Northeastern Chinese Population Research Articles

Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern Chinese population

Variants in the gene encoding transcription factor 7-like 2 (TCF7L2) are associated with type 2 diabetes mellitus (T2D) in several ethnic groups. Two intronic variants, rs290487 and rs11196218, were originally identified as T2D modifiers in Hong Kong Chinese and Taiwan Chinese populations, respectively. However, discrepancies were noted in subsequent replicated studies. In this study, an association of these two loci with T2D was investigated in a Harbin Chinese population. Whereas the two populations in the initial studies were southern Han Chinese, Harbin Chinese are from northeastern China. The SNPs rs290487 and rs11196218 were genotyped by ligase detection reactions in 700 T2D patients and 570 unrelated non-diabetic controls. Association analyses, which were carried out using the case-control sample set, yielded a significant association between rs290487 and T2D, with a trend opposite to that described in a previous report. Specifically, rs290487T was found to be significantly associated with disease susceptibility (p=0.039), and the allelic OR of rs290487T carriers was 1.184 (95% CI 1.008–1.391). There was no significant association between rs11196218 and T2D. Taken together, TCF7L2 may be an important susceptibility gene for T2D in some Chinese populations. The discrepancies in the allelic associations determined for northern vs. southern Chinese allude to the presence of genetic variation among the Han Chinese.

SEMA3A rs7804122 polymorphism is associated with Hirschsprung disease in the Northeastern region of China

Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon. Our previous results showed increased semaphorin 3A (SEMA3A) expression may be the risk factor for HSCR pathology in a subset of patients. Therefore, the association between polymorphisms in SEMA3A and the risk of HSCR was examined. The genotypes of two SNPs (rs7804122 and rs797821) in the SEMA3A gene in 119 patients with HSCR and 93 controls were examined using PCR-sequencing to determine the contribution of SEMA3A to the HSCR phenotype. PCR reaction with cDNA template was also used to find out whether a novel mutation (Chr7:83634610A→T) influences the SEMA3A pre-mRNA splicing. Genotypes comprising allele G of rs7804122 (GG or AG) were over-represented in patients (48.74 vs. 24.8%; p = 0.0013) which indicated that the risk of HSCR was significantly higher among subjects with the GG or AG genotype than among the subjects with the AA genotype. No statistically significant associations were found for SNP rs797821 at the allele or genotype levels. The differences in genotypes and allele distributions of rs7804122 and rs797821 between various clinical classifications were not statistically significant. The novel heterozygous mutation (Chr7:83634610A→T) 30bp away from an intron/exon boundary, had no detectable effect on splicing efficiency. Our results for rs7804122 provided preliminary evidence that the SEMA3A gene is involved in the susceptibility to HSCR in the Northeastern Chinese population.

Association of ADAM33 gene polymorphisms with COPD in a northeastern Chinese population

BackgroundChronic obstructive pulmonary disease (COPD) is influenced by both environmental and genetic factors. ADAM33 (a disintegrin and metalloproteinase 33) has been one of the most exciting candidate genes for asthma since its first association with the disease in Caucasian populations. Recently, ADAM33 was shown to be associated with excessive decline of lung function and COPD. The aim of this study was to evaluate the potential relationship between polymorphisms of ADAM33 and COPD in a Han population in northeastern China.MethodsA total of 312 COPD patients and a control group of 319 healthy volunteers were recruited for this study. Eight polymorphic loci (V4, T+1, T2, T1, S2, S1, Q-1, and F+1) of ADAM33 were selected for genotyping. Genotypes were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.ResultsStatistically significant differences in the distributions of the T2G, T1G, S2C, and Q-1G alleles between patients and controls were observed (P < 0.001, odds ratio (OR) = 2.81, 95% confidence interval (CI) = 2.19-3.61; P < 0.001, OR = 2.60, 95% CI = 2.06-3.30; P = 0.03, OR = 1.31, 95% CI = 1.02-1.69; and P < 0.001, OR = 1.93, 95% CI = 1.50-2.50, respectively). Haplotype analysis showed that the frequencies of the CGGGGAGC, CGGGGAGT, CGGGCAGC, and CGGGGGGC haplotypes were significantly higher in the case group than in the control group (P = 0.0002, 0.0001, 0.0005, and 0.0074, respectively). In contrast, the haplotype CGAAGAGC was more common in the control group than in the case group (P < 0.0001).ConclusionThese preliminary results suggest an association between ADAM33 polymorphisms and COPD in a Chinese Han population.

Association of MIF promoter polymorphisms with childhood asthma in a northeastern Chinese population

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in pathogenesis of asthma. A high level of MIF has been detected in bronchoalveolar lavage fluid, serum and sputum in asthma. Polymorphisms associated with inflammatory diseases exist in the promoter region of MIF, which alter its expression. The aim of this study was to evaluate the potential relationship between functional polymorphisms of MIF and childhood asthma in a northeastern Chinese population. The study consisted of a set of 41 trios and an independent sample set of 189 childhood asthma patients and 261 healthy controls. We genotyped MIF-173G/C using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Additionally, MIF-794CATT(5-8) microsatellite polymorphism was genotyped by polyacrylamide gel electrophoresis (PAGE). A statistically significant difference in the distribution of the MIF-173C allele between patients and controls [P = 0.01, odds ratio (OR) = 1.55, 95% confidence interval (CI) = 1.13-2.18] was observed. In addition, the frequency of the MIF-173CC genotype was higher in asthmatic children (P < 0.01, OR = 3.37, 95% CI = 1.27-8.93). No difference in the distribution of CATT(5-8) was found between patients and healthy controls. Haplotype analysis showed that only the MIFCATT(7)-173C haplotype was associated with greater susceptibility to childhood asthma (P = 0.03, OR = 1.54, 95% CI 1.03-2.28). However, the transmission disequilibrium test confirmed a positive association between MIF-173G/C and childhood asthma (P = 0.005), and the absence of an association between the MIF-794CATT(5-8) and the disease. These preliminary results suggest an association between the MIF-173C allele and childhood asthma.

Genetic Polymorphisms of DNA Repair Gene: XRCC1 Pro206Pro and Gln632Gln in a Chinese Han Population

DNA repair genes are increasingly studied because of their critical role in maintaining genome integrity. The base excision repair (BER) pathway is a DNA repair pathway that operates on small lesions, such as oxidized or reduced bases, fragmented or nonbulky adducts, or those produced by methylating agents. The XRCC1 polymorphic system is the key gene of the BER pathway. In this study, polymorphisms of XRCC1 Pro206Pro on exon 7 and Gln632Gln on exon 17 were analyzed in a northeastern Chinese Han population. Genomic DNA extracted from 303 unrelated individuals and the PCR-RFLP technique were used to identify variants. The allele frequencies were 0.90 (A) and 0.10 (G) for XRCC1 Pro206Pro and 0.88 (G) and 0.12 (A) for XRCC1 Gln632Gln. The genotype frequencies were 0.797 (AA), 0.203 (AG), and 0 (GG) for XRCC1 Pro206Pro and 0.007 (AA), 0.222 (AG), and 0.771 (GG) for XRCC1 Gln632Gln. The expected heterozygosity and PIC were 18 and 16.38% for Pro206Pro and 21.12 and 18.89% for Gln632Gln. The two polymorphisms were in strong linkage disequilibrium (D' = 0.921, r (2) = 0.735). The results are compared with those of other reported populations. They showed marked ethnic group differences. This study provides the first analysis of the distribution of allele frequency for XRCC1 Pro206Pro and Gln632Gln in a Chinese population.

A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population

The effect of the polymorphism of the DNA repair gene ERCC2/XPD Asp312Asn on the risk of lung cancer was investigated in a northeastern Chinese population. A hospital-based case–control study consisted of 201 lung cancer cases and 171 cancer-free controls matched to age, sex, and ethnicity. A polymerase chain reaction–restriction fragment length polymorphism method was used for genotyping. Frequency of the variant C-allele of ERCC2 Asp312Asn was 0.006 among the controls in present study, which differs markedly from previous reports both in European ancestry populations and in other Chinese populations (all P < 0.001). The polymorphism was not associated with risk of lung cancer. Haplotype analysis including three previously studied polymorphisms ( ERCC1 Asn118Asn, ERCC2 Arg156Arg, and ERCC2 Lys751Gln) revealed that a haplotype consisting of ERCC1Asn118Asn G– ERCC2 Arg156Arg C– ERCC2 Asp312Asn G– ERCC2 Lys751Gln C was marginally associated with an increased risk of lung cancer (OR = 3.61, 95% CI = 1.00–13.06, P = 0.04). Our data suggest that the polymorphism ERCC2 Lys751Gln or a haplotype encompassing the variant allele is associated with risk of lung cancer in this population. Studies including larger sample sizes are needed to elucidate the effects of these polymorphisms on lung cancer risk in this northeastern Chinese population.

The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population

To evaluate the effect of DNA repair gene XRCC1 polymorphisms on the risk of lung cancer in a northeastern Chinese population, we studied five cSNPs in the XRCC1 gene, three that lead to non-synonymous changes: Arg194Trp, Arg280 His and Arg399Gln and two that lead to synonymous changes: Pro206Pro and Gln632Gln. A hospital-based case-control study consisted of 247 lung cancer cases and 253 cancer-free controls matched on age, gender and ethnicity. PCR-RFLP was used for genotyping. Carriers of the minor G-allele of Pro206Pro were at significantly increased risk of lung cancer (adjusted OR=1.96, 95% CI=1.26-3.06, P=0.003). Stratified analyses revealed a significantly decreased risk of lung cancer associated with the AG/AA genotype of Arg280His (AG+AA versus GG, OR=0.38, 95% CI=0.19-0.75, P=0.005) among never smokers, although there was no interaction between Arg280His and smoking. In a haplotype analysis, a haplotype defined by Arg194Trp(C)-Pro206Pro(G)-Arg280His(G)-Arg399Gln(G)-Gln632Gln(G) was associated with increased risk of lung cancer (OR=28.60, 95% CI=2.49-331.31, P=4.45x10(-5)). No associations were observed for the other polymorphisms or haplotypes. Our results suggest that the XRCC1 Pro206Pro polymorphism or the haplotype encompassing the minor allele may contribute to genetic susceptibility for lung cancer in this northeastern Chinese population. To our knowledge, this is first report that XRCC1 Pro206Pro influences cancer risk.

Polymorphism of the DNA repair gene ERCC2 Lys751Gln and risk of lung cancer in a northeastern Chinese population

The ERCC2 gene (excision repair cross-complementing rodent repair deficiency, complementation group 2 [xeroderma pigmentosum D]) (previously XPD), encoding a DNA repair protein, is involved in nucleotide excision repair and basal transcription. To test the effect of the polymorphism ERCC2 Lys751Gln on the risk of lung cancer in a northeastern Chinese population, a hospital-based case–control study was designed consisting of 147 newly diagnosed and previously untreated subjects with lung cancer and 145 cancer-free control subjects matched on age (±3 years), gender, and ethnicity. Among the controls, the allele frequency of the C-allele of ERCC2 Lys751Gln was 0.02. The C-allele of ERCC2 Lys751Gln was significantly overrepresented among lung cancer cases (C versus A: adjusted odds ratio OR adj = 2.61, 95% CI = 1.12–6.05, P = 0.03). The carriers of AC genotype were at 2.78-fold (OR adj = 2.78, 95% CI = 1.12-6.93) higher risk of lung cancer than carriers of the AA genotype. Subdivided by tumor type, carriers of AC genotype had a 4.65-fold higher risk of squamous cell carcinoma of lung compared with carriers of AA genotype (OR adj = 4.65, 95% CI = 1.67–12.98, P = 0.003); similar, but not statistically significant estimates were found for adenocarcinoma of lung. In conclusion, our results suggest that ERCC2 Lys751Gln C allele is a potential risk marker for lung cancer in this northeastern Chinese population.

Polymorphisms of DNA Repair Genes: ERCC1 G19007A and ERCC2/XPD C22541A in a Northeastern Chinese Population

DNA repair systems are responsible for maintaining the integrity of the genome and have a critical role in protecting against mutations that can lead to cancer. DNA repair gene products of ERCC1 and ERCC2/XPD are involved in the nucleotide excision repair pathway. The allele frequencies of the polymorphisms ERCC1 G19007A and ERCC2/XPD C22541A were examined in a northeastern Chinese population. The allele frequencies were 0.21 (A) and 0.79 (G) for ERCC1 G19007A and 0.49 (A) and 0.51 (C) for ERCC2/XPD C22541A. Comparison with average frequencies from previously reported Caucasian studies demonstrated that the A-allele frequency of ERCC1 G19007A was much lower in the northeastern Chinese population, indicating a remarkable ethnic difference (chi((1)) (2) = 160.09, p < 0.001), and that allele frequencies of ERCC2/XPD C22541A showed marginal racial differences (chi((1)) (2) = 4.36, p = 0.04). We have previously reported that both homozygote carriers of the A-allele as well as homozygous carriers of a high-risk haplotype (which includes the AA genotype in ERCC1 G19007A) were at increased risk of basal cell carcinoma, breast cancer, and lung cancer among Caucasians. The low A-allele frequency of ERCC1 G19007A in the Chinese population may suggest that the genetic contribution to cancer risk differs substantially between ethnic groups.

The DNA repair gene ERCC2/XPD polymorphism Arg 156Arg (A22541C) and risk of lung cancer in a Chinese population

To determine the effect of the DNA repair gene XPD Arg156Arg polymorphism on the risk of lung cancer in a North-Eastern Chinese population, a hospital-based case-control study was designed consisting of 149 newly diagnosis subjects with lung cancer and 137 cancer-free control subjects matched on age (±3 years), gender and ethnicity. In the whole study group, XPD Arg156Arg was not associated with risk of lung cancer. In stratified analyses, the variant A-allele of XPD Arg156Arg was associated with increased risk of adenocarcinoma of lung (AA/AC versus CC; adjusted OR=1.65; 95% CI=1.09–2.50) ( P=0.02). Furthermore, the presence of one or two variant A-alleles was associated with increased risk for lung cancer (OR=2.49; 95% CI=1.10–5.64) ( P=0.03) and adenocarcinoma of lung (OR=5.60; 95% CI=1.52–20.56) ( P=0.005) among never-smokers only. These results suggest a possible gene–environment interaction. This is the first study to report a significant association of XPD Arg156Arg with risk of lung cancer.