Association of the <Emphasis Type="Italic">PTPN22</Emphasis> polymorphism <Emphasis Type="Italic">C1858T</Emphasis> with type 1 diabetes mellitus

PTPN22 encodes a lymphoid protein tyrosine phosphatase LYP. Association of the PTPN22 polymorphism C1858T with type 1 diabetes mellitus was investigated using the transmission disequilibrium test (TDT) and a comparative analysis of the allele and genotype frequency distributions. The study involved two groups of families from Russian populations of Moscow and Samara with concordantly (27 families) and discordantly (62 families) affected sibs, as well as groups of type 1 diabetes patients and healthy individuals. The association of the PTPN22 polymorphism with type 1 diabetes was not significant by TDT analysis, but was significant by comparison of the allele and genotype frequency distributions. Thus, a case-control analysis detected an association of the PTPN22 polymorphism C1858T with type 1 diabetes mellitus in Russians.     

The ?159C/T polymorphism in the CD14 gene and the risk of asthma: a meta-analysis

The -159C/T polymorphism in the CD14 gene has been implicated in susceptibility to asthma, but a large number of studies have reported inconclusive results. The aim of this study is to investigate the association between the -159C/T polymorphism in the CD14 gene and the risk of asthma by meta-analysis. We searched Pubmed, Embase, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on April 20, 2010). Statistical analysis was performed by using the softwares Revman 4.2 and STATA 10.0. A total of 17 case-control studies in 17 articles (4,246 cases and 3,631 controls) were included in this meta-analysis. There was no association between this polymorphism and asthma risk in combined analyses (odds ratio (OR)?=?0.86 and 95% confidence interval (95% CI)?=?0.72-1.02, P?=?0.09 for TC?+?TT vs. CC). In the subgroup analysis by age, ethnicity, and atopic status, no significant associations of asthma risks were obtained from age groups, ethnic groups, and atopic groups for TC?+?TT vs. CC comparison. For atopic population, significant decreased atopic asthma risks were found among Asian population (OR?=?0.69, 95% CI 0.52-0.92, P?=?0.01) and children population (OR?=?0.69, 95% CI 0.54-0.89, P?=?0.0004) for TC?+?TT vs. CC comparison. This meta-analysis suggests that CD14 is a candidate gene for atopic asthma susceptibility. The -159C/T polymorphism may be a protective factor for atopic asthma in Asian and children. More studies are needed to validate these associations.     

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.     

Genetic polymorphism of <Emphasis Type="Italic">GSTT1</Emphasis> may be under natural selection in a population chronically exposed to natural sour gas

Objective In order to examine whether chronic exposure to natural sour gas containing sulfur compounds act as natural selection force on genetic polymorphisms of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1), the present study was done. Methods The study was performed on two groups of healthy individuals of Masjid-i-Sulaiman (Khozestan province, southwest of Iran) citizens with the mean ages of 47.5 ± 12.4 (36 male and 58 female) and 16.3 ± 2.4 (47 male and 140 female) that were considered as first and second generation, respectively. The GSTT1 and GSTM1 genotypes were determined using a PCR-based method. Results The genotypic frequencies of GSTM1 did not change significantly (χ² = 0.085, df = 1, P = 0.770). The frequency of the GSTT1 null genotype was 52.1% in the first generation and reached to 36.4% in the second generation. There was significant difference between two generations for the GSTT1 polymorphism (χ² = 6.397, df = 1, P = 0.011). Conclusion It was suggested that the GSTT1 polymorphism may be under natural selection because of probably favored ability of GSTT1-active genotype to survival and reproduction.     

Genetic contribution of chemokine receptor 2 (CCR2) polymorphisms towards increased serum total IgE levels in Indian asthmatics

The chemokine (C–C motif) receptors (CCR) 2 and 5 are members of a large family of G protein-coupled receptors, playing important roles in asthma pathogenesis. Using standard sequencing techniques, a total of 15 single nucleotide and 8 insertion/deletion polymorphisms (DIPs) (5 novels) were identified in and around these two genes. None of the studied polymorphisms (N = 7, selected on the basis on linkage disequilibrium) was associated with asthma in a case (N = 315) – control (N = 337) study and showed no evidence for non-random transmission to individuals with asthma/atopy in Indian pedigrees (n = 235). However, multilocus haplotype analysis based on simulations yielded a P = 0.00005 in the case–control study and a P = 0.03 for the family-based association studies. Furthermore, rs3918356 and rs743660 polymorphisms in CCR2 were found to be associated with total serum IgE levels in both the study designs. Thus, our study supports a significant role for chemokine receptor polymorphisms in genetic susceptibility to asthma.     

<Emphasis Type="Italic">M31R</Emphasis> and <Emphasis Type="Italic">R335C</Emphasis> polymorphic variants of the <Emphasis Type="Italic">IL8RA</Emphasis> gene in Russian and Buryat patients with atopic bronchial asthma

To test the M31R and R335C polymorphisms of the Il8RA gene for association with atopic bronchial asthma (BA), the allele and genotype frequency distributions of the polymorphisms were studied in Russian patients from Moscow and Buryat patients from Ulan-Ude. The study involved two Russian groups, one including 291 DNA samples of patients with atopic BA, and the other, 266 DNA samples of healthy people. The two Buryat groups included 124 and 152 DNA samples from patients with atopic BA and healthy people, respectively. The M31R polymorphism proved to be associated with atopic BA in Russians. Allele Arg and genotype Met/Arg suggested a higher risk of BA (OR = 4.45, P = 0.003 and OR = 4.58, P = 0.003, respectively), while allele Met and genotype Met/Met were associated with a lower risk (OR = 0.22, P = 0.003 and OR = 0.22, P = 0.003, respectively). The R335C polymorphism was not associated with atopic BA in Russians and was in Buryats. Allele Arg and homozygous genotype Arg/Arg suggested a higher risk of the disease (OR = 3.06, P = 0.030 and OR = 3.20, P = 0.027, respectively), while allele Cys and genotype Arg/Cys suggested a lower risk (OR = 0.33, P = 0.030 and OR = 0.31, P = 0.027, respectively). The results support the role of the IL8RA gene in atopic BA.     

Association of polymorphisms in the β2-adrenoreceptor gene with higher levels of parasitic infection

The diminishing incidence of parasitic infection in westernised societies has been suggested to result in an increased prevalance of asthma. Asthma is a polygenic disease and genome screens have shown that genes on chromosome 5q31–33 are strongly linked to the disease. The gene for the β₂-adrenoreceptor is located in this region and two polymorphisms have been identified that result in amino acid changes at positions 16 (ArgGly) and 27 (GlnGlu). To determine whether these polymorphisms influence asthma and parasitic infection, a genotype/phenotype study has been performed on a cohort of 126 children from Coche Island in Venezuela. There is a high incidence of asthma on the island and intestinal helminthiasis is endemic. Genotyping for both polymorphisms was carried out by using the polymerase chain reaction and allele-specific oligonucleotide hybridisation. Genotype frequencies in this cohort were consistent with other studies and both polymorphisms were in significant linkage disequilibrium. Individuals who were homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P=0.001) and significantly larger wheal sizes following skin-prick testing with A. lumbricoides allergen (P=0.008). There was no association between either polymorphism and total serum IgE or asthma in this population. A combination of mast cell degranulation and the lung migratory phase of A. lumbricoides larvae may result in bronchoconstriction in infected individuals. These results suggest that the Gly 16 allele confers resistance to high levels of parasitic infection in this population. An alternative explanation for the association is that it may be the result of linkage disequilibrium with other genes in the chromosome 5q31–33 region. Received: 25 November 1998 / Accepted: 30 January 1999     

Negative association between asthma and variants of CC16(CC10) on chromosome 11q13 in British and Japanese populations

The gene encoding Clara cell-derived inflammatory molecule CC16 has been cited as a candidate gene for atopic asthma on chromosome 11q13. A genetic association study was performed with variants of the CC16 gene on chromosome 11q13 in relation to asthma in British (n=275) and Japanese (n=300) populations. No significant association was found between asthma and CC16 genotypes, irrespective of atopic status in these two populations. These data suggest that CC16 might not be the major locus for asthma on 11q13. Received: 22 December 1997 / Accepted: 9 February 1998     

Association between CD14 Promoter -159C/T Polymorphism and the Risk of Sepsis and Mortality: A Systematic Review and Meta-Analysis

Background

Recent studies on the association between CD14-159C/T polymorphism and sepsis showed inconclusive results. Accordingly, we conducted a comprehensive literature search and a meta-analysis to determine whether the CD14-159C/T polymorphism conferred susceptibility to sepsis or was associated with increased risk of death from sepsis.

Methodology

Data were collected from the following electronic databases: PubMed, Embase, Medline, Web of Knowledge, and HuGE Navigator, with the last report up to June 15, 2012. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. We summarized the data on the association between CD14-159C/T polymorphism and sepsis in the overall population and subgroup by ethnicity and sepsis subtype.

Principal Findings

A total of 16 studies on sepsis morbidity (1369 cases and 2382 controls) and 4 studies on sepsis mortality (731 sepsis patients) met the inclusion criteria for meta-analysis. Overall analysis showed no strong evidences of association with sepsis susceptibility under any genetic model. However, slight associations were found in Asian populations (dominant model: OR = 1.38, 95%CI = 0.96–1.98, P = 0.08) and septic shock patients (dominant model: OR = 1.72, 95%CI 1.05–2.83, P = 0.03; allelic model: OR = 1.52, 95%CI 1.09–2.12, P = 0.01) in the stratified analysis. Moreover, there was borderline association between CD14-159C/T and sepsis mortality under the dominant genetic model (OR = 1.44, 95%CI = 0.98–2.11, P = 0.06).

Conclusions/Significance

This meta-analysis suggests that the CD14-159C/T polymorphism may not be a significant susceptibility factor in the risk of sepsis and mortality. Only weak associations were observed in Asian populations and septic shock patients. More studies based on larger sample sizes and homogeneous sepsis patients are needed to confirm these findings.     

Genetic polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> (at codons 194 and 399) in Shiraz population (Fars province,southern Iran)

Objective Several potential functional polymorphisms in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been reported. There has been no information on interindividual variability of Arg194Trp and Arg399Gln polymorphisms of XRCC1 in the Iranian population. Due to the association between the polymorphisms of XRCC1 and the risk of some types of cancers, the present study was done. Methods The genetic polymorphisms of XRCC1 were detected by PCR-based method in 707 healthy individuals from Shiraz population, (Fars province, southern Iran). Results Considering that there was no statistically significant difference between males and females, the sex groups were pooled. The frequencies of 194Trp and 399Gln alleles were 9.05% and 33.95%, respectively. When both polymorphisms were considered, the linkage-disequilibrium was observed (D′ = 0.8986, r ² = 0.0413, P < 0.00001). Conclusion The present results indicated that the allelic frequencies in Iranian populations showed intermediate frequencies in comparison with European and other Asian countries.     

Association of <Emphasis Type="Italic">ADAM33</Emphasis> gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent (n = 44), mild persistent (n = 108) or moderate persistent (n = 23) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma (P = 0.010-<0.001). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed (P = 0.020-<0.001). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found (P = 0.036-<0.001, OR = 2.07–8.49). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma (P = 0.013-<0.0001, OR = 0.34–0.10). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.     

Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma

Bronchial asthma (BA) is a common chronic inflammatory disease characterized by hyperresponsive airways, excess mucus production, eosinophil activation, and the production of IgE. The complement system plays an immunoregulatory role at the interface of innate and acquired immunities. Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness. To determine whether genetic variations in the genes of the complement system affect susceptibility to BA, we screened single nucleotide polymorphisms (SNPs) in C3, C5, the C3a receptor gene (C3AR1), and the C5a receptor gene (C5R1) and performed association studies in the Japanese population. The results of this SNP case-control study suggested an association between 4896C/T in the C3 gene and atopic childhood BA (P=0.0078) as well as adult BA (P=0.010). When patient data were stratified according to elevated total IgE levels, 4896C/T was more closely associated with adult BA (P=0.0016). A patient-only association study suggested that severity of childhood BA was associated with 1526G/A of the C3AR1 gene (P=0.0057). We identified a high-risk haplotype of the C3 gene for childhood (P=0.0021) and adult BA (P=0.0058) and a low-risk haplotype for adult BA (P=0.00011). We also identified a haplotype of the C5 gene that was protective against childhood BA (P=1.4×10^–6) and adult BA (P=0.00063). These results suggest that the C3 and C5 pathways of the complement system play important roles in the pathogenesis of BA and that polymorphisms of these genes affect susceptibility to BA.     

Search for nucleotide diversity patterns of local adaptation in dehydrins and other cold-related candidate genes in Scots pine (Pinus sylvestris L.)

Nucleotide variation at several cold candidate genes including seven members of the dehydrin gene family was surveyed in haplotypes of Scots pine (Pinus sylvestris) sampled in populations showing divergence for cold tolerance in Europe. Patterns of nucleotide diversity, linkage disequilibrium, and frequency spectrum of alleles were compared between north and south populations to search for signs of directional selection potentially underlying adaptation to cold. Significant differentiation between populations in allelic frequency or haplotype structure was detected at dhn1, dhn3, and abaH loci. Allelic dimorphism with no evidence of haplotype clustering by geographical distribution was found at dhn9. An excess of fixed non-synonymous mutations as compared to the outgroup P. pinaster pine species was found at dhn1. Differences in nucleotide polymorphisms were found between the members of the Kn class of dehydrin upregulated during cold acclimation (average π_sil = 0.004) as compared to the SKn class (average π_sil = 0.024). The multilocus nucleotide diversity at silent sites (θ _W = 0.009) was moderate compared to other conifer species, but higher than previous estimates for Scots pine. There was an excess of rare and high frequency derived variants as revealed by significantly negative multilocus value of Tajima’s D (D = −0.72, P < 0.01) and negative mean value of Fay and Wu H statistics (H = −0.50). The level of linkage disequilibrium decayed rapidly with an average expected r ² of 0.2 at about 200 bp. Overall, there was a positive correlation between polymorphism and divergence at ten loci when outgroup sequence was available. The discovered polymorphism will be used for further evaluation of the adaptive role of genes through association mapping studies. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Twelve polymorphic microsatellite loci for <Emphasis Type="Italic">Achnatherum inebrians</Emphasis> (Poaceae)

Microsatellites are often highly variable and abundant in most complex genomes, therefore are widely used in population genetic studies. In this study, twelve polymorphic microsatellite loci were isolated and characterized for the Achnatherum inebrians, a plant abundant in grasslands of Northwest China. Characterization of 24 A. inebrians individuals form four geographically distant populations (Gansu, Qinghai, Xinjiang and Inner Mongolia provinces) showed moderate to high allelic diversity ranging from 3 to 13 alleles per locus, and the expected heterozygosity ranging from 0.41 to 0.67. No evidence of linkage disequilibrium was found for any locus pairwise comparisons. The markers described here will be useful for investigating the genetic diversity, genetic structure and gene flow of this species. Na Chen and Yan-Zhuo Yang contributed equally to this work.     

<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 domestication in shaping <Emphasis Type="Italic">Castanea sativa</Emphasis> genetic variation in Europe

The genetic structure of sweet chestnut (Castanea sativa Mill.) across Europe was assessed using 73 inter-simple sequence repeat markers to screen 1,768 individuals from 68 stands distributed across 29 sites in five European countries (Italy, France, Spain, Greece, and UK). At each site, trees were sampled from three distinct management types (domestication levels): naturalized stands, managed coppice, and grafted fruit orchards. In more than a third of the orchards, nonlocal genetic material (grafted clones) were evident, showing (as predicted) large differences from the other two domestication levels for most of the within-population genetic diversity parameters estimated. Randomly generated linkage disequilibrium analysis revealed weak though significant differences in two-locus allelic correlations between naturalized stands and coppice, suggesting that long-term management techniques may influence the genetic makeup of the populations. Multivariate analysis revealed the existence of five distinct gene pools across the study area; three were located in Greece, one on the northwestern coast of the Iberian peninsula and a large gene pool covering the rest of the Mediterranean basin. The implications of the results are discussed in relation to developing conservation strategies for chestnut genetic resources in Europe.     

A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence

Alcohol dependence (AD) is a common neuropsychiatric disorder with high heritability. A number of studies have analyzed the association between the Taq1A polymorphism (located in the gene cluster ANKK1/DRD2) and AD. In the present study, we conducted a large-scale meta-analysis to confirm the association between the Taq1A polymorphism and the risk for AD in over 18,000 subjects included in 61 case–control studies that were published up to August 2012. Our meta-analysis demonstrated both allelic and genotypic association between the Taq1A polymorphism and AD susceptibility [allelic: P(Z) = 1.1 × 10^?5, OR = 1.19; genotypic: P(Z) = 3.2 × 10^?5, OR = 1.24]. The association remained significant after adjustment for publication bias using the trim and fill method. Sensitivity analysis showed that the effect size of the Taq1A polymorphism on AD risk was moderate and not influenced by any individual study. The pooled odds ratio from published studies decreased with the year of publication, but stabilized after the year 2001. Subgroup analysis indicated that publication bias could be influenced by racial ancestry. In summary, this large-scale meta-analysis confirmed the association between the Taq1A polymorphism and AD. Future studies are required to investigate the functional significance of the ANKK1/DRD2 Taq1A polymorphism in AD.     

Association between asthma-related phenotypes and the CC16 A38G polymorphism in an unselected population of young adult Danes

The gene for Clara cell 16-kDa (CC16) protein is a promising candidate for asthma susceptibility. The CC16 38A allele has been associated with decreased CC16 plasma levels and increased incidence of asthma in Australian children. To date these results have not been replicated in adults. Therefore, potential links between CC16 A38G, asthma and atopy were investigated in an unselected population of young adult Danes. Four hundred sixty-four Danes, aged 19–29 years, from Copenhagen participated in an asthma and allergy phenotype–genotype study. Genotyping was done by Sau96I restriction digestion of PCR products spanning the A38G polymorphism. Potential A38G genotype and asthma-related phenotype associations were investigated using regression analysis, adjusting for potential confounders where appropriate. Adults with the 38AA genotype had higher odds of current asthma (OR 3.2, P=0.013) and ever asthma (OR 2.2, P=0.045) compared with those with the 38GG genotype. Adjusting for atopy had minimal effect on this relationship. A positive linear trend was evident between the 38A allele and atopic dermatitis (OR 1.67, P=0.02). No associations were found between the A38G polymorphism and rhinitis, atopy, forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), airway responsiveness (AR) to histamine or peripheral blood eosinophil level (PBEL). An atopy-independent association between CC16 38AA and asthma prevalence was identified, suggesting the CC16 38A allele predisposes to adult asthma independent of Th1/Th2 processes. This finding is consistent with previous studies in children, but is the first reported association between CC16 A38G and asthma in adults. CC16 38A also displayed a positive linear trend with atopic dermatitis.