An SNP in the 5'-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage

A compelling genetic association with osteoarthritis (OA) of a functional SNP (rs143383, T/C) in the 5'-UTR of the GDF5 gene was recently reported in case-control cohorts from Japan and China. GDF5 is a pro-chondrogenic growth factor. The T-allele frequency of the gene was elevated in cases, with an odds ratio (OR) of 1.79, and in vitro functional studies demonstrated that this allele mediated a moderate but significant reduction in the activity of the GDF5 promoter in several cell lines. Our initial objective was to assess whether the SNP was also associated with OA in a broad European population by genotyping the SNP in 2487 cases and 2018 age-matched controls from the UK and Spain. The T-allele was associated with OA (P = 0.03, OR = 1.10) as was carrier status for this allele (P = 0.004, OR = 1.28), demonstrating that the SNP is associated with OA in two diverse ethnic groups, Asians and Europeans. We subsequently assessed the functional effect of the SNP on GDF5 allelic expression using RNA extracted from the cartilage of OA patients who had undergone joint-replacement surgery. The associated T-allele showed up to a 27% reduction in expression relative to the C-allele (P = 0.00007), revealing that the functional effect mediated by SNP rs143383 on GDF5 expression is active in patients who have severe disease up to the point at which they require surgery. A small but persistent imbalance of GDF5 expression throughout life therefore appears to render an individual more susceptible to OA.     

Rs143383 in the Growth Differentiation Factor 5 (GDF5) Gene Significantly Associated with Osteoarthritis (OA)-A Comprehensive Meta-analysis

Family, twin, adoption studies show osteoarthritis (OA) has a substantial genetic component. Several studies have shown an association between OA and Growth Differentiation Factor 5 (GDF5), some others have not. Thus, the status of the OA-GDF5 association is uncertain. This meta-analysis was applied to case-control studies of the association between OA and GDF5 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. Relevant studies were identified from the following electronic databases: MEDLINE and current contents before Feb. 2012.For the case-control studies, the authors found 1) support for the association between OA and GDF5. The rs143383 polymorphism was significantly associated with OA [fixed: OR and 95%CI: 1.193 (1.139-1.249), p<0.001; random: OR and 95%CI: 1.204 (1.135-1.276), p<0.001], 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. Although the effect size of the association between OA and GDF5 is small, there is suggestive evidence for an association. Further studies are needed to clarify what variant of GDF5 (or some nearby gene) accounts for this association.     

Meta-analysis of association between the ASPN D-repeat and osteoarthritis

Osteoarthritis (OA) is the most common form of human arthritis. Genetic factors have been implicated in OA. It was reported that an aspartic acid (D)-repeat polymorphism in the gene encoding asporin (ASPN) was associated with OA of knee and hip joints in Japanese; in the three independent studies performed, the D14 allele of the ASPN polymorphism was over-represented and the D13 allele was under-represented. Subsequently, four replication studies, three in Europeans and one in Chinese populations, have been reported; however, they showed inconsistent results. To evaluate between-study heterogeneity and to estimate the common genetic effect of the D-repeat polymorphism on OA, we performed a meta-analysis of the five reports that include seven association studies, using the DerSimonian-Laird procedure. We detected association between knee OA and the susceptible D14 allele [P = 0.003, summary odds ratio (OR) = 1.46] with significant heterogeneity (P = 0.047) among the studies. We also detected positive association between knee OA and the protective D13 allele (P = 0.026, summary OR = 0.84) with significant heterogeneity (P = 0.040) among the studies. Because of significant heterogeneity, we stratified the studies by ethnicity. We detected positive association between knee OA and the D14 allele (P = 0.0000013, summary OR = 1.95) with non-significant heterogeneity (P = 0.535) in Asian populations. In hip OA, significant heterogeneity was identified and there was no positive association for any allele in any comparison. The present results suggest that the association of the ASPN D14 allele and knee OA has global relevance, but that its effect has ethnic differences.     

Lack of association of single nucleotide polymorphism in LRCH1 with knee osteoarthritis susceptibility

A genetic association of knee osteoarthritis (OA) and a C/T transition single nucleotide polymorphism (SNP) (rs912428) located in intron 1 of the LRCH1 gene has recently been reported in European Caucasians; however, the results are inconsistent. Our objective was to evaluate the association in different knee OA populations. Three case-control association studies were conducted in Han Chinese, Japanese, and Greek Caucasian populations. The LRCH1 SNP was genotyped in patients who had primary symptomatic knee OA with radiographic confirmation and in matched controls, and the association was examined. We performed a meta-analysis for the studies together with results of two previous papers using the DerSimonian–Laird procedure and calculated the power of the pooled studies by the software R. A total of 1,145 OA patients and 1,266 controls were genotyped. No significant difference was detected in genotype or allele frequencies between knee OA and control groups in the three populations (all P > 0.05). Association was not observed even after stratification by gender and Kellgren/Lawrence (K/L) scores. Meta-analysis also supported the lack of association between LRCH1 and knee OA. The strong heterogeneity between original and replication studies was detected in Caucasian populations. However, a tendency for the increase of TT genotype was observed in the European populations (OR = 1.46, P = 0.06). The powers for European and Asian replication studies were less than 0.8. Our results suggest that there is no association between LRCH1 and knee OA. However, lack of association should be concluded by further replication studies. Qing Jiang and Dongquan Shi contributed equally to this work.     

Associations of the 5‐hydroxytryptamine (serotonin) Receptor 1B gene (HTR1B) with alcohol,cocaine, and heroin abuse

Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5‐hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5‐HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta‐analysis based on the available genotype data from individual candidate gene‐based association studies. Evidence of association was found between the functional SNP ?161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio (OR) = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP ?261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non‐Europeans (e.g., P = 0.0018 with OR = 1.42 (1.14, 1.76) and P = 0.01 with ORs = 0.5 (0.3, 0.85), respectively). This meta‐analysis supports the associations of HTR1B ?261T>G and ?161A>T with alcohol and drug abuse and further investigations are warranted in larger samples. © 2013 Wiley Periodicals, Inc.     

Pooled analyses of the associations of polymorphisms in the GRK4 and EMILIN1 genes with hypertension risk

Background: The GRK4 and EMILIN1 genes have been suggested to be involved in the development of hypertension. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the associations of polymorphisms in the GRK4 and EMILIN1 genes with hypertension risk.Methods: Published literature from PubMed and Embase databases were retrieved. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model.Results: Five studies for polymorphisms in the GRK4 gene and five studies for polymorphisms in the EMILIN1 gene were identified. The results suggested that rs1801058 polymorphism in the GRK4 gene was inversely associated with hypertension among East Asians (TT vs. CC: OR=0.39, 95%CI 0.28-0.55) and positively associated with hypertension among Europeans (TT vs. CC: OR= 2.38, 95%CI 1.38-4.10). Rs2960306 polymorphism in the GRK4 gene was significantly associated with hypertension among Europeans (TT vs. GG: OR=1.92, 95%CI 1.13-3.27). The significant associations were also observed for rs2011616 and rs2304682 polymorphisms in the EMILIN1 gene among Japanese (rs2011616: AA vs. GG: OR=0.38, 95%CI 0.18-0.82; rs2304682: GG vs. CC: OR=0.37, 95%CI 0.17-0.81) but not among Chinese.Conclusions: This meta-analysis suggested that rs1801058 polymorphism in the GRK4 gene was associated with hypertension in East Asians and Europeans. The significant association was also found for rs2960306 polymorphism in the GRK4 gene among Europeans. In addition, there were significant associations of rs2011616 and rs2304682 polymorphisms in the EMILIN1gene with hypertension among Japanese.     

Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp). Recently, the minor allele of a single-nucleotide polymorphism (SNP) at nucleotide position 1858 (rs2476601, +1858C > T) was found to be associated with type 1 diabetes. However, the degree of the association is variable among ethnic populations, suggesting the presence of other disease-associated variants in PTPN22. To examine this possibility, we carried out a systemic search for PTPN22 using direct sequencing of PCR-amplified products in the Japanese population. Association and linkage studies were also conducted in 1,690 Japanese samples, 180 Korean samples, and 472 Caucasian samples from 95 nuclear families. We identified five novel SNPs, but not the +1858C > T SNP. Of these two frequent SNPs, -1123G > C, and +2740C > T were in strong linkage disequilibrium (LD), and the -1123G > C promoter SNP was associated with acute-onset but not slow-onset type 1 diabetes in the Japanese population (odds ratio [OR] = 1.42, 95% CI = 1.07-1.89, P = 0.015). This association was observed also in Korean patients with type 1 diabetes (Mantel-Haenszel chi2= 6.543, P = 0.0105, combined OR = 1.41 95% CI = 1.09-1.82). Furthermore, the affected family-based control (AFBAC) association test and the transmission disequilibrium analysis of multiplex families of European descent from the British Diabetes Association (BDA) Warren Repository indicated that the association was stronger in -1123G > C compared to +1858C > T. In conclusion, the type 1 diabetes association with PTPN22 is confirmed, but it cannot be attributed solely to the +1858C > T variant. The promoter -1123G > C SNP is a more likely causative variant in PTPN22.     

Replication of the association of the aspartic acid repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese

A genetic association of osteoarthritis (OA) and functional polymorphisms in the aspartic acid (D) repeat of the asporin gene was reported in Japanese and European Caucasians; however, the results were controversial. Our objective was to evaluate whether the D repeat polymorphism was associated with knee OA in Han Chinese. The D repeat polymorphism was genotyped in 218 patients who suffered from primary symptomatic knee OA with radiographic confirmation and in 454 age-matched controls, and the allelic association of the repeat was examined. Frequencies of the D13 and D14 alleles were similar to those of Japanese, but different from those of European Caucasians. The D14 allele was significantly over-represented in knee OA patients (P=0.0013; odds ratio 2.04; 95% confidence interval 1.32–3.15). D14 was more frequent in early-onset patients than in late-onset patients (P=0.043) and the age at onset in patients with D14 was earlier (P=0.028; log-rank test). Thus, the association of the D14 allele with knee OA susceptibility was replicated in Han Chinese. This was the first instance that association of the OA susceptibility gene was definitely replicated between different ethnic groups.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Here, we report on a case–control association study of 178 SLE patients and 899 control subjects, using genome-wide gene-based single nucleotide polymorphism (SNP) markers. An SNP, rs3130342, in a 5’ flanking region of the TNXB gene revealed a significant association with SLE [P = 0.000000930, odds ratio (OR) 3.11, with 95% confidence interval (95%CI) of 1.89–5.28] in a Japanese population. This association was replicated independently with 203 cases and 294 controls (P = 0.0440, OR 1.52, with 95%CI of 1.01–2.78). Although a copy number variation (CNV) of the C4 gene adjacent to the TNXB gene was reported to be associated with SLE, our analysis on this CNV revealed that the association of CNV of the C4 gene was weaker than the SNP in the TNXB gene and likely to reflect the linkage disequilibrium between C4 CNV and this particular SNP. Stratified analysis also revealed that the association of SNP rs3130342 with SLE was independent of the HLA-DRB1*1501 allele that has been shown to be associated with SLE. Our findings strongly imply that the TNXB gene is a candidate gene susceptible to SLE in the Japanese population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous conditionwith unknown etiology and is considered to be the most commonendocrine disorder in women of reproductive age. Two meta-analysesare presented here concerning the association of PlasminogenActivator Inhibitor 1 (PAI-1) 4G/5G polymorphism and the methylene-tetrahydrofolatereductase (MTHFR) C677T polymorphism with the risk of developingPCOS. Seven studies were included concerning PAI-1 (1538 cases,710 controls) and six studies concerning MTHFR C677T (223 cases,392 controls). Overall, a significant association was foundfor PAI-1, with the odds ratio (OR) for 4G carriers versus 5Ghomozygotes being equal to 1.600 (95% CI 1.052, 2.434) withstrong evidence for dominant inheritance. There was howevera large between-studies variability (I² = 67.3%). No evidencewas found for association of MTHFR C677T polymorphism with PCOS(OR for the TT+CT versus CC comparison equal to 0.940 with 95%CI 0.561, 1.575). No evidence of publication bias was foundin these meta-analyses. PAI-1 4G/5G polymorphism seems to beassociated with the risk of developing PCOS. Further studiesare needed in order to investigate the etiologic mechanism behindthis association, as well as the interrelations with other componentsof the metabolic syndrome (hypertension, diabetes, etc.).     

A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus

To more precisely estimate the association between interferon regulatory factor 5 (IRF5) polymorphisms and systemic lupus erythematosus (SLE) risk, we surveyed studies on the association of IRF5 rs2204640, rs10954213, rs729302 or rs2280714 with SLE using PubMed, Embase and Web of Science up to February 2011. Two investigators independently assessed the data quality and extracted the data. A total of 17 comparisons from ten relevant studies involving 6403 patients and 7475 controls were included to analyse the association between IRF5 rs2004640 and SLE risk (odds ratio, OR = 1.41, 95% confidence interval (CI) 1.34-1.49, P = 0.000). As for rs10954213, there were ten comparisons from six relevant studies involving 3461 patients and 3692 controls were included to analyse the association between IRF5 rs10954213 and SLE risk (OR = 1.23, 95% CI 1.08-1.39, P = 0.002). And this meta-analysis also showed a significant association of rs729302 (OR = 0.78, 95% CI 0.74-0.83, P = 0.000), rs2280714 (OR = 0.90, 95% CI 0.83-0.98, P = 0.021) with SLE. In a subgroup analysis by ethnicity, significantly increased SLE risk was associated with IRF5 rs2004640 T allele in populations of European, Asian and Latin American origin, and the rs10954213 A allele is significantly associated with SLE in European origin but not in Asian origin. This meta-analysis suggested that IRF5 gene polymorphism was associated with SLE in multiple ethnic populations.     

Molecular analysis of estrogen receptor alpha gene AGATA haplotype and SNP12 in European populations: potential protective effect for cryptorchidism and lack of association with male infertility

BACKGROUND: A specific haplotype (AGATA) in the estrogen receptor alpha (ER1) gene was recently described as a new risk factor for cryptorchidism in the Japanese population. In this ethnic group, single-nucleotide polymorphism 12 (SNP12) was concluded to be the tag SNP for the AGATA haplotype. MATERIALS AND METHODS: A large group of patients (total number=335) and controls (total number=567) of two Caucasian populations were analysed for the AGATA haplotype and SNP12 to verify whether this genetic variant and its tag SNP were associated with cryptorchidism or with severe spermatogenic failure. RESULTS: We confirm that SNP12 is the tag SNP for the AGATA haplotype also in Caucasians. However, in contrast with the Japanese population we found a protective effect for ESR1 SNP12 on cryptorchidism in the Italian population. No association between SNP12 and severe spermatogenic disturbances was observed. CONCLUSIONS: The observed associations (although with opposite effect) with cryptorchidism encourage future studies on independent cases and controls from different ethnic and geographic origins. On the other hand, in contrast with other ESR1 polymorphisms, SNP12 polymorphism is not associated with severe male factor infertility in two independent European population.     

ZNF804A and schizophrenia susceptibility in Asian populations

ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N?=?21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P?=?0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520?kb) identified no association except for SNP rs359895 (P?=?7.8?×?10(-5) , N?=?5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P?=?0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations. ? 2012 Wiley Periodicals, Inc.     

ABCC5 Transporter is a Novel Type 2 Diabetes Susceptibility Gene in European and African American Populations

Numerous functional studies have implicated PARL in relation to type 2 diabetes (T2D). We hypothesised that conflicting human association studies may be due to neighbouring causal variants being in linkage disequilibrium (LD) with PARL. We conducted a comprehensive candidate gene study of the extended LD genomic region that includes PARL and transporter ABCC5 using three data sets (two European and one African American), in relation to healthy glycaemic variation, visceral fat accumulation and T2D disease. We observed no evidence for previously reported T2D association with Val262Leu or PARL using array and fine‐map genomic and expression data. By contrast, we observed strong evidence of T2D association with ABCC5 (intron 26) for European and African American samples (P = 3E?07) and with ABCC5 adipose expression in Europeans [odds ratio (OR) = 3.8, P = 2E?04]. The genomic location estimate for the ABCC5 functional variant, associated with all phenotypes and expression data (P = 1E?11), was identical for all samples (at Chr3q 185,136 kb B36), indicating that the risk variant is an expression quantitative trait locus (eQTL) with increased expression conferring risk of disease. That the association with T2D is observed in populations of disparate ancestry suggests the variant is a ubiquitous risk factor for T2D.     

Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort

To examine the genetics of susceptibility to primary biliary cirrhosis (PBC), genome-wide association studies GWAS have been performed in patients of European ancestry and have shown the significant associations of IL12-related pathways, SPIB, IRF5-TNPO3, and 17q12-21. We tested whether these findings could be extended to a Japanese cohort, 303 Japanese PBC and 298 controls. We failed to detect significant associations at IL12A (rs574808, rs1075498) and IL12RB2 (rs3790567). There was no genetic variance at IRF5-TNPO3 (rs10488631) in Japanese. A single nucleotide polymorphism (SNP) at SPIB (rs3745516) reached nominal significance, but the corrected P value did not reach significance. For the 17q12-21 region, two SNPs had nominally significant associations [GSDMB (rs2305480, P = 0.022) and ZPBP2 (rs11557467, P = 0.021)] and we noted a significant P value at a SNP in IKZF3 (rs939327, P = 0.0024, P(c) = 0.017) after correction for multiple comparisons. Thus, these results indicate a haplotype on 17q12-21 with a similar association in Japanese and European PBC.     

High-resolution SNP map of ASPN, a susceptibility gene for osteoarthritis

Osteoarthritis (OA) is a very common bone and joint disease characterized by breakdown of cartilage in the joint. We recently found that an aspartic-acid repeat polymorphism of the asporin gene (ASPN) on chromosome 9 is associated with susceptibility to OA in Japanese. We provide here a high-resolution single nucleotide polymorphism (SNP) map within a 33.4-kb genomic region containing ASPN. A total of 19 SNPs were isolated from the region by systematic screening using 48 Japanese patients with OA: 7 SNPs in the 5 flanking region, 8 in introns, and 4 in the 3 untranslated region. Nine SNPs were novel. This high-resolution SNP map will be a useful resource for analyzing genes associated with OA and other bone and joint diseases.     

Arg462Gln and Asp541Glu polymorphisms in ribonuclease L and prostate cancer risk: a meta-analysis

Objective

The association between ribonuclease L (RNASEL) gene polymorphisms and prostate cancer risk has been widely reported, but the results of these studies remained controversial and underpowered. We performed a meta-analysis of 28 studies to evaluate the association between Arg462Gln and Asp541Glu polymorphisms in the RNASEL gene and prostate cancer risk.

Methods

Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between RNASEL polymorphisms and prostate cancer risk.

Results

A significantly increased prostate cancer risk was found for the Arg462Gln polymorphism in Africans (Gln/Gln vs Arg/Arg: OR = 2.50, 95%CI = 1.28-4.87; Gln/Gln vs Gln/Arg + Arg/Arg: OR = 2.54, 95%CI = 1.30-4.95), but not in Europeans and Asians. Additionally, the Asp541Glu polymorphism was associated with increased total prostate cancer risk (Glu-allele vs Asp-allele: OR = 1.04, 95%CI = 1.01-1.07; Glu/Glu vs Asp/Asp: OR = 1.22, 95%CI = 1.03-1.46; Glu/Glu vs Glu/Asp + Asp/Asp: OR = 1.09, 95%CI = 1.02-1.16). In the stratified analysis for the Asp541Glu polymorphism, there was a significantly increased prostate cancer risk in Africans and Europeans, and in hospital-based prostate cancer cases.

Conclusion

The meta-analysis results showed evidence that RNASEL Arg462Gln and Asp541Glu polymorphisms are associated with prostate cancer risk and could be low-penetrance prostate cancer susceptibility biomarkers.     

Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis

Objective

The aim of this study was to determine whether phox homology domain containing serine/threonine kinase (PXK) and tyrosine kinase 2 (TYK2) confer susceptibility to systemic lupus erythematosus (SLE).

Materials and methods

The authors conducted meta-analyses on associations between SLE susceptibility and the rs6445975 polymorphism of PXK and the rs2304256, rs12720270, rs280519, and rs1272036 polymorphisms of TYK2.

Results

A total of 13 separate comparisons studies were included in this meta-analysis. Meta-analysis identified an association between SLE and the 2 allele of the rs6445975 polymorphism in the overall population [odds ratio (OR)?=?1.151, 95?% confidence interval (CI)?=?1.086–1.291, P?=?1.8E?06]. Stratification by ethnicity identified a significant association between this polymorphism and SLE in Europeans (OR?=?1.198, 95?% CI?=?1.118–1.285, P?=?3.4E?07), but not in Asians. Meta-analysis identified a significant negative association between SLE and the 2 allele of the rs2304256 polymorphism in the overall population (OR?=?0.808, 95?% CI?=?0.659–0.990, P?=?0.040), and a significant negative association was found in Europeans, but not in Asians.

Conclusions

This meta-analysis shows that the rs6445975 polymorphism of PXK and the rs2304256 polymorphism of TYK2 are associated with the development of SLE in Europeans.     

Association of PTPN22 C1858T polymorphism and type 1 diabetes: a meta-analysis

Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identified as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a fixed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859～2.041, P < 0.001). After stratification by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was significantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852~2.045, P < 0.001; OR = 1.946, 95% CI = 1.690~2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations.     

Association of cyclin D1 G870A polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2

BACKGROUND: Many studies have shown that a polymorphism (G870A) in cyclinD1 (CCND1) is associated with carcinogenesis in a variety ofcancers. Our aim was to determine if an association exists betweenthe CCND1 G870A polymorphism and uterine leiomyoma in Koreanwomen. METHODS: Blood samples of 331 cases and 204 controls aged 47.4 ±7.6 and 46.8 ± 10.4 years (mean ± SD), respectively,were collected. CCND1 genotyping was determined by PCR and restrictionfragment length polymorphism. RESULTS: Allelic frequencies of cases (A, 0.53; G, 0.47) were not significantlydifferent from those of controls (A, 0.49; G, 0.51) (P = 0.22).After adjustment for menarche age and BMI, multivariate logisticregression analysis showed that the AA genotype was not associatedwith increased risk for uterine leiomyoma [odds ratio (OR) =1.38, 95% confidence interval (CI); 0.85–2.26, P = 0.19].However, in stratification analysis of cases and controls withBMI >25 kg/m², allelic frequencies of cases (A, 0.56; G,0.44) were significantly different from controls (A, 0.36; G,0.64) (P = 0.005), and the AA genotype was associated with increasedrisk for uterine leiomyoma (OR = 3.61, 95% CI; 1.02–12.73,P = 0.046). Furthermore, the OR for AA compared with combinedGG and AG genotypes was 3.16 (95% CI 1.01–9.92, P = 0.048). CONCLUSIONS: The A allele and AA genotype of CCND1 G870A polymorphism havea significant association with an increased risk of the uterineleiomyoma in obese Korean women.