Changchun Qiu

Haplotype-based association of the renin-angiotensin-aldosterone system genes polymorphisms with essential hypertension among Han Chinese: the Fangshan study.

Background Widely evaluated regarding the genetic make-up of essential hypertension are the renin-angiotensin-aldosterone system (RAAS) genes polymorphisms, whereas results are often not reproducible. Method We thus focused on a large Fangshan population to explore association of thirteen polymorphisms in five genes of RAAS. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing techniques. Data were analyzed using MDR and Haplo.stats programs. Results All studied polymorphisms satisfied Hardy–Weinberg equilibrium in controls. Three polymorphisms (AGT M235T, ACE I/D and AT1R A1166C) displayed significant differences in the genotype and allele distributions between patients and controls (P < 0.05). Interaction analysis suggested a six-locus model that can be decomposed into three sets of polymorphisms (TaqI and M235T, A-20C and A-6G, I/D and A2350G) each with nonadditive effects. Logistic regression analysis indicated that TaqI [Recessive: crude odds ratio (ORcrude) = 1.47, P = 0.030 and adjusted (ORadjusted) = 1.46, P = 0.050] and I/D (Recessive: ORcrude = 1.40, P = 0.002 and ORadjusted = 1.49, P = 0.002) polymorphisms were significantly and positively associated with the risk of essential hypertension. Under additive and recessive modes of inheritance, similar tendency was observed for M235T polymorphism. Two haplotypes (H6 and H9) were found to significantly reduce essential hypertension risk, whereas after correction only H6 remained significant (OR = 0.25, P = 0.0006). In contrast, haplotype H13 was significantly associated with essential hypertension with a 2.14–2.16-fold increased risk (P < 0.01). Haplotype-phenotype analysis showed significant association of inferred haplotypes with SBP (hap-score = 0.44, simulated P = 0.036). Conclusion Taken together, we demonstrated three two-locus pairs of polymorphisms with synergistic effect out of three genes in RAAS and found significant haplotype-phenotype interaction. Functional studies to confirm or refute these findings are warranted.

Genetic interaction of Hsp70 family genes polymorphisms with high-altitude pulmonary edema among Chinese railway constructors at altitudes exceeding 4000 meters.

BACKGROUND High-altitude pulmonary edema (HAPE) is thought of as an independent clinical disorder with a constitutional or genetic component in its etiology. We focused on 5 common polymorphisms within HSPA1A (rs1043618 and rs1008438), HSPA1B (rs1061581 and rs539689) and HSPA1L (rs2227956) of Hsp70 family to explore their potential interaction upon susceptibility to HAPE in Chinese. METHODS A total of 148 HAPE patients and 483 matched controls were recruited during the construction of Qinghai-Tibet railway from 2001 to 2006. Genotyping was performed using PCR-RFLP, PCR-SSCP and PCR-direct-sequencing techniques. Promoter activity was evaluated by luciferase reporter assays. Gene-gene interaction was conducted by MDR v.2.0, and haplotype-diplotype analysis by Haplo.stats v.1.4.0. RESULTS Significant differences were observed in the genotype (P=0.0136) and allele (P=0.0299) distributions of rs1008438, and in rs1061581 allele distribution (P=0.0421) between HAPE patients and controls. Interaction analysis indicated that 3 polymorphisms (rs1061581, rs1043618 and rs1008438) shared strong synergism with a testing accuracy of 0.792 and cross-validation consistency 10 out of 10 (P=0.001). Haplotypes Hap4 (G-C-A, in order of rs1061581, rs1043618 and rs1008438) and Hap5 (G-G-A) had an 86% reduced risk (P=0.0009) against and Hap7 (A-C-C) had a 2.43-fold increased risk for HAPE. When considered as diplotypes, significance was noted for Dip5 (Hap1-Hap7) (OR=3.39; 95% CI: 1.28-9.17; P=0.0140). Functional assessment supported the involvement of rs1008438 in the pathogenesis of HAPE. CONCLUSION We demonstrated strong interaction of rs1061581, rs1043618 and rs1008438 polymorphisms within Hsp70 family upon susceptibility to HAPE in Chinese. Moreover, polymorphism rs1008438 might cause the development of HAPE via a change in HSPA1A promoter activity.

Genetic Polymorphisms of Angiotensinogen and Essential Hypertension in a Tibetan Population

The human angiotensinogen gene (AGT) is a promising candidate for an essential hypertension-susceptibility gene. We aimed to explore the single-locus, haplotype and epistasis patterns of three polymorphisms of AGT (A−20C, A−6G and M235T) and their relation to the risk of essential hypertension in a Tibetan population. The three polymorphisms were genotyped in 333 essential hypertension patients and 235 healthy controls on the basis of a door-to-door cross-sectional study. Genotyping was performed using polymerase chain reaction (PCR)−restriction fragment length polymerase (RFLP) and direct sequencing techniques. The data were analyzed using the EH/EH+ program and the multifactor dimensionality reduction (MDR) method. Our single-locus analysis revealed that except for a marginal, significant association of A−20C allele distribution, no significant association between genotype and allele distributions of the A−20C, A−6G, or M235T polymorphism of AGT and essential hypertension was found. In haplotype analysis, we found that the H1 haplotype may be the risk-conferring factor for hypertension, even after the Bonferroni correction. In epistasis analysis, we selected the final best model, which included the A−20C and A−6G polymorphisms with a strong synergistic effect. This model had a maximum testing accuracy of 0.564 and a maximum cross validation consistency of 10 out of 10 (p=0.001). The present study thus provides evidence of a strong synergistic effect of the A−20C and A−6G polymorphisms of AGT, which were not found to be associated with essential hypertension in the single-locus analysis. Moreover, we have proposed a promising data–mining analytical method using the open-source MDR software package for detecting and characterizing gene-gene interactions.

A novel DSPP mutation causes dentinogenesis imperfecta type II in a large Mongolian family

BackgroundSeveral studies have shown that the clinical phenotypes of dentinogenesis imperfecta type II (DGI-II) may be caused by mutations in dentin sialophosphoprotein (DSPP). However, no previous studies have documented the clinical phenotype and genetic basis of DGI-II in a Mongolian family from China.MethodsWe identified a large five-generation Mongolian family from China with DGI-II, comprising 64 living family members of whom 22 were affected. Linkage analysis of five polymorphic markers flanking DSPP gene was used to genotype the families and to construct the haplotypes of these families. All five DSPP exons including the intron-exon boundaries were PCR-amplified and sequenced in 48 members of this large family.ResultsAll affected individuals showed discoloration and severe attrition of their teeth, with obliterated pulp chambers and without progressive high frequency hearing loss or skeletal abnormalities. No recombination was found at five polymorphic markers flanking DSPP in the family. Direct DNA sequencing identified a novel A→G transition mutation adjacent to the donor splicing site within intron 3 in all affected individuals but not in the unaffected family members and 50 unrelated Mongolian individuals.ConclusionThis study identified a novel mutation (IVS3+3A→G) in DSPP, which caused DGI-II in a large Mongolian family. This expands the spectrum of mutations leading to DGI-II.

Endothelial nitric oxide synthase gene polymorphisms associated with susceptibility to high altitude pulmonary edema in Chinese railway construction workers at Qinghai-Tibet over 4 500 meters above sea level.

Objective To examine whether the polymorphisms of endothelial nitric oxide synthase (eNOS) gene are associated with the susceptibility to high altitude pulmonary edema (HAPE) in Chinese railway construction workers at Qinghai-Tibet where the altitude is over 4 500 m above sea level. Methods A case-control study was conducted including 149 HAPE patients in the construction workers and 160 healthy controls randomly recruited from their co-workers, matching the patients in ethnicity, age, sex, lifestyle, and working conditions. Three polymorphisms of eNOS gene, T-786C in promoter, 894G/T in exon 7, and 27bp variable number tandem repeat (VNTR) in intron 4, were genotyped using polymerase chain reaction (PCR) and confirmed with DNA sequencing. Results The frequencies of 894T allele and heterozygous G/T of the 894G/T variant were significantly higher in HAPE patients group than in the control group (P=0.0028 and P=0.0047, respectively). However, the frequencies of the T-786C in promoter and the 27bp VNTR in intron 4 were not significantly different between the two groups. Haplotypic analysis revealed that the frequencies of two haplotypes (H3, T-T-b, b indicates 5 repeats of 27 bp VNTR; H6, C-G-a, a indicates 4 repeats of 27 bp VNTR) were significantly higher in HAPE patients (both P Conclusion Two haplotypes (T-T-b and C-G-a) may be strongly associated with susceptibility to HAPE. Compared with the individual alleles of eNOS gene, the interaction of multiple genetic markers within a haplotype may be a major determinant for the susceptibility to HAPE.

Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with high-altitude pulmonary oedema: a meta-analysis

Background and objective: High-altitude pulmonary oedema (HAPE) is a non-cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data. Materials and methods: We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate. Results: A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98–1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15–2.08; p = 0.004). Funnel plot and Egger’s test suggested no evidence of publication bias. Conclusions: Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE.

Influence of Salt Intake on Association of Blood Uric Acid with Hypertension and Related Cardiovascular Risk.

Background A relationship of blood uric acid (UA) with hypertension and cardiovascular risk is under debate thus salt intake is hypothesized to contribute to such associations. Methods In this cross-sectional study, stratified cluster random sampling elicited a sample of 1805 Kazakhs with 92.4% compliance. Hypertension and moderate-or-high total cardiovascular risk (mTCR) were defined according to guidelines. Sodium intake was assessed by urinary sodium excretion. Prevalence ratios (PRs) were used to express associations of UA with hypertension and mTCR. Results In the highest tertile of sodium intake in women, the adjusted PRs (95% confidence intervals) of low to high quartiles compared with the lowest quartile of UA, were 1.22(0.78–1.91), 1.18(0.75–1.85), and 1.65(1.09–2.51) for hypertension and 1.19(0.74–1.90), 1.39(0.91–2.11), and 1.65(1.10–2.47) for mTCR (P for trend <0.05). However, these findings were not shown for other sodium intake levels. There were similar results in men. PRs markedly increased with a concomitant increase in UA and sodium intake and there was a significant interaction (P = 0.010) for mTCR with PRs of 1.69(1.10–2.60) for men and 3.70(2.09–6.52) for women in those with the highest compared with the lowest quartile of UA and tertile of sodium intake. Similar findings were shown for hypertension. Conclusions This study implied that a high salt intake may enhance the associations of UA with hypertension and cardiovascular risk.

GNB3, eNOS, and Mitochondrial DNA Polymorphisms Correlate to Natural Longevity in a Xinjiang Uygur Population

Background In centenarian populations, application of the positive biology approach (examination of positive phenotypes in aging) has revealed that mitochondrial DNA (mtDNA) mutation accumulation may be linked to human longevity; however, the role of guanine nucleotide-binding protein (G protein) abnormalities modulated by G-protein beta-3 (GNB3) and nitrate (NO2) production associated with endothelial nitric oxide synthase (eNOS), commonly appearing in age-related diseases, remains undetermined. Objective The association between the mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS polymorphisms and longevity in a Uygur population (Xinjiang region, China) were investigated. Methods A total of 275 experimental subjects aged ≥100 or with 4 generations currently living were screened for inclusion in the centenarian (>100 years) and nonagenarian groups (90–100 years), and 112 65–70 year old control subjects were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS. Associations between polymorphic loci, genotypes, and longevity were analyzed. Results 165 included subjects (M∶F = 107∶58; mean age = 97±3 years; mean age 100–113 years) were assigned to the centenarian (M∶F = 46/19; n = 65) and nonagenarian groups (M∶F = 61/39; n = 100). Associations between mtDNA C5178A and A10398G polymorphisms with longevity in the centenarian group with mtDNA genotype frequencies 5178A and 10398G were 66.79% and 36.8%. Conclusions Applying the overwhelming longevity observed in Uygur populations, these findings demonstrate that mtDNA 5178A/C and 10398A/G, GNB3 C825T, and eNOS polymorphisms are useful as a genetic basis for longevity.

Interactive association of heat shock protein 70 genes variants with natural longevity in Xinjiang Hetian Uygur ethnicity

Mounting evidence suggests that all organisms at the cellular level respond to stress by synthesizing heat shock proteins at the expense of other proteins, and the ability of human cells to respond to heat stress decreases with aging. We thus investigate the association of 3 variants (A1267G in HSPA1B, G190C in HSPA1A, and T2437C in HSPA1L) in the heat shock protein 70 (Hsp70) family with natural longevity in a Xinjiang Hetian Uygur population. A case-control study was conducted in 191 healthy individuals greater than 90 years of age, and 53 naturally died persons 65-70 years of age. Promoter activity was evaluated by luciferase reporter assays. The data were analyzed using an EH/EH+ program for haplotype prediction and MDR software for gene-gene interaction. All studied variants satisfied the Hardy-Weinberg equilibrium in each group. In single-locus analysis, no significant differences were found between long-lived people and short-lived people in the genotype/allele distributions of all variants. In contrast, haplotype analysis indicated that haplotypes A-G-C and A-C-T were more prevalent in long-lived people than short-lived people (P=0.026 and 0.017), and the analysis conferred a 3.46- and 4.51-fold increased tendency for longevity, respectively (P=0.025 and 0.016). The haplotype results were strengthened by interaction analysis, which suggests an optimal model in which G190C and T2437C exert an interacting effect on longevity. No functional significance was observed between 190G and 190C alleles in both control and heat-inducible A549 cells (P>0.05). Taken together, our findings suggested that common genetic variants in Hsp70 family might contribute interactively to longevity the Xinjiang Hetian Uygur population.

Prevalence of conventional cardiovascular disease risk factors among Chinese Kazakh individuals of diverse occupational backgrounds in Xinjiang China.

Kazakh is a typical transnational ethnic group with the Eurasian lineage. It is the main ethnic group in Kazakhstan, and one of the ethnic minorities in China, Russia, Turkeymore than 40 other countries and regions. There are an approximately 1.25 million Kazak populations in China, of which 96.4% is located in northern Xinjiang [1]. For thousands of years, Chinas Kazakh people are mainly active in raising livestock on the prairie grasslands.With the development of the urbanization, Kazak people naturally formed three different subgroups with different occupation backgrounds (i.e., nomads, farmers, and urban residents). When cardiovascular disease (CVD) risk factors are more prevalent in urban China, little is known about the prevalence about this ethnic group. To investigate the prevalence of CVD conventional risk factors among Kazakh individuals of different occupational backgrounds the baseline data of The Xinjiang Altay Kazakh Heart Study (XAKHS) was used.