue requiring hospitalization. The ‘T’ allele of rs2228570 polymorphism in a dominant mode of inheritance is associated with DHF.     

The <Emphasis Type="Italic">NLRP3</Emphasis> and <Emphasis Type="Italic">CASP1</Emphasis> gene polymorphisms are associated with developing of acute coronary syndrome: a case-control study

The protein products of NLRP3 and CASP1 genes are involved in the cleavage of pro-IL-1B and pro-IL-18 leading to the active cytokines, which play an important role in the development of the acute coronary syndrome (ACS). The aim of the present study was to evaluate whether NLRP3 and CASP1 gene polymorphisms are biomarkers of ACS susceptibility in Mexican population. Two polymorphisms of the CASP1 gene [G+7/in6A (rs501192) and A10370-G Exon-6 (rs580253)] and one of the NLRP3 gene [UTR′3 G37562-C (rs10754558)] were genotyped by 5′ exonuclease TaqMan assays in a group of 617 patients with ACS and 609 control individuals. Under recessive model, the CASP1 G+7/in6A polymorphism was associated with an increased risk of developing ACS when compared to healthy controls (OR = 1.76, 95% CI 1.08–2.86, P _Res  = 0.022). In the same way, under recessive model, the CASP1 A10370-G was associated with increased risk of ACS (OR = 1.75, 95% CI 1.07–2.85, P _Res  = 0.025). Moreover, under co-dominant, dominant, over-dominant, and additive models, the NLRP3 UTR′3 G37562-C was associated with a decreased risk of ACS (OR = 0.45, 95%CI 0.22–0.92, P _Co-dom  = 0.006; OR = 0.61, 95%CI 0.44–0.84, P _Dom  = 0.002; OR = 0.67, 95%CI 0.48–0.94, P _Over-dom  = 0.02; and OR = 0.65, 95%CI 0.50–0.94, P _Add  = 0.02, respectively). In summary, this study demonstrates that the G+7/in6A and A10370-G polymorphisms of the CASP1 gene are associated with increased risk of developing ACS, whereas the UTR′3 G37562-C polymorphism of the NLRP3 gene is associated with a decreased risk of developing ACS in Mexican population.     

Gene Polymorphisms of Novel Immunotolerant Molecule BTLA: Distribution of Alleles,Genotypes and Haplotypes in Polish Caucasian Population

B and T lymphocyte attenuator (BTLA) is one of the members of immunoglobulin superfamily which, like CTLA-4 and PD-1, is involved in down regulation of immune response. Despite the important role of BTLA in maintaining immune homeostasis, relatively little studies were devoted to the relationship of polymorphisms in the gene encoding BTLA with susceptibility to autoimmune disease and cancer. Moreover, all published works were done in Asian populations. BTLA gene is located on chromosome 3 in q13.2 and consists of five exons. The aim of this study was to investigate the alleles, genotypes and haplotypes frequency of selected BTLA gene polymorphisms in Caucasian population originating from Poland. For this study, the single-nucleotide polymorphisms (SNPs) were chosen on the basis of literature data. Additionally, the tag dSNP under linkage equilibrium r ² > 0.8 and available at the National Center for Biotechnology Information (NCBI) for Caucasian population of rare alleles at a frequency greater than 5 % have been chosen using the NCBI database. The ten BTLA SNPs investigated were: rs1844089, rs2705535, rs9288952, rs9288953, rs1982809, rs2633580, rs2705511, rs2705565, rs76844316, rs16859633. For all SNPs selected on the basis of literature data the significantly different distributions of genotypes between Asian and Caucasian populations were observed.     

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.     

The <Emphasis Type="Italic">PTPN22</Emphasis> R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis,while <Emphasis Type="Italic">PTPN22</Emphasis> R620W confers susceptibility to Graves’ disease in a Mexican population

Objective

The functional PTPN22 R620W polymorphism (rs2476601) is clearly associated with susceptibility to several autoimmune diseases (ADs). However, the PTPN22 R263Q polymorphism (rs33996649) has been scarcely explored in different ADs. Here we aimed to examine the associations of the PTPN22 R620W and R263Q polymorphisms with susceptibility to or protection against rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves’ disease (GD) among Mexican patients.

Methods

We conducted a case–control study including 876 patients (405 with SLE, 388 with RA, and 83 with GD) and 336 healthy control individuals. PTPN22 genotypes were determined using the TaqMan 5′ allele discrimination assay.

Results

PTPN22 R620W was associated with GD susceptibility (OR 4.3, p = 0.004), but was not associated with SLE (OR 1.8, p = 0.19). We previously demonstrated that this polymorphism is associated with RA susceptibility (OR 4.17, p = 0.00036). Moreover, PTPN22 R263Q was associated with protection against SLE (OR 0.09, p = 004) and RA (OR 0.28, p = 0.045), but was not associated with GD.

Conclusions

Our data provide the first demonstration that PTPN22 R620W confers GD susceptibility among Latin-American patients. Moreover, this is the second report documenting the association of PTPN22 R263Q with protection against SLE and RA.

     

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.     

Association of SNPs/haplotypes in promoter of TNF A and IL-10 gene together with life style factors in prostate cancer progression in Indian population

Objective

Levels of proinflammatory (TNF A) and anti-inflammatory (IL-10) cytokines play a key role in the progression of inflammation as well as cancer disease. We were investigating the potential association of single-nucleotide polymorphisms (SNPs)/haplotypes in proinflammatory (TNF A) and anti-inflammatory (IL-10) cytokines locus with the development of PCa in Indian population.

Materials and methods

We had genotyped 235 BPH/PCa samples (130 BPH and 105 cancer) along with 115 control samples for proinflammatory (TNF A ?238G/A and ?308G/A) and anti-inflammatory (IL-10 ?1082A/G, ?819C/T and ?592C/A) cytokines SNPs in the gene promoter region using ARMS-PCR method.

Results

Allelic frequencies of TNF A and IL-10 SNPs were found to be significantly associated with the risk of prostate cancer and BPH when compared to controls (p = 0.05). Further haplotypic analysis showed that two haplotypes of TNF A (AG and AA) and IL-10 gene (CCG and CTG) were serving as risk haplotypes for prostate cancer development. IL-10 risk haplotypes were found to be positively associated with aggressiveness of prostate cancer. We also noticed successively increasing percentage of TNF A and IL-10 risk haplotypes with life style habits like smoking (10 and 26%) and alcohol consuming (9 and 27%).

Conclusions

According to our data, TNF A ?238G>A and IL-10 ?1082A>G, ?819C>T and ?592C>A may be associated with the development of prostate cancer and BPH. We could also notice higher frequency of TNF A and IL-10 risk haplotypes in smoker and alcohol user. Interestingly, IL-10 risk haplotype was positively associated with aggressiveness of tumor. This information can be used for the early diagnosis of disease and to improve tissue-specific treatment’s efficacy which will be moving ultimately towards the discovery of personalized therapy.

     

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.     

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.     

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).     

Distribution of <Emphasis Type="Italic">PTPN22</Emphasis> polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 ?1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to ?1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR–RFLP technique for the PTPN22 ?1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were ?1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of ?1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10–5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D′ = 0.98 for PTPN22 ?1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among ?1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = ?0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 ?1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.     

Serum levels of P-glycoprotein and persistence of disease activity despite treatment in patients with systemic lupus erythematosus

Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.     

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.     

ApoE gene polymorphism and its relationship with coronary artery disease in ethnic Kashmiri population

Apolipoprotein E is a fundamental component of various lipoproteins and plays substantial role in cholesterol/lipid transport among cells of various tissues. The ApoE gene is polymorphic with three alleles ε2, ε3, and ε4, coding for isoforms E2, E3, and E4 having different binding inclination for corresponding receptors. This work aimed to investigate the association between ApoE gene polymorphism and coronary artery disease (CAD) in Kashmiri population. APOE genotyping was done by polymerase chain reaction-restriction fragment length polymorphism. Our study indicated ApoE ε3/ε3 to be the most common genotype in both CAD and control group. The frequency of ε2, ε3, and ε4 alleles of ApoE gene in cases was observed to be 0.06, 0.72, and 0.20, while in control subjects it was 0.075, 0.82, and 0.11, respectively. A significant difference was found between cases and controls with respect to TC, LDL, and HDL levels. Our data showed that frequency of ε4/ε4, ε4/ε3 genotype and ε4 allele was significantly higher in cases than in controls (p = 0.02, p = 0.004, p < 0.001 respectively). Moreover, the CAD patients carrying ε4 allele had significantly higher TC and LDL levels (p value <0.01). Thus our data showed a significant association of ApoE ε4 allele with the risk of CAD. The data revealed that ApoE ε4 allele is associated with increased risk of CAD and increased levels LDL and TC in Kashmiri population.     

Genome-wide association with bone mass and geometry in the Framingham Heart Study

Background

Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.

Methods

We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates ≥80%, HWE p ≥ 0.001, and MAF ≥10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.

Results

Heritability estimates for all bone phenotypes were 30–66%. LOD scores ≥3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679–58,934,236 bp) and 22 (35,890,398–48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 × 10^-6 and 2.5 × 10^-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.