Hematologic Profile and Lymphocyte Subpopulations in Hemoglobin SC disease: Comparison With Hemoglobin SS and Black Controls

Compared with subjects with homozygous SS disease (Hb SS), persons with hemoglobin SC (Hb SC) are known to have a more gradual loss of splenic function, a lower incidence of bacterial infections, and fewer end-organ failures. We studied hematological indices and lymphocyte subpopulations of 27 Hb SC subjects and compared them with 173 Hb SS patients and 131 black controls. Hb SC patients had higher hemoglobin levels than Hb SS subjects, lower total leukocyte, granulocyte, monocyte, and lymphocyte counts. Platelets decresed with age but not significantly, instead of incressing as among Hb SS patients. Mononuclerar cells were generally similar to controls with the exception of CD8⁺HLA-DR⁺ counts resembling Hb SS, Hematologic changes in Hb SC are limited to moderate granulocytosis in children and aduts, mild monocytosis in aduts, and increased activation of just one lymphocyte subset among those measured.     

Genetics of Hb F/F Cell Variance in Adults and Heterocellular Hereditary Persistence of Fetal Hemoglobin

Hb F and F cell values in normal adults vary considerably with a continuous distribution that is substantially skewed to the right implicating a polygenic influence. The high values of Hb F and F cells are transmitted in the condition referred to as heterocellular hereditary persistence fetal hemoglobin which should be regarded as a multifactorial quantitative trait, quite distinct from the classical pancellular hereditary persistence of fetal hemoglobins. Several factors have been shown to influence F cell/Hb F levels in normal adults including age, gender, genetic determinants linked and unlinked to the β-globin locus on chromosome 11p. Two trans-acting quantitative trait loci for F cell variance have been mapped, one on 6q and the other on Xp, with at least one other implicated. As an initial step towards hunting for the other quantitative trait loci we have carried out a preliminary analysis of F cell variance in 182 pairs of monozygotic and 373 pairs of dizygotic twins. The correlation coefficient of F cell variance in monozygotic twins was 0.89, while that in the dizygotic twins was 0.51. Overwhelming evidence for a strong genetic component in the control of Hb F/F cell levels is provided by a heritability of 0.87. However, the role and extent of contribution from the quantitative trait loci on 6q and Xp are still not known.     

Bone mass in young adults: relationship with gender, weight and genetic factors

OBJECTIVES: To determine the relationship of the bone mass attained in young adults with anthropometric and genetic factors. DESIGN: Cross-sectional study of normal individuals. METHODS: We studied 341 healthy subjects between 22 and 45 years of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) and correlated with body weight, height and nine polymorphisms in six genes involved in sex steroid metabolism (17-hydroxylase, aromatase and 5-reductase) and activity (oestrogen receptors (ER)-alpha and -beta, and androgen receptor). RESULTS: The BMD was higher in men than in women (spine: 1.048 +/- 0.120 vs. 1.034 +/- 0.112; hip: 0.907 +/- 0.131 vs. 0.822 +/- 0.104 g cm(-2), P < 0.001). However, the difference was due, at least in part, to the larger body size in men and diminished markedly after height adjustment. There was a negative correlation between age and hip BMD. Body weight was the single most influential factor on spine and hip BMD in both sexes, explaining 8-9% of BMD variance. Amongst the genetic factors studied, a common CA repeat polymorphism in ER-beta showed a significant association with BMD in women (P = 0.03 at the spine, and 0.008 at the hip). The relationship between ER-beta genotype and BMD persisted after adjustment by body weight and age, explaining a further 2-3% of BMD variance. Allelic variants of other genes studied were not related with BMD. CONCLUSIONS: Body weight and allelic variants of ER-beta are associated with BMD in young adults.     

Hemoglobin H (Hb H) disease in Canada: molecular diagnosis and review of 116 cases

Over the past decade, we have characterized at the DNA level a total of 116 hemoglobin H (Hb H) disease patients living in Canada. The majority of patients were of southeast Asian descent (Chinese, Filipino, Laotian, Vietnamese), with a small number being of Mediterranean, Middle Eastern or East Indian background. A total of 15 distinct genotypes were detected, all but one being compound heterozygotes for a two-gene cis deletion and a single-gene deletion (-alpha/-) or a non-deletion mutation of the alpha2-globin gene (alpha(T) alpha/-). Seven different two-gene cis deletions were encountered, along with nine single-gene deletions and point mutations. The wide range of mutations associated with Hb H disease in Canada is a reflection of the population heterogeneity. The diagnosis of Hb H disease at the molecular level is important with respect to genetic counseling and the identification of families at risk for having pregnancies affected with Hb Bart's hydrops fetalis syndrome and/or Hb H disease. Six of the Hb H disease patients in our cohort had spouses who carried single-gene deletions, making these couples at risk for having children with Hb H disease. More important, seven patients had partners who carried two-gene cis deletions. These couples are at reproductive risk for both Hb Bart's hydrops fetalis syndrome and Hb H disease.     

Functional genetic variations of cyclooxygenase-2 and susceptibility to acute myeloid leukemia in a Chinese population

Background: Cyclooxygenase‐2 (COX‐2) is a key enzyme involved in the synthesis of prostaglandins, which are known to play important roles in the proliferation and differentiation of leukemia cells, and inhibitors of COX‐2 can suppress the proliferation and differentiation of human leukemia cell lines. Single‐nucleotide polymorphisms (?765G/C: rs20417, ?1195A/G: rs689466, and ?1290A/G: rs689465) in the COX‐2 promoter might contribute to differential COX‐2 expression and subsequent interindividual variability in susceptibility to cancer. Methods: In this case–control study, the genotypes of potential functional Single‐nucleotide polymorphisms in COX‐2 gene were determined with PCR–RFLP method in 446 patients and 725 controls. COX‐2 mRNA level in Acute myeloid leukemia (AML) bone marrow and COX‐2 protein level in serum samples were examined by real‐time PCR and ELISA, respectively. Results: It was found that carriers with ?765CC genotypes had a 2.19‐fold (95% CI = 1.24–3.88; P < 0.001) excess risk of developing AML compared with non‐carriers. A greater risk of developing AML was observed for A_?1195‐C_?765 haplotype compared with G_?1195‐G_?765 haplotype. Moreover, individuals with ?765C‐containing genotypes had significantly increased COX‐2 mRNA level and protein level compared with the ?765G‐containing counterparts. Conclusions: These findings indicate that ?765G/C polymorphism in COX‐2 may play a vital role in mediating individual susceptibility to AML.     

Meta-analysis of association of microRNAs genetic variants with susceptibility to rheumatoid arthritis and systemic lupus erythematosus

Background:An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE.Methods:Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs).Results:Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684–0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed.Conclusions:Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a² rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.     

Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle cell disease

Variation in the level of fetal hemoglobin (HbF) accounts for much of the clinical heterogeneity observed in patients with sickle cell disease (SCD). The HbF level has emerged as an important prognostic factor in both sickle cell pain and mortality, and a % HbF of 10–20% has been suggested as a threshold level for diminished clinical severity. The number of erythrocytes that contain HbF (termed F cells) may also be critically important, as F cells resist intravascular sickling and have preferential in vivo survival. Since F cells can be enumerated with high accuracy using flow cytometry methods, we prospectively studied a cohort of 242 children with SCD. Children with HbS and hereditary persistence of fetal hemoglobin (S/HPFH) had essentially 100% F cells. In contrast, children with homozygous sickle cell anemia (HbSS), HbS/β⁰ thalassemia, or HbS/β⁺ thalassemia had significantly lower mean % F cell values (55.9, 61.6, and 51.3%, respectively; P < 0.001), and children with HbSC had even fewer F cells (27.0%; P < 0.001). There was a highly significant correlation between the % F cells and the log (% HbF), which was observed for the total population of children (r = 0.95, P < 0.001), as well as for each of the individual subgroups of children with HbSS (r = 0.94, P < 0.001), HbSC (r = 0.89, P < 0.001), or HbS/β⁰ thalassemia and HbS/β⁺ thalassemia (r = 0.95, P <0.001). This logarithmic correlation between % F cells and % HbF has not been previously described and has important implications for the pharmacologic manipulation of HbF in patients with SCD. Am. J. Hematol. 54:40–46, 1997 © 1997 Wiley-Liss, Inc.     

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.     

Effect of PRDX6 gene polymorphism on susceptibility to chronic obstructive pulmonary disease in the Chinese Han population

Background

To explore the relationship of peroxiredoxin6 (PRDX6) tag-single nucleotide polymorphisms (SNPs) with susceptibility to chronic obstructive pulmonary disease (COPD) in the Chinese Han population.

Methods

A total of 502 patients with COPD and 481 healthy controls from nine hospitals in China were enrolled in this study. The PRDX6 tag-SNPs were identified by linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between identified tag-SNPs and COPD risk were further evaluated.

Results

Four PRDX6 tag-SNPs, including rs7314, rs34619706, rs33951697, and rs4382766, were identified in 30 healthy controls. Moreover, in the allele model, there was no statistical difference in locus in PRDX6 between patients with COPD and healthy controls (P > 0.05). However, in the recessive model, rs33951697 locus in PRDX6 gene carrier with T/T had an increased risk of COPD (odds ratio [OR] = 2.59, 95% CI = 1.06–6.33, P = 0.028). Furthermore, in the relevance analysis between genetic polymorphisms and smoking behavior and lung function indexes, we found that the number of smoked cigarettes per day and FEV1/FVC differed among different genotypes of PRDX6, rs4382766, and rs7314 (P < 0.05).

Conclusion

PRDX6 gene polymorphism with smoking status may contribute to the etiology of COPD in the Chinese Han population.     

白细胞介素-1F7基因单核苷酸多态性对强直性脊柱炎易感性与病情的影响

目的 探讨白细胞介素(IL)-1F7基因rs3811047位点单核苷酸多态性(SNP)对强直性脊柱炎(AS)易感性和临床表现型的影响.方法 收集AS患者158例和同期健康献血人群181名,采用连接酶检测反应(LDR-PCR)方法检测IL-1F7基因rs3811047位点SNP,分析其等位基因频率及基因型频率在AS和对照组中的分布,并比较不同基因型AS患者间临床表现型的差别.结果 AS患者和对照人群中rs3811047位点A等位基因频率(12.03%,17.68%)和G等位基因频率(87.97%,82.32%)的分布差异有统计学意义(x2=4.2204,P=0.0399);AA,AG,GG基因型频率在AS中分别为0,24.05%,75.95%,与对照组分布(2.76%,29.83%,67.41%)相比,差异亦有统计学意义(x2=6.2675,P=0.043).AG基因型的AS患者中人类白细胞抗原(HLA)-B27阳性率为70.27%(26/37),明显低于GG基因型AS中HLA-B27的阳性率94.23%(98/104),差异有统计学意义(x2=2.168,P=0.030);其红细胞沉降率和C反应蛋白水平明显亦低于GG基因型组(t=2.971,P=0.013;t=3.300,P=0.001).结论 安徽籍汉族人群AS易感性与IL-1F7基因rs3811047位点SNP有关,其基因型对AS的临床表现型有影响,携带A等位基因患者的炎症表现轻于不携带A等位基因的患者.     

A pooled analysis of three studies evaluating genetic variation in innate immunity genes and non-Hodgkin lymphoma risk

Genetic variation in immune-related genes may play a role in the development of non-Hodgkin lymphoma (NHL). To test the hypothesis that innate immunity polymorphisms may be associated with NHL risk, we genotyped 144 tag single nucleotide polymorphisms (tagSNPs) capturing common genetic variation within 12 innate immunity gene regions in three independent population-based case-control studies (1946 cases and 1808 controls). Gene-based analyses found IL1RN to be associated with NHL risk (minP = 0·03); specifically, IL1RN rs2637988 was associated with an increased risk of NHL (per-allele odds ratio = 1·15, 95% confidence interval = 1·05-1·27; P(trend) = 0·003), which was consistent across study, subtype, and gender. FCGR2A was also associated with a decreased risk of the follicular lymphoma NHL subtype (minP = 0·03). Our findings suggest that genetic variation in IL1RN and FCGR2A may play a role in lymphomagenesis. Given that conflicting results have been reported regarding the association between IL1RN SNPs and NHL risk, a larger number of innate immunity genes with sufficient genomic coverage should be evaluated systematically across many studies.     

Sequence type 1 group B Streptococcus,an emerging cause of invasive disease in adults,evolves by small genetic changes

The molecular mechanisms underlying pathogen emergence in humans is a critical but poorly understood area of microbiologic investigation. Serotype V group B Streptococcus (GBS) was first isolated from humans in 1975, and rates of invasive serotype V GBS disease significantly increased starting in the early 1990s. We found that 210 of 229 serotype V GBS strains (92%) isolated from the bloodstream of nonpregnant adults in the United States and Canada between 1992 and 2013 were multilocus sequence type (ST) 1. Elucidation of the complete genome of a 1992 ST-1 strain revealed that this strain had the highest homology with a GBS strain causing cow mastitis and that the 1992 ST-1 strain differed from serotype V strains isolated in the late 1970s by acquisition of cell surface proteins and antimicrobial resistance determinants. Whole-genome comparison of 202 invasive ST-1 strains detected significant recombination in only eight strains. The remaining 194 strains differed by an average of 97 SNPs. Phylogenetic analysis revealed a temporally dependent mode of genetic diversification consistent with the emergence in the 1990s of ST-1 GBS as major agents of human disease. Thirty-one loci were identified as being under positive selective pressure, and mutations at loci encoding polysaccharide capsule production proteins, regulators of pilus expression, and two-component gene regulatory systems were shown to affect the bacterial phenotype. These data reveal that phenotypic diversity among ST-1 GBS is mainly driven by small genetic changes rather than extensive recombination, thereby extending knowledge into how pathogens adapt to humans.The recent increase in large-scale DNA sequencing feasibility has allowed for significant advances in understanding the population genetics of bacteria that cause disease in humans (1, 2). A major outcome of the rapid expansion of available bacterial genomes has been the appreciation of the marked intraspecies genetic variability present in a wide variety of human bacterial pathogens (3, 4). This genetic variation can have profound impact on host–pathogen interaction by affecting transmissibility, infection severity, and antimicrobial resistance (2, 5, 6). The observed genetic intraspecies variability can arise via many distinct mechanisms including large-scale events such as recombination and bacteriophage-mediated horizontal gene transfer as well as small-scale genetic changes such as short insertions, deletions, and/or single nucleotide changes (2, 3, 5).Group B Streptococcus (GBS) is a common colonizer of humans that emerged in the 1970s as the leading cause of invasive bacterial disease in neonates and infants less than 3 mo of age (7). GBS is divided into 10 serotypes based on the carbohydrate composition of its sialic acid containing capsule, but gene content at the genomic level does not necessarily correlate with capsular serotype (8, 9). A seven-gene multilocus sequence typing (MLST) allows for the classification of the majority of GBS strains isolated from humans into five major clonal complexes (CCs) with a recent study by Da Cunha et al. showing that the major GBS CCs are primarily derived from a limited number of tetracycline-resistant clones, suggesting a key role of tetracycline resistance in GBS strain emergence (10, 11). CC-17 GBS strains have been particularly well studied given their role as the major cause of severe, invasive infant disease (10, 12). In contrast, serotype V strains cause a larger percentage of invasive disease in nonpregnant adults compared with neonates (13–15). Importantly, rates of invasive GBS disease have been increasing during the past 25 y in nonpregnant adults, with a significant part of the rise resulting from serotype V GBS strains (15–17).Despite the clear and increasing impact of serotype V strains, data are limited regarding molecular epidemiology of serotype V GBS causing invasive disease in nonpregnant adults (14, 15, 18). Only a few studies of serotype V strains have investigated the noncapsular genetic makeup of the strains, and those that have done so have included colonizing and invasive GBS strains isolated from infants or have not described the clinical origin of the tested strains (18, 19). Thus, we sought to analyze a large cohort of clinically well-defined, geographically distinct, and temporally disparate GBS isolates by using a whole-genome approach to elucidate the population structure of serotype V GBS causing invasive disease in nonpregnant adults. Data using non–genome-wide level approaches found that many serotype V strains were closely related, suggesting that a particular clone, rather than a genetically diverse array of strains arising from large-scale recombination, might be responsible for the majority of serotype V disease (18). Thus, we specifically sought to test the hypothesis that genetic diversity among invasive serotype V GBS strains is driven by small genetic changes at loci that are critical to GBS host–pathogen interaction.     

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.     

Genetic variations of the CDC2L2 gene are associated with type 2 diabetes in a Han Chinese cohort

OBJECTIVE: The purpose of the present study was to study the potential association of CDC2L2 variations with type 2 diabetes (T2D). METHODS: SNPs (single nucleotide polymorphisms) were extensively screened across the CDC2L2 gene by the site-specific PCR method ARMS (Amplification Refractory Mutation System). The identified novel polymorphisms were further evaluated in a Han Chinese cohort comprising of 467 patients with diabetes and 569 nondiabetic controls. In addition, 76 parent-offspring trios were also included in this association study.The case-control and TDT/sibTDT studies are applied for association analysis in this study. RESULTS: Seven loci (rs1059831, SNP33, rs7528782, SNP11, SNP36, rs11488590 and SNP30) were shown to be significantly associated with T2D in unrelated individuals (p < 0.05). When individuals were stratified by age, sex and body mass index (BMI), the SNP11 was shown to be strongly associated with female patients with T2D, patients whose age was over 45 years and individuals whose BMI was less than 23 (p = 0.018, 0.011 and 0.0089, respectively). However, it was not replicated in the family-based TDT/sibTDT analysis (p = 0.085, OR = 0.63 (CI 95% 0.34-1.06)). CONCLUSION: Our data suggested that the CDC2L2 gene may contribute to the susceptibility of type 2 diabetes in the northern Han Chinese population, but further studies are needed to replicate these findings.     

Genetic polymorphisms in non-alcoholic fatty liver disease： Clues to pathogenesis and disease progression

The spectrum of non-alcoholic fatty liver disease (NAFLD)ranges from simple steatosis through steatohepatitis to advanced fibrosis and cirrhosis. Although the reason why only a minority of patients develop progressive forms of disease still remains largely unclear, recent research has identified genetic factors as a possible basis for this variation in disease presentation. Most of the studies have been focused on finding associations between advanced disease forms and selected single nucleotide polymorphisms in genes encoding various proteins involved in disease pathogenesis. Although there are many limitations regarding the study design and interpretation of published data, further carefully planned studies together with implementation of new genetic technologies will likely bring new insights into disease pathogenesis and potential benefits to the management of patients with NAFLD.     

Role of a functional polymorphism in the F2R gene promoter in sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by increased inflammation, and results from gene–environment interactions. Proteinase‐activated receptor‐1 mediates the interplay between coagulation and inflammation. The rs2227744G > A promoter single nucleotide polymorphism has been linked to inflammation, cardiovascular disease and chronic obstructive pulmonary disease exacerbations. Using a case‐control study (184 cases with sarcoidosis and 368 controls), we show that the rs2227744A allele significantly associates with protection from sarcoidosis (P = 0.003, OR = 0.68 (0.52–0.88)).