The polymorphism of Knops blood group system in Korean population and their relationship with HLA system

The main purpose of this report is to provide baseline gene frequencies of Knops blood group in the complement receptor 1 gene (CR1) in Korean population. In addition, possible relationship between the CR1 polymorphism and HLA specificities were studied, because the two systems had principal importance in immunity. CR1, which contains Knops antigens, was investigated by PCR-direct sequencing from 238 cord blood from Koreans. HLA data was archived from the enrolled cord blood units. Among the 7 SNPs, only 4843 (for KCAM antigen) and 4223 (for Yk^a) nucleotide positions showed polymorphism. The genotype frequencies of KCAM were A/A (62.2%), A/G (33.2%), and G/G (4.6%); Yk^a were C/C (29.4%), C/T (50%), and T/T (20.6%). KCAM (A/A) associated with HLA-DRB1^∗13 (p = 0.003, P_c = 0.0513); KCAM (G/G) with HLA-A^∗30 (p < 0.001, P_c = 0.0012). The Knops blood group system in Korean population has no diversity, except SNPs for KCAM and Yk^a, and the genotype of KCAM related with specific HLA alleles.     

Association analysis of Group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population

Background

Several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP). Preclinical antidepressant effects were also reported for group II metabotropic glutamate receptor (Group II mGluRs) antagonists show dose-dependent antidepressant-like effects in murine models of depression. Also, it has been suggested that abnormalities in the hypothalamic-pituitary-adrenal axis and serotonergic neural transmission are important mechanisms in the pathophysiology of mood disorders. Group II mGluRs play an important role in regulating the function of these mechanisms. From these results, it has been suggested that abnormalities in Group II mGluRs might be involved in the pathophysiology of mood disorders, including MDD) and BP, and may influence the clinical response to treatment with SSRIs in MDD. Therefore, we studied the association between Group II mGluR genes (GRM2 and GRM3) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients.

Materials and methods

Using three tagging SNPs in GRM2 and an SNP (rs6465084) reported functional variant in GRM3, we conducted a genetic association analysis of case-control samples (325 MDD patients, 155 BP patients and 802 controls) in the Japanese population. In addition, we performed an association analysis of GRM2 and GRM3 and the efficacy of fluvoxamine treatment in 117 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks.

Results

We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni's correction (P-value = 0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis.

Discussion

We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on LD and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.     

Association between IL-6 -174G/C polymorphism and acute rejection of renal allograft: evidence from a meta-analysis

Background

Results from published studies on the association of donor or recipient IL-6 -174G/C (rs1800795) polymorphism with acute rejection (AR) of renal allograft are conflicting. We performed a meta-analysis to estimate the possible association.

Methods

Studies were identified by searching PUBMED and EMBASE until July 1, 2011. Meta-analysis was performed in a fixed/random effects model using Revman 5.0.25 and STATA10.0.

Results

Seven studies addressing the association between donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism and acute rejection of renal allograft were identified. Pooled OR based on 341 cases (whose recipient developed acute rejection) and 702 controls (whose recipient did not develop acute rejection) was 0.59 (95% CI, 0.26-1.33; p = 0.20), with a strong between-study heterogeneity. No association was observed in the subgroup analysis based on ethnicity. 13 studies evaluating the association between recipient IL-6 -174G/C polymorphism and acute rejection were identified. Pooled OR based on 451 cases (patients did not develop acute rejection) and 848 controls was 1.00 (95% CI = 0.72-1.37; p = 0.98), with a weak between-study heterogeneity.

Conclusions

Donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism had a tendency of decreased risk for acute rejection, although it was not statistically significant. Recipient high producer genotype was not associated with acute rejection of renal allograft. Additional well designed studies with larger sample size are needed to support our findings, especially for the association between donor high producer genotype (G/G and G/C) of IL-6 -174G/C polymorphism and acute renal allograft rejection.     

HLA alleles and haplotypes observed in 263 US families

The 17th International HLA and Immunogenetics Workshop (IHIW) conducted a project entitled “The Study of Haplotypes in Families by NGS HLA”. We investigated the HLA haplotypes of 1017 subjects in 263 nuclear families sourced from five US clinical immunogenetics laboratories, primarily as part of the evaluation of related donor candidates for hematopoietic stem cell and solid organ transplantation. The parents in these families belonged to five broad groups – African (72 parents), Asian (115), European (210), Hispanic (118) and “Other” (11). High-resolution HLA genotypes were generated for each subject using next-generation sequencing (NGS) HLA typing systems. We identified the HLA haplotypes in each family using HaplObserve, software that builds haplotypes in families by reviewing HLA allele segregation from parents to children. We calculated haplotype frequencies within each broad group, by treating the parents in each family as unrelated individuals. We also calculated standard measures of global linkage disequilibrium (LD) and conditional asymmetric LD for each ethnic group, and used untruncated and two-field allele names to investigate LD patterns. Finally we demonstrated the utility of consensus DNA sequences in identifying novel variants, confirming them using HLA allele segregation at the DNA sequence level.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: A meta-analysis

Introduction

The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies.

Materials and Methods

A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6^th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0.

Results

A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery.

Conclusion

Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.     

Association of FKBP5 gene haplotypes with completed suicide in the Japanese population

Background

The hypothalamus-pituitary-adrenal (HPA) axis is known to have a role in suicidal behaviors in patients with affective disorders. However, the incomplete overlapping of the genetic factors of suicidal behaviors and the genetic factors of affective disorders suggest that the genes associated with predisposition to suicidal behaviors and affective disorders are different. There is increasing evidence that genes regulating the HPA axis have effects on suicidal behaviors. To test this idea, we examined the association of three HPA axis-related genes (glucocorticoid receptor (NR3C1), mineralocorticoid receptors (NR3C2), and FK506 binding protein 5 (FKBP5)) with suicide.

Methods

We selected 3 SNPs of the FKBP5 (rs3800373, rs1360780, and rs2395635), 2 SNPs of the NR3C1 (rs6196 and rs10052957), and 3 SNPs of the NR3C2 genes (rs5525, rs5522, and rs2070951) based on their frequency in the Japanese population. Using TaqMan probe assays, we determined these SNPs in 219 completed suicide victims and 228 age- and gender-matched healthy control subjects.

Results

No significant differences in genotypic distribution or allelic frequency of any single SNPs between the completed suicide and control groups were observed. The distributions of TT, TC, and GT haplotypes of the FKBP5 gene (comprised of rs3800373 and rs1360780) between the completed suicide and control groups were significantly different (p < 0.05 for each haplotype). The TC haplotype withstood correction for multiple comparisons (corrected p = 0.034).

Conclusion

Our results suggest that haplotypes in FKBP5 gene are associated with completed suicide. This finding needs to be confirmed using rigorous SNPs selection in a larger sample.     

Donor or recipient TNF-A -308G/A polymorphism and acute rejection of renal allograft: A meta-analysis

Background

Results from published studies on the association of donor or recipient TNF-A −308G/A polymorphism with acute rejection (AR) of renal allograft are inconsistent. We performed a meta-analysis to summarize the possible association.

Methods

Studies were identified by searching PUBMED, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases until March 22, 2011. Meta-analysis was performed in a fixed/random-effect model using Revman 5.0.25 and STATA10.0.

Results

Eight studies evaluating the association between donor TNF-A −308G/A polymorphism and acute rejection of renal allograft were identified. Pooled OR based on 460 cases (whose recipient developed AR) and 623 controls (whose recipient did not develop AR) was 1.44 (95% CI = 1.05-1.99, p = 0.03). No association was detected in the subgroup analysis based on ethnicity. 28 studies evaluating the association between recipient TNF-A −308G/A polymorphism and acute rejection were identified. Pooled OR based on 1411 cases (patients did not develop AR) and 2088 controls was 1.39 (95% CI = 1.06-1.82, p = 0.02). Two studies evaluating the association between recipient TNF-A −308G/A polymorphism and recurrent acute rejection were identified. Pooled OR based on 225 cases (patients with ≤ 1 AR) and 34 controls (patients with ≥ 2 AR) was 0.28 (95% CI = 0.13-0.62, p = 0.002).

Conclusions

Our meta-analysis provided evidence that TNF2 allele positive genotype of donor or recipient was associated with increased risk of incidence of acute rejection of renal allograft. Recipient TNF2 allele positive genotype is also associated with increased risk of recurrence of acute rejection of renal allograft. However, additional studies with large sample size and better study designs are warranted to verify our finding.     

How many genes are involved in schizophrenia? A simple simulation

We attempted to estimate how many genes are involved in schizophrenia using a simulation based on the polygenic threshold model. The basic assumptions were as follows: (1) All genes involved are transmitted independently; (2) every locus is composed of two alleles - one pathogenic and the other non-pathogenic; (3) all pathogenic alleles are dominant; (4) the two alleles at any locus are in Hardy-Weinberg Equilibrium (HWE) in the general population (GP) but not within the patient (PP) or non-patient (NP) subpopulations; (5) the number of affected loci determines the disease genetically; and (6) only a fraction of genetically determined individuals actually becomes ill. A range of the total number of disease-related genes (N) and threshold genetic load (T) was set for the simulation. Assuming that the number of affected loci follows a binomial distribution, the mean gene frequencies satisfying a disease prevalence of 1.12% in the GP were sought for various N and T combinations. Based on these gene frequencies, the odds ratio and the incidence rate in relatives under random mating were calculated. These results were then compared with real genetic epidemiologic data to obtain best-fit estimates for N and T. The results indicated that a polygenic threshold model with an N greater than 100 and a T in the range of 0.3-0.8 fits the empirical data. It was estimated that at least several hundreds of study subjects are required to yield a statistically significant frequency difference for a single gene between the patient and the control groups.     

Association of ADIPOQ gene polymorphisms and coronary artery disease risk: a meta-analysis based on 12 465 subjects

Introduction

Coronary artery disease (CAD) is one of the most common cardiovascular diseases and is a major cause of morbidity and mortality worldwide. Various researchers have investigated the role of ADIPOQ gene in the risk of CAD, yet their results have been inconsistent.

Methods

To evaluate the association between ADIPOQ genetic polymorphisms and CAD risk, relevant studies published before October 2011 were identified by searching PubMed and EMBASE. Studies were selected using previously defined criteria. The strength of the relationship between the four single nucleotide polymorphisms (SNPs) of the ADIPOQ gene and CAD risk was assessed using odds ratios (ORs).

Results

A total of 12 465 subjects from 17 case-control studies were identified in the present study. Based on the relevant studies, it was determined that the risk of CAD was not associated with rs2241766 in any genetic model. Increased risk of CAD was associated with rs266729 in allele contrast (1.11, [1.03, 1.20]) and dominant genetic model (1.15, 95%CI: [1.05, 1.27]); increased risk of CAD was also associated with rs822395 in additive (1.63, 95%CI: [1.19, 2.22]) and recessive genetic model (1.71, 95%CI: [1.27, 2.30]). It was further determined that the rs1501299 polymorphism reduced the risk of CAD in the additive (0.80, 95%CI: [0.67, 0.94]) and recessive genetic model (0.81, 95%CI: [0.68, 0.95]). In the stratified analysis, significant associations were found in Asian subjects for rs266729 and in Caucasian subjects for rs1501299.

Conclusion

There is an association between ADIPOQ gene polymorphisms and CAD risk. Different SNPs of the ADIPOQ gene have different associations with CAD risk, and appear to increase risk in individuals of Asian ethnicity while decrease the CAD risk in Caucasians. However, the overall strength of association was mild to moderate.