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Background: C5aR-like receptor 2 (C5L2) has been identified as a receptor for the inflammatory factor Complement 5a (C5a) and acylation-stimulating protein (ASP). ASP binding to C5L2 leading to a net accumulation of TG stores and glucose transporter. The aim of the present study is to evaluate the association of the SNPs of C5L2 gene with coronary artery disease (CAD) in a Chinese population., Methods: We examined the role of the tagging single nucleotide polymorphisms (SNPs) of C5L2 gene for CAD using a case-control design. We determined the prevalence of C5L2 genotypes in 505 CAD patients and 469 age and sex-matched healthy control subjects of Han population., Results: There was significant difference in genotype distributions of rs2972607 and rs8112962 between CAD patients and control subjects. The rs2972607 was found to be associated with CAD in a dominant model (AA vs. AG + GG, P<0.001). Similarly, the rs8112962 was found to be associated with CAD in a dominant model (TT vs CT + CC, P=0.016). The difference remained statistically significant after multivariate adjustment (OR =1.401, 95% confidence interval [CI]:1.026~1.914, P=0.034; OR = 1.541, 95%CI:1.093~ 2.172, P=0.014; respectively)., Conclusion: The results of this study indicate that both rs2972607 and rs8112962 of C5L2 gene are associated with CAD in a Han population of China.

Background: C5L2, a G protein-coupled receptor (GPCR), has been demonstrated to be a ligand for acylation-stimulating protein (ASP). The aim of the present study is to evaluate the association of a novel variation (901A > G) of C5L2 gene with coronary artery disease (CAD)., Methods: We identified a novel single nucleotide polymorphism (SNP), (901G > A), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from Arginine to glutaminate at codon 300. We analyzed the relationship between this SNP and CAD in two independent case-control studies: one was in a Han population (492 CAD patients and 577 control subjects) and the other was in a Uygur population (319 CAD patients and 554 control subjects)., Results: The frequency of AG genotype in CAD subjects was less than that in the control subjects not only in Han (1.8% vs 8.6%, P < 0.001, OR = 0.143, 95% CI: 0.068 ~ 0.302) but also in Uygur population (0.9% vs 5.2%, P = 0.001, OR = 0.246, 95% CI: 0.072 ~ 0.837). After adjustment for known CAD risk factors such as hypertension, diabetes, smoking, age and gender, the difference remained significant., Conclusion: The 901G > A polymorphism of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.

In a previous study, we reported a novel single nucleotide polymorphism (SNP) 698C>T (P233L) in the gene, C5L2. This gene has been demonstrated to encode a functional receptor of acylation-stimulating protein (ASP), a G-protein-coupled receptor (GPCR), that has been shown to influence insulin secretion in cultured pancreatic islet cells in vitro and is a stimulator of triglyceride synthesis and glucose transport in vivo. In this study, we evaluated the relationship between this novel C5L2 SNP and development of type 2 diabetes mellitus (T2DM) in the Chinese Han population. A case-control study examining Chinese Han T2DM patients (n = 554) and healthy controls (n = 648) was performed to investigate the role of the 698C>T (P233L) C5L2 polymorphism. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to determine expression of this SNP. Heterozygote carriers of the 698CT C5L2 genotype were more frequent among T2DM patients (13.5%) than controls (3.2%; P < 0.001). The frequency of 698CT heterozygote carriers was significantly higher in women (12.8%) than in male subjects (5.7%, P < 0.001). The odds ratio (OR) of T2DM for 698CT carriers was 4.675 [95% confidence interval (CI) 2.840-7.694]. After adjustment of confounding factors such as age, sex, smoking, drinking, hypertension, and triglyceride (TG), total cholesterol, high-density lipoprotein, and low-density lipoprotein levels, the difference remained significant (P < 0.001, OR 5.556, 95% CI 2.444-12.630). Furthermore, the diabetic 698CT carriers displayed an increase in their serum TG level. However, there were no significant differences observed in any of the parameters measured in the control group. We conclude that the 698CT genotype of C5L2 may be an influencing genetic factor for T2DM in the Chinese Han population. These findings also indicate that heterozygous expression of 698CT C5L2 may contribute to metabolic abnormalities.

C5L2, a G protein-coupled receptor, is known to be a functional receptor of acylation-stimulating protein, which is a stimulator of triglyceride synthesis and glucose transport. A novel C5L2 variant (S323I) was identified and its association with familial combined hyperlipidemia (FCH) was recently reported. We looked for this SNP in three Chinese ethnic groups, including Han, Uygur, and Kazakh controls and patients with FCH and type 2 diabetes. One hundred and eighty-two unrelated subjects (77 of Han, 57 of Uygur, and 48 of Kazakh) with FCH were genotyped by direct sequencing, and 852 subjects (342 of Han, 338 of Uygur, 172 of Kazakh) with type 2 diabetes and 200 healthy controls (67 of Han, 72 of Uygur, and 61 of Kazakh) chosen from a cardiovascular risk survey study were genotyped with PCR-RFLP analysis. All 182 subjects with FCH, 99.5% of the type 2 diabetes patients and 100% of the healthy controls were successfully genotyped. Neither the FCH subjects nor the type 2 diabetes patients were found to have the S323I variant. This variant was also not identified in the healthy controls. We found no evidence to demonstrate that the S323I polymorphism contributes to familial combined hyperlipidemia or type 2 diabetes in the Chinese population.

The human cytomegalovirus (HCMV)-encoded chemokine receptor US28 is also a seven-transmembrane G-protein coupled receptor, whose signaling pathway is known for its involvement in host immune system evasion. HCMV infection can result in serious disease in immunocompromised individuals and is also linked to atherosclerosis and cardiovascular disease. Identifying amino acid residues that play a crucial role in successful viral adaptation in response to the host's immune defense is critical for effective drug design. In this study maximum likelihood-based codon substitution analyses were carried out to determine whether any codon of US28 has evolved adaptively. If the rate of nonsynonymous (dn) to the rate of synonymous (ds) nucleotide substitutions (ω = dn/ds) is greater than one, the codon is said to be under positive selection, indicating adaptive evolution. Although the overall ω for US28 gene was 0.154, indicating that most codon sites were subject to strong purifying selection, five codon sites are under strong positive selection. Three (E18D/L, D19A/E/G, and R267K/Q) of these positively selected sites are located in extracellular domains, the domains that play a crucial role for successful viral adaptation in response to the host's immune defense. The C-terminal (R329Q/W) and the fifth transmembrane domain (V190I), each have one positively selected site. These results suggest that relative to the extracellular domains, amino acid residues present in intracellular domains are more selectively constrained. A few amino acid residues in extracellular domains of US28 evolved more rapidly, presumably due to positive selection pressure resulting from ligand-binding and pathogen interactions of extracellular domains., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: Our study aimed to detect the frequency of age-related macular degeneration (AMD)-susceptibility single nucleotide polymorphisms (SNPs) in control subjects of Han Chinese in a population-based study., Methods: A total of 419 subjects of Han Chinese without AMD were recruited from our population-based Nantong Eye Study. Nine AMD-susceptibility SNPs were genotyped. The allele/genotype frequencies were compared with the data from the literature and NCBI Reference Assembly., Results: The call rates of genotyping were > 98%. All tested SNPs except for HTRA1 rs11200638 were in Hardy-Weinberg Equilibrium (HWE). The allele distributions of some AMD-susceptibility SNPs were different from the records for the Chinese population in the National Center for Biotechnology Information (NCBI) Reference Assembly. Compared to those in a Caucasian population, the frequency of minor alleles of CFH rs800292 (48% vs. 19.2%) and HTRA1 rs11200638 were much higher (47% vs. 25%), while the frequency of minor alleles of CFH rs1061170 (9% vs. 35%), CX3CR1 rs3732379 (3% vs. 21%), CX3CR1 rs3732378 (3% vs. 11%) and SERPING1 rs2511989 (11% vs. 48%) were much lower in the Han Chinese population. Minor differences were observed in the frequency of minor alleles of CFB rs4151667, C2 rs547154 and TLR3 rs3775291. The allele/genotype frequencies of CFH rs1061170 and HTRA1 rs11200638, two well-confirmed AMD-susceptible SNPs, were close to each other in the Han Chinese and Japanese population., Conclusion: The distribution of AMD-susceptibility SNPs shows ethnicity specificity. Substantial differences of the SNPs' distribution were noted from study to study, even within the same ethnic group. The genotype data will be used for longitudinal observation of AMD onset in the follow-up of the cohort.

Chemokine receptor-2 (CCR2) is a co-receptor for the entry of human immunodeficiency virus-1 (HIV-1) into the target cells. A mutation in CCR2 (CCR2-64I) exhibited a protective effect to delay the progression of acquired immunodeficiency syndrome (AIDS). To study the mutant frequency and polymorphism of CCR2 in Chinese populations, 1082 individuals from 15 Chinese populations distributing widely from north to south were collected. The genotypes of CCR2-64I were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with the digestion of restriction endonuclease FokI. Of the 1082 individuals, 352 (32.53%) were carriers of CCR2-64I allele, 257 of whom (23.75%) were heterozygotes (CCR2-64V/I), whereas 95 (8.78%) were homozygotes (CCR2-64V/V). The frequency of the CCR2-64I allele in those tested individuals was 20.66%. This prevalence of CCR2-64I was higher than what was known for American and European populations. Moreover, the frequencies of CCR2-64I were generally higher in northern China than they were in southern China, and the frequencies had significant variance in 15 populations of China (chi2 = 27.135, P = 0.018).

Objective: To explore the spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in the population of Shandong Province, China., Methods: Using the techniques of spatial stratified sampling and spatial statistics, the spatial genetic structure of the locus (CCR2-64 I and SDF1-3'A), which was shown to be important co-receptor for HIV infection, was quantified from the populations of 36 sampled counties of Shandong Province, and a total of 3147 and 3172 samples were taken for testing CCR2-64I and SDF1-3'A respectively from individuals without known history of HIV-I infection and AIDS symptoms., Results: There were significantly spatial genetic structures of the two alleles at different spatial distance classes on the scale of populations, but on the scale of individuals, no spatial structure was found in either the whole area of Shandong Province or the area of each sampled county. Although the change of frequencies of the two alleles with geographic locations in Shandong Province both showed gradual increase trends, their changing directions were inverse. The frequency of CCR2-64I allele gradually increased from the southwest to the northeast, while the frequency of SDF1-3'A allele gradually increased from the northeast to the southwest. However the RH to AIDS of combined types of their different genotypes did not represent obvious geographic diversity on the whole area of the Province., Conclusion: The frequency of allele usually has some spatial genetic structures or spatial autocorrelation with different spatial distance classes, but the genotypes of individuals have random distribution in the same geographic area. Evaluating spatial distribution of the genetic susceptibility of HIV (AIDS) to CCR2-64I and SDF1-3'A alleles, should focus on the frequencies of combined genotypes of CCR2 and SDF1 based on the two-locus genotypes of each individual rather than the frequencies of CCR2-64I and SDF1-3'A alleles.

Two chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms, V249I and T280M, and 10 CC chemokine receptor 5 (CCR5) promoter haplotypes, P1-P10, have recently been reported to influence the progression of acquired immune-deficiency syndrome (AIDS). As these studies were performed mainly with Caucasian and African-American subjects, we determined the distribution of these alleles in Chinese people for the purpose of predicting possible clinical responses to the human immunodeficiency virus type 1 (HIV) epidemics in countries with significant Chinese populations, as well as to establish their effects on the expression of surface CCR5. Ninety-six HIV-negative Chinese individuals in Taiwan were subjected to genotyping, and we thus determined that the allelic frequencies of CX3CR1V249I and T280M changes were 2.6% and 2.1%, respectively, which were lower than found in Caucasians (25.5% and 14.0%, respectively). Unlike the previous reports, we only detected CCR5P1 and P4 haplotypes in Taiwanese people, and the P1/P1, P1/P4 and P4/P4 genotype frequencies were 21.0%, 41.1% and 37.9%, respectively. The sequencing data confirmed the results of previous studies, showing that CCR5P1 exhibited a complete linkage disequilibrium with a polymorphic allele 59029A present in the CCR5 promoter. Furthermore, fluorescence-activated cell sorter analysis revealed that, in the absence of the CCR2-64I mutation, individuals carrying CCR5P1 tended to express more surface CCR5 on monocytes and CD4+ cells. Therefore, this study not only reports the frequencies for the CX3CR1 and CCR5 promoter haplotypes in a Chinese population living in Taiwan, but also identifies a statistical link between the P1/P1 haplotype and the elevated CCR5 expression levels in the study group.

Objective: To investigate the V249I and T280M allelic polymorphisms of human immunodeficiency virus (HIV) coreceptor CX3CR1 in HIV-1 infected and uninfected population of Chinese indigenous Han and Uygur people and to probe the association between I249-M280 haplotype and HIV-1 susceptibility as well as AIDS progression., Methods: Genomic DNA of 223 Uygur subjects and 316 Han subjects were purified from PBMC. I249 and M280 allelic frequencies were identified by polymerase chain reaction (PCR)/nest polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All data were tested by chi(2) or u statistics analysis., Results: Allelic frequencies of I249 and M280 were 16.1% and 13.3% in Uygur people, and 3.3% and 2.4% in Han people. No obvious difference existed between three groups of either ethnic group. However the allelic frequencies of HIV infected population were higher than those of general population, and those of general population higher than those of HIV-1 high-risk group. There was a strong linkage between I249 and M280 (P almost zero)., Conclusions: I249 mutation was the sine qua non of M280 mutation, and most I249 alleles were accompanied by M280. The frequency of I249-M280 haplotype in Uygur population (13.3%) was adjacent to Caucasian people (15.8%), and that of I249-T280 haplotype (2.8%) was obviously lower than Caucasian people (12.5%); while both of them in Han people were much lower (0.9% and 2.4%). I249-M280 haplotype could accelerate AIDS progression according to Faure et al, while might be associated with HIV-1 susceptibility.

The aim of this study is to determine in indigenous Chinese ethnic groups the frequencies of the chemokine (SDF1 3'A) and chemokine receptors (CCR5 delta32, CCR5 m303, and CCR2b 64I) HIV-1/AIDS restriction alleles. The study includes two cohorts; the first comprised 3165 indigenous healthy subjects representing eight ethnic groups: Han (n = 1406), Uygur (n = 316), Mongolia (n = 134), Hui (n = 386), Tibetan (n = 330), Zhuang (n = 378), Dai (n = 101), and Jingbo (n =114). The second cohort consisted of 330 HIV-1-infected (86 subjects infected by sexual transmission and 198 subjects infected by HIV-1-contaminated blood or by sharing injection equipment; the remaining 46 subjects said nothing about HIV-1 transmission) and 474 HIV-1-uninfected Han Chinese belonging to one of two HIV-1 high-risk groups: intravenous drug users (n = 215) and individuals with sexually transmitted diseases (n = 259). Genotypes for the four genes were obtained using PCR (CCR5 delta32) or PCR-restriction fragment length polymorphism. Randomly selected amplified PCR products were further confirmed by direct DNA sequencing. The variant allele frequencies were determined to be 0% to 3.48% for CCR5 delta32, 0% for CCR5 m303, 16.23% to 28.79% for CCR2b 64I, and 17.70% to 27.76% for SDF1 3'A in Chinese healthy individuals from eight ethnic groups. These findings show that allele frequencies differ among the eight Chinese ethnic groups for CCR5 delta32, CCR2b 64I, and SDF1 3'A and that the CCR5 m303 and CCR5 delta32 mutant alleles were absent or infrequent in Chinese, which may be helpful for studies of specific anti-HIV-1 vaccine trials and coreceptor inhibitor drug targets in Chinese populations. Furthermore, we observed no significant differences in allele or genotypic frequencies between HIV-1-infected and HIV-1-uninfected groups from the Han ethnic group. Our finding is the first reporting that there is likely no effect of the examined polymorphisms in our study on HIV-1 transmission in the Chinese Han population, However, the genetic effects of these and other AIDS-modifying polymorphisms on the pathogenesis and clinical outcome of HIV-1/AIDS diseases is under investigation in Chinese populations.

Objective: To evaluate the frequencies and polymorphisms of CCR5-delta 32, CCR2-64I and SDF1-3' A alleles conferring resistance to HIV-1 infection in Chinese population from Han ethnic origin., Methods: This cohort was comprised of 1251 subjects (915 men and 336 women) aged 15-80 years and none was HIV-1 positive. Genotyping of allelic CCR5-delta 32, CCR2-64I and SDF1-3' A variants was performed using PCR or PCR/RFLP assay, and further confirmed by direct DNA sequencing., Results: Our finding shows that the delta 32 deletion mutation in the CCR5 gene does occur in this population and can be inherited in a Mendelian fashion in indigenous Han Chinese at a very low frequency of 0.00119 (n = 1254). The frequencies of mutant CCR2-64I and SDF1-3' A alleles were 0.20023 (n = 1251) and 0.2873 (n = 893), in this population, which are higher than those found in American Caucasians. Furthermore the polymorphisms of CCR2-64I and SDF1-3' A alleles in the Han Chinese population were different from those in American Caucasians. Statistical analysis showed that the genotype distribution of CCR5-delta 32, CCR2-64I and SDF1-3' A alleles was in equilibrium according to the Hardy-Weinberg equation., Conclusion: The CCR5-delta 32 mutation may not be a major resistant factor against HIV-1 infection in indigenous Han Chinese. The significance of higher frequencies of CCR2-641 and SDF1-3' A alleles (0.20023 and 0.2791) in the Han population remains to be clarified in HIV-1-positive carriers and AIDS patients.

Objective: Mutant frequency and polymorphism of HIV-1 resistance CCR5-Delta32, CCR2b-64I and SDF1-3'A alleles were investigated in Chinese population from Mongolian ethnic origin., Methods: Whole blood samples from 134 Mongolian subjects were collected randomly and their genomic DNA were extracted using Qiagen Blood Kit. Allelic frequency was identified by means of PCR or PCR-RFLP analysis. Allelic polymorphism in population and between sex in the sample as well as correlation of the three genes were analyzed by chi(2) test., Results: The frequencies of the three alleles were as following: CCR5-Delta32 1.1%, CCR2b-64I 24.8% and SDF1-3'A 22.0% respectively. Distribution of the three mutant alleles among the Mongolian population was in accordance with Hardy-Weinberg equilibrium. Statistical analysis showed there was a higher frequency of CCR2b-64I in female than in male subjects (29.2% vs 19.7%). No Statistical difference was found in the allelic frequencies of both CCR5-Delta32 and SDF1-3'A between male and female individuals., Conclusion: Compared with the Caucasian American, there were higher frequencies of CCR2b-64I and SDF1-3'A alleles and lower frequency of CCR5-Delta32 allele found in Mongolian population while the factors responsible for the variation of genetic polymorphisms in different ethnic populations need to be clarified.

Objective: To study the frequency and polymorphism of three mutations (CCR5(Delta)32, CCR2-64I and SDF1-3'A alleles) conferring resistance to determined HIV-1/AIDS in the indigenous Han population in China., Methods: The study population included 1,267 subjects, of which consisted 98.7% (1,251/1,267) Han people. The genotypes of the three mutations were respectively, detected by polymerase chain reaction (PCR) for CCR5(Delta)32 mutation, or by PCR/RFLP (restriction fragment length polymorphism) assay with the digestion of restriction endonuclease Bsa BI and Msp I for CCR2-64I and SDF1-3'A mutations. DNA sequencing was employed to confirm the accuracy of PCR or PCR/RFLP products., Results: The frequency of the mutant alleles were: 0.00119 for CCR5(Delta)32; 0.20023 for CCR2-64I, and 0.28723 for SDF1-3'A. The three heterozygous CCR5-wt/Delta32 mutants were identified and no homozygotes were detected in indigenous Han population. The frequencies of CCR2-64I and SDF1-3'A alleles in China were higher than those of Caucasians descents in the USA and Europe., Conclusion: Our data was the first findings on the frequency and polymorphism of CCR5(Delta)32, CCR2-64I and SDF1-3'A alleles in indigenous Han population in China which implied that the indigenous Han people might have a higher genetic susceptibility to the infection of sexually transmitted HIV-1 (R-5) strain. Further study is needed to clarify the significance of higher frequency of CCR2-64I and SDF1-3'A alleles in Han population.