Intercellular adhesion molecule 1 gene K469E polymorphism is associated with coronary heart disease risk: a meta-analysis involving 12 studies

Coronary atherosclerosis is a leading cause of coronary heart disease (CHD). Atherosclerotic lesion is a complex polygenic disease in which gene-environment interactions play a critical role in disease onset and progression. The ICAM1 gene-E469K polymorphism has been reported to be associated with CHD, but results were conflicting. A systematic review and meta-analysis of the published studies were performed to gain a clearer understanding of this association. The PubMed, Embase, and CNKI databases were searched for case–control studies published up to August 2011. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Twelve eligible studies, comprising 2,157 cases and 1,952 controls, were included in the meta-analysis. The pooled result showed that the ICAM1 gene-E469K polymorphism was significantly associated with an increased risk of CHD (OR = 1.496, 95% CI = 1.363–1.642, for the allele K vs. allele E; OR = 1.919, 95% CI = 11.635–2.253, for the K allele carriers vs. EE). Subgroup analysis supported the results in the Asian populations and in the Caucasian populations. This meta-analysis suggests that the ICAM1 gene K469E polymorphism is associated with CHD risk and the K allele is a more significant risk factor for developing CHD among Asian and Caucasians populations.     

The significance of Exonuclease 1 K589E polymorphism on hepatocellular carcinoma susceptibility in the Turkish population: a case–control study

Exonuclease 1 (Exo 1) is an important nuclease involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. A guanine (G)/adenine (A) common single nucleotide polymorphism at first position of codon 589 in Exo 1 gene determines a glutamic acid (Glu, E) to lysine (Lys, K) (K589E) aminoacidic substitution which may alter cancer risk by influencing the activity of Exo 1 protein. Exo 1 K589E polymorphism has been studied in various cancers, but its association with hepatocellular carcinoma (HCC) has yet to be investigated. To determine the association of the Exo 1 K589E polymorphism with the risk of HCC development in a Turkish population, a hospital-based case–control study was designed consisting of 224 subjects with HCC and 224 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the Exo 1 K589E polymorphism was determined by using a polymerase chain reaction–restriction fragment length polymorphism assay. Our data shows that the Lys/Lys genotype of the Exo 1 K589E polymorphism is associated with increased risk of HCC development in this Turkish population [odds ratio (OR) = 2.15, 95% confidence interval (CI): 1.13–4.09, P = 0.02]. Furthermore, according to stratified analysis, a significant association was observed between the homozygote Lys/Lys genotype and HCC risk in the subgroups of male gender (OR = 2.67, 95% CI: 1.27–5.61, P = 0.009) and patients with non-viral-related HCC (OR = 3.14, 95% CI: 1.09–8.99, P = 0.03). Because our results suggest for the first time that the Lys/Lys homozygote genotype of Exo 1 K589E polymorphism may be a genetic susceptibility factor for HCC in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins.     

Intracellular Adhesion Molecule-1 K469E Gene Polymorphism and Risk of Diabetic Microvascular Complications: A Meta-Analysis

Background

A number of studies evaluated the association of intracellular adhesion molecule-1 (ICAM-1) K469E (rs5498, A/G) gene polymorphism with diabetic microvascular complications (DMI) including diabetic nephropathy (DN) and diabetic retinopathy (DR) in different populations. However, the results of individual studies remain conflicting.

Methods

A comprehensive search was conducted to identify all eligible studies of the above-mentioned associations. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were assessed using the fixed or random effect model.

Results

Seven studies involving 3411 subjects were included. Overall, the meta-analysis showed a significant association of the A allele with increased risk of DMI susceptibility in a recessive model (OR = 1.37, 95% CI 1.04–1.80, P = 0.02). In the subgroup analysis stratified by ethnicity, significant association was found in Asians but not in Caucasians (OR = 1.78, 95% CI 1.13–2.81, P = 0.01; OR = 1.10, 95% CI 0.79–1.54, P = 0.58, respectively). Moreover, it showed a significant association between the A allele and risk of DN in a recessive model (OR = 1.25, 95% CI 1.02–1.55, P = 0.04).

Conclusions

This meta-analysis suggested that the K469E polymorphism in ICAM-1 gene might affect individual susceptibility to DMI and showed a discrepancy in different ethnicities. Further investigations are needed to validate the association.     

ICAM‐1 and MKL‐1 polymorphisms impose considerable impacts on coronary heart disease occurrence

This study was aimed to explore the correlation of intercellular adhesion molecule‐1 (ICAM‐1) K469E and megakaryoblastic leukaemia factor‐1 (MKL‐1) ?184C/T polymorphisms with the susceptibility to coronary heart disease (CHD) in the Chinese Han population. 100 CHD patients and 91 healthy people that had no blood connection with each other were enrolled in this case‐control study. ICAM‐1 and MKL‐1 polymorphisms were genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) approach. Multiple logistic regression was used to analyse the correlation between polymorphisms of ICAM‐1 and MKL‐1 and CHD susceptibility. Differences of genotype and allele frequencies of the two SNPs between case and control groups were analysed by chi‐square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were indicated relative susceptibility of CHD. The distributions of ICAM‐1 and MKL‐1 polymorphisms in each group conformed to Hardy‐Weinberg equilibrium (HWE). After adjusting for traditional risk factors, the TT genotype frequency of MKL‐1 ?184C/T polymorphism was found significantly higher in case group than in control group (P < .05). Meanwhile, T allele frequency increased in case group compared with control group, and the differences had statistical significance (P = .04, OR = 2.34, 95% CI = 1.34‐5.26). Logistic regression analysis in this study proved that smoking, hypertension, diabetes and triglyceride (TG) were all risk factors for CHD ICAM‐1 K469E polymorphism has no association with the onset of CHD. But MKL‐1 ?184C/T polymorphism is associated with the risk of CHD and T allele might be a susceptibility factor for CHD.     

K<Subscript>ATP</Subscript> channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response

ATP-sensitive K⁺ (K_ATP) channels maintain cardiac homeostasis under stress, as revealed by murine gene knockout models of the KCNJ11-encoded Kir6.2 pore. However, the translational significance of K_ATP channels in human cardiac physiology remains largely unknown. Here, the frequency of the minor K23 allele of the common functional Kir6.2 E23K polymorphism was found overrepresented in 115 subjects with congestive heart failure compared to 2,031 community-based controls (69 vs. 56%, P < 0.001). Moreover, the KK genotype, present in 18% of heart failure patients, was associated with abnormal cardiopulmonary exercise stress testing. In spite of similar baseline heart rates at rest among genotypic subgroups (EE: 72.2 ± 2.3, EK: 75.0 ± 1.8 and KK: 77.1 ± 3.0 bpm), subjects with the KK genotype had a significantly reduced heart rate increase at matched workload (EE: 32.8 ± 2.7%, EK: 28.8 ± 2.1%, KK: 21.7 ± 2.6%, P < 0.05), at 75% of maximum oxygen consumption (EE: 53.9 ± 3.9%, EK: 49.9 ± 3.1%, KK: 36.8 ± 5.3%, P < 0.05), and at peak VO₂ (EE: 82.8 ± 6.0%, EK: 80.5 ± 4.7%, KK: 59.7 ± 8.1%, P < 0.05). Molecular modeling of the tetrameric Kir6.2 pore structure revealed the E23 residue within the functionally relevant intracellular slide helix region. Substitution of the wild-type E residue with an oppositely charged, bulkier K residue would potentially result in a significant structural rearrangement and disrupted interactions with neighboring Kir6.2 subunits, providing a basis for altered high-fidelity K_ATP channel gating, particularly in the homozygous state. Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired stress performance and underscoring the essential role of K_ATP channels in human cardiac physiology.     

<Emphasis Type="Italic">ACE2</Emphasis> gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects

The polymorphisms of angiotensin-converting enzyme 2 (ACE2) gene have been suggested to be linked to increase risk of essential hypertension in multiple populations. However, the results are still debatable. To assess the association between ACE2 G8970A genetic polymorphism and essential hypertension, we conducted a meta-analysis of case–control studies across different ethnicity. PubMed, Embase, CBM, Wanfang and VIP databases were searched, and a total of 11 separate studies in females and nine separate studies in males met the inclusion criteria. Because ACE2 is on the X chromosome, data for each sex were analyzed separately. The selected studies contained 7,251 (4,472 females/2,779 males) hypertensive patients and 3,800 (2,161 females/1,639 males) normotensive controls. A statistically significant association was observed between the G8970A gene polymorphism and essential hypertension risk in female hypertensive group in the recessive genetic model (AA vs. GG+GA: P = 0.03, OR = 1.15, 95% CI = 1.02–1.30, P _{heterogeneity} = 0.40, I ² = 5%, fixed-effects model). Although no association was shown between the frequency of the A allele and the genetic susceptibility to essential hypertension in all male patients (A Allele: P = 0.38, OR = 1.10, 95% CI = 0.89–1.38, P _{heterogeneity} = 0.02, I ² = 56%, random-effects model), we found that the relationship between carrier of A allele and the essential hypertension risk in Han-Chinese male patients subgroup (A Allele: P = 0.006, OR = 1.21, 95% CI = 1.06–1.38, P _{heterogeneity} = 0.10, I ² = 44%, fixed-effects model). The current meta-analysis provided solid evidence suggesting that ACE2 gene polymorphism G8790A was probably a genetic risk factor for essential hypertension across different ethnic populations in female subjects and in Han-Chinese male subjects.     

<Emphasis Type="Italic">IGFBP3</Emphasis> polymorphisms and risk of cancer: a meta-analysis

Until now, there were several studies evaluating the association between the polymorphisms in the IGFBP3 gene and cancer risk in diverse populations and in multiple types of cancer, but their outcomes have been contradictory and need to be investigated further. Here, we performed a meta-analysis from all eligible case–control studies to address the association of IGFBP3 A-202C and Gly32Ala polymorphisms to cancer. 20 articles including 41 studies for A-202C variant including 28,322 cancer patients and 36,772 healthy controls and six articles for Gly32Ala variant including 4,477 cases and 5,443 controls were selected in our analysis. Overall, A-202C polymorphism was appeared to be a risk factor of cancer (OR = 0.98, P = 0.05). A allele of IGFBP3 A-202C SNP was significantly less common in the cancer patients than in controls and AA genotype significantly decreased the cancer risk in additive genetic model when comparing to CC genotype (OR = 0.93, P = 0.004). Another SNP, Gly32Ala, seemed to be in linkage equilibrium with A-202C SNP. However, no significance was found when we analyzed the relation of cancer risk and Gly32Ala polymorphism (OR = 0.93, P = 0.36). Further, we compared the distributions of A-202C SNP in different types of cancer, significant association was found in additive genetic model in breast cancer (OR = 0.93, P = 0.01) and prostate cancer (OR = 0.88, P = 0.05). In the analysis of the variants in different population, A-202C variant was significantly associated with cancer risk in Africans (OR = 0.90, P = 0.05), but not in Caucasians (OR = 0.98, P = 0.12) or in Asians (OR = 1.03, P = 0.61). These results indicated that polymorphisms of IGFBP3 might have different effect in different types of cancer and different population. Further large study combining both IGFBP3 A-202C and Gly32Ala SNPs on different types of cancer in different populations were needed to validate former results.     

Role of p53 and p73 genes polymorphisms in susceptibility to esophageal cancer: a case control study in a northern Indian population

Genetic variants in p53 and in its homologue p73 may modulate Esophageal Cancer (EC) risk because they are supposed to influence cell cycle progression, apoptosis and DNA repair. Therefore, we aimed to evaluate the association of p53 intron3 16 bp duplication and p73 G4C14-to-A4T14 polymorphisms with susceptibility to EC in a northern Indian population in 255 EC patients and 255 age and sex matched healthy controls. We found that p53 intron3 16 bp duplication polymorphism was not associated with EC and its clinical characteristics. However, p73 G4C14-to-A4T14 polymorphism was associated with significant higher risk of EC (OR = 1.74, 95% CI = 1.16–2.60, P = 0.007) in an allele dose-dependent manner (P_trend = 0.0047). Stratification of subjects on the basis of clinical characteristics showed that p73 AT genotype carriers were at significant increased risk of developing esophageal squamous cell carcinoma (OR = 1.78, 95% CI = 1.18–2.67, P = 0.006) at middle third tumor location (OR = 1.87, 95% CI = 1.18–2.97, P = 0.007) with lymph node metastasis (OR = 1.77, 95% CI = 1.04–3.02, P = 0.035). No interaction with environmental risk factors was observed with any of the studied polymorphisms. In summary, p73 G4C14-to-A4T14 polymorphism but not the p53 intron3 16 bp duplication polymorphism is associated with EC and its clinical characteristics in northern Indian population.     

Meta-analyses of the effect of cytochrome P450 2E1 gene polymorphism on the risk of head and neck cancer

Many studies have investigated the association between the CYP2E1 5′-flanking region (RsaI/PstI) polymorphism and head and neck cancer susceptibility, but the results were conflicting. In this meta-analysis, we assessed 24 published studies involving 12,562 subjects of the association between CYP2E1 RsaI/PstI polymorphism and head and neck cancer risk. Using the fixed effects model, we found significant association between PstI/RsaI polymorphism and head and neck cancer risk [OR = 1.11 (95%CI: 1.00–1.22) for c2 allele (P = 0.04) and OR = 1.57 (95% CI: 1.14–2.15) for c2 homozygous (P = 0.006) compared with wild type homozygote]. Significant results were also found in East Asians and Mix populations when stratified by ethnicity. However, no significant associations were found for Caucasians in all genetic models. Stratified analyses according to source of controls, significant associations were found only in hospital base controls. In the subgroup analyses by tumor types, significant association was detected only in oral cancer group, while no significant associations among laryngeal- or pharyngeal- cancer subgroup. This meta-analysis suggests that the CYP2E1 RsaI/PstI polymorphism may be a risk factor for head and neck cancer in Asians and Mix population, and that different carcinogenic processes involved in the genesis of various tumor types may exist.     

The association between the mannose-binding lectin codon 54 polymorphism and systemic lupus erythematosus: a meta-analysis update

The aim of this study was to determine whether the functional mannose-binding lectin (MBL2) exon 1 codon 54 polymorphism (rs1800450) confers susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. A meta-analysis was conducted on the MBL2 codon 54 polymorphism across 21 comparative studies. Meta-analysis showed an association between the MBL2 codon 54 B allele and SLE in all study subjects [odds ratio (OR) = 1.298, 95% confidence interval (CI) = 1.154–1.459, P = 1.4 × 10⁻⁵]. Analysis after stratification by ethnicity indicated that the MBL2 codon 54 B allele is significantly associated with SLE in Europeans, Asian, and Africans (OR = 1.246, 95% CI = 1.062–1.462, P = 0.007; OR = 1.268, 95% CI = 1.049–1.532, P = 0.014; OR = 1.939, 95% CI = 1.269–2.962, P = 0.002, respectively). However, African Americans had a much lower prevalence of the T allele (5.8%) than any other populations studied, whereas Asians had the highest prevalence (16.2%). This meta-analysis confirms that the MBL2 codon 54 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.     

MTHFR 677C>T and 1298A>C polymorphisms and male infertility risk: a meta-analysis

Epidemiological studies have evaluated the association between MTHFR 677C>T and 1298A>C polymorphisms and risk of male infertility. However, the results from the published studies on the association between these two MTHFR polymorphisms and male infertility risk are conflicting. To derive a more precise estimation of association between the MTHFR polymorphisms and risk of male infertility, we performed a meta-analysis. A comprehensive search was conducted to identify all case–control studies of MTHFR polymorphisms and male infertility risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that both 677C>T and 1298A>C polymorphisms were not significantly associated with male infertility risk. However, in stratified analysis by ethnicity, we found that the 677C>T polymorphism was significantly associated with the risk of male infertility in Asian population (TT vs. CC: OR = 1.57, 95% CI: 1.05–2.37, P = 0.03; TT vs. TC + CC: OR = 1.40, 95% CI: 1.05–1.86, P = 0.02; TT + TC vs. CC: OR = 1.34, 95% CI: 1.01–1.77, P = 0.04). Although some modest bias could not be eliminated, this meta-analysis suggested that the MTHFR 677T allele might be a low-penetrant risk factor for male infertility, especially in Asian population.     

Genetic diversity of the apolipoprotein E gene and diabetic nephropathy: a meta-analysis

In the past decade, a number of case–control studies have been carried out to investigate the relationship between the ApoE polymorphism and diabetic nephropathy. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the ApoE polymorphism and DN. The 23 studies in the meta- analysis included 6,012 diabetic patients with (n = 2,979) and without (n = 3,033) DN. The ApoE ε2 allele was significantly associated with DN (OR = 1.64, 95% CI: 1.26–2.13; P(Z) = 0.00027), whereas the ε4 allele was non-significantly associated with DN (OR = 0.93, 95% CI: 0.78–1.11; P(Z) = 0.418). However, significant heterogeneity was detected. In further subgroup analyses, genotyping methods, outcome of cases and duration of diabetes in controls were found to explain some of the heterogeneity. Genotypic analysis also found a strong association between the ε2 carriers and DN (OR = 1.61, 95% CI: 1.22–2.13; P(Z) = 0.001) and indicated that ε4 tended to have a marginally significant protective effect for DN (OR = 0.82, 95% CI: 0.65–1.03; P(Z) = 0.085). The results of our meta-analysis support a genetic association between the ApoE polymorphism and DN. ε2 increases the risk of DN in diabetes patients, while ε4 trends to be protective. These findings may have implications for therapeutic intervention in diabetic nephropathy.     

Association of <Emphasis Type="Italic">Cytotoxic T Lymphocyte-associated antigen-4</Emphasis> gene haplotype with the susceptibility to gastric cancer

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) was widely accepted as a pivotal molecule in downregulating T-cell mediated immune responses. In this study we investigated the polymorphisms which would impact the CTLA-4 gene expression and function to assess the association with the risk of gastric cancer. 205 gastric cancer patients and 262 healthy controls were included in the case-control study. PCR and restriction fragment length polymorphism (RFLP) methods were performed to identify the +49A/G and promoter −1661A/G polymorphisms. The promoter −1772T/C polymorphism was detected by PCR amplification refractory mutation system (ARMS) technique. A significant difference was observed between case and control groups. The frequency of +49A/G polymorphism AG and −1661A/G polymorphism GG genotype were significantly higher in patients than in controls (OR = 2.15, OR = 1.88, respectively). No significant difference was found in the allelic frequency of −1772T/C polymorphism between cases and controls (P = 0.478). By the haplotype analysis, logistic regression showed the frequency of haplotype A (GAT) and D (AGT) in the case group revealed significant difference compared with in control group(OR = 2.00, P < 0.001; OR = 1.62, P = 0.043, respectively). Our findings implied the genetic variations within CTLA-4 gene would be a critical risk factor to the susceptibility of gastric cancer.     

Analysis of two sequence variants in peroxisome proliferator activated receptor gamma gene in Tajik population at high altitudes and Han population at low altitudes in China

The Tajik people in China have resided at high altitude for thousands of years. We analyzed the Pro12Ala (C > G) polymorphism in exon B and the 161C > T polymorphism in exon 6 of peroxisome proliferator activated receptor gamma gene (PPARG) in Chinese Tajik population living at high altitude and Chinese Han population living at low attitude. Significant higher frequencies of the CG and GG genotypes and G allele of the Pro12Ala (C > G) polymorphism were observed in the Tajik population than that in the Han population (P < 0.0001), which suggested the G allele was associated with high-altitude adaptation in the dominate model. The significant differences were remained in both of the male and female groups after stratified by gender, and the differences were more pronounced in men (G versus C, OR = 7.700) than in women (OR = 5.056). No significant difference was observed for the 161C > T polymorphism in the two populations. The frequencies of haplotypes GT (P < 0.0001) and GC (P < 0.05) were significantly higher, while the frequency of CT (P < 0.0001) was significantly lower in the Tajik population than that in the Han population. Our results suggest that PPARG is a candidate gene for high-altitude adaptation in the Chinese Tajik population.     

The association of CLOCK gene T3111C polymorphism and hPER3 gene 54-nucleotide repeat polymorphism with Chinese Han people schizophrenics

Many reports have shown that the biologic rhythm could be altered due to mutations of circadian gene hClock or hPeriod, and the mutations of circadian genes have some relationship with psychosis according to recent studies. A preliminary study has been conducted to examine wether the T3111C single nucleotide polymorphism of the hClock gene or the length polymorphism of the hPer3 gene is associated with the development of schizophrenia. The samples from schizophrenics (n = 148, male: 57.4%, female: 42.6%) and normal controls (n = 199, male: 59.3%, female: 40.7%) were examined. Allele frequencies of T3111C SNP of hClock were significantly different between schizophrenics and controls (χ² = 19.738, P < 0.05). Schizophrenics had a significantly higher frequency of the C allele compared with controls (OR = 2.613, 95% CI = 1.693–4.034). On the other hand, there is no significant difference of allele frequencies of 18 exon of hper3 between schizophrenics and controls (χ² = 0.192, P > 0.05). Our results suggest that the T3111C (RS1801260) polymorphism of hClock gene is associated with schizophrenia, but it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. It is important to address of the relationship between circadian gene polymorphisms and dopamine functions in further study.     

CYP2E1 Rsa I/Pst I polymorphism contributes to oral cancer susceptibility: a meta-analysis

Previous data on association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk were controversial. To investigate the association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk. We performed a meta-analysis to assess the relationship between oral cancer and genotype with English language until June 2010. Twelve published case–control studies of 1259 patients with oral cancer and 2262 controls were acquired. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association in codominant and dominant models. Overall, the pooled ORs indicated a significant association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk (for c1/c2 vs. c1/c1: OR = 1.30, 95% CI = 1.04–1.62, P_{heterogeneity} = 0.57; for (c1/c2 + c2/c2) vs. c1/c1: OR = 1.32, 95% CI = 1.07–1.64, P_{heterogeneity} = 0.57, respectively). In subgroup analysis by race, the same significant risks were found among Asian (for c1/c2 vs. c1/c1: OR = 1.41, 95% CI = 1.05–1.91, P_{heterogeneity} = 0.92; for (c1/c2 + c2/c2) vs. c1/c1: OR = 1.43, 95% CI = 1.08–1.88, P_{heterogeneity} = 0.97, respectively). In conclusion, this meta-analysis demonstrates that CYP2E1 Rsa I/Pst I c2 allele may be a biomarker for oral cancer, especially among Asian populations.     

Contribution of the IBD5 locus to inflammatory bowel disease: a meta-analysis

To evaluate the association of the IBD5 locus to the predisposition of inflammatory bowel diseases (IBDs), a series of meta-analyses between five IBD5 variants (OCTN1 C1672T, OCTN2 G-207C, OCTN1/2 TC haplotype, IGR2096a_1, IGR2198a_1 and IGR2230a_1) and Crohn’s disease (CD) and ulcerative colitis (UC) were performed, which included a total of 26 studies. Overall, five IBD5 variants in a per-allele model of inheritance were significantly associated with elevated CD risk (for OCTN1: OR = 1.23, 95% CI = 1.16–1.30, P < 0.001; for OCTN2: OR = 1.20, 95% CI = 1.11–1.30, P < 0.001; for IGR2096a_1: OR = 1.36, 95% CI = 1.24–1.46, P < 0.001; for IGR2198a_1: OR = 1.34, 95% CI = 1.24–1.46, P < 0.001; for IGR2230a_1: OR = 1.35, 95% CI = 1.23–1.48, P < 0.001) and OCTN1/2 TC haplotype (OR = 1.32, 95% CI = 1.22–1.43, P < 0.001). In the subgroup analysis, the statistically significant associations were also observed in adult- and pediatric-onset CD and in Caucasians for five IBD5 variants and the OCTN1/2 TC haplotype. A statistically significant increase in the risk of UC was detected in a recessive model of inheritances for OCTN1 (OR = 1.23, 95% CI = 1.08–1.40, P < 0.001), OCTN2 (OR = 1.18, 95% CI = 1.05–1.33, P = 0.006), IGR2096a_1 (OR = 1.37, 95% CI = 1.15–1.62, P < 0.001) and IGR2198a_1 (OR = 1.35, 95% CI = 1.10–1.66, P = 0.004); the increased risks of UC were maintained in the adult and Caucasian subgroups, but not the pediatric subgroup. In summary, our results suggested that the IBD5 locus contributes to the susceptibility of CD in a per-allele manner in adults, children and Caucasians, and the locus contributes to the susceptibility of UC in a recessive manner in adult and Caucasian populations.     

Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population

Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of enteric ganglia. There are more than 15 genes identified as contributed to HSCR by family‐based or population‐based approaches. However, these findings were not fulfilled to explain the heritability of most sporadic cases. In this study, using 1470 HSCR and 1473 control subjects in South Chinese population, we replicated two variants in NRG1 (rs16879552, P = 1.05E‐04 and rs7835688, P = 1.19E‐07), and further clarified the two replicated SNPs were more essential for patients with short‐segment aganglionosis (SHSCR) (P = 2.37E‐05). We also tried to replicate the most prominent signal (rs7785360) in AUTS2, which was a potential susceptibility gene with HSCR. In our results, in terms of individual association, marginal effect was observed to affect the HSCR patients following recessive model (P = 0.089). Noteworthy, significant intergenic synergistic effect between rs16879552 (NRG1) and rs7785360 (AUTS2) was identified through cross‐validation by logistic regression (P = 2.45E‐03, OR = 1.53) and multifactor dimensionality reduction (MDR, P < 0.0001, OR = 1.77). Significant correlation was observed between expression of these two genes in the normal segments of the colons (P = 0.018), together with differential expression of these genes between aganglionic colonic segments and normal colonic segments of the HSCR patients (P value for AUTS2 <0.0001, P value for NRG1 = 0.0243). Although functional evaluation is required, we supply new evidence for the NRG1 to HSCR and raised up a new susceptibility gene AUTS2 to a specific symptom for the disease.     

Role of tissue plasminogen activator and plasminogen activator inhibitor polymorphism in myocardial infarction

A case–control association study on 229 Myocardial Infarction (MI) patients and 217 healthy controls was carried out to determine the role of tissue-plasminogen activator (t-PA) (Alu-repeat insertion (I)/deletion (D)) and plasminogen activator inhibitor (PAI-1) (4G/5G insertion/deletion) polymorphisms with MI in the Pakistani population. In MI patients the genotype distribution of the PAI-1 gene was not found to be different when compared with the unaffected controls (P > 0.05, χ² = 1.03). The risk allele 4G was also not associated with MI (P > 0.05, χ² = 0.46, odds ratio (OR) = 1.1 (95% confidence interval (CI) = 0.84–1.43), P > 0.05). Similarly, the genotype frequencies of t-PA I/I, I/D and D/D were not different from the unaffected controls (P > 0.05, χ² = 1.60), and the risk allele “I” was not found to be associated with MI (P > 0.05, χ² = 1.35, OR = 0.86 (95% CI = 0.66–1.11), P > 0.05). However, when the data were distributed along the lines of gender a significant association of the 4G/4G PAI-1 genotype was observed with only the female MI patients (P < 0.05, z-test = 2.21). When the combined genotypes of both the polymorphisms were analyzed, a significant association of MI was observed with the homozygous DD/4G4G genotype (P < 0.01, z-test = 2.61), which was specifically because of the female samples (P = 0.01, z-test = 2.53). In addition smoking (P < 0.001, χ² = 13.52, OR = 3.45 (95% CI = 1.77–6.94)), diabetes (P < 0.001, χ² = 22.45, OR = 8.89 (95% CI = 2.96–29.95)), hypertension (OR = 7.76 (95% CI = 2.88–22.68), P < 0.001) family history (P < 0.001, χ² = 13.72, OR = 3.7 (95% CI = 1.71–8.18)) and lower HDL levels (P < 0.05) were found to be significantly associated with the disease. In conclusion the PAI-1 gene polymorphism was found to have a gender specific role in the female MI patients.