North American Caucasian Population Research Articles

Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis.

Despite recent scientific inquiry, idiopathic subglottic stenosis (iSGS) remains an enigmatic disease. The consistent demographics of the affected population suggest genetic factors may contribute to disease susceptibility. Given the inflammation observed in the affected proximal airway mucosa, we interrogated disease association with human leukocyte antigen (HLA) polymorphisms. Polymorphisms in the HLA locus have previously been shown to influence individuals' susceptibility to distinct inflammatory diseases. High-resolution HLA typing of 37 iSGS patients was compared with 1,242,890 healthy Caucasian controls of European ancestry from the USA National Marrow Donor Program and 281 patients with granulomatosis with polyangiitis (GPA). Complete HLA genotyping of an iSGS population showed no significant associations when compared to a North American Caucasian control population. Unlike GPA patients, iSGS was not associated with allele DPB1*04:01 nor did allele homozygosity correlate with disease severity. There was not a detectable HLA association observed in iSGS. These results support the concept that iSGS possesses a distinct genetic architecture from GPA. If genetic susceptibility exists in iSGS, it likely lies outside the HLA locus. NA, basic science Laryngoscope, 133:2533-2539, 2023.

Anthropometric analysis of linear parameters of the Indian nose: A cross-sectional study and comparison with literature

Many studies have been done to find out the accepted "ideal" appearance and proportions of the nose. However, much of this work has been limited to the facial architecture of the North American Caucasian population. Therefore, most beauty standards are driven by Western influences. To measure different standard linear parameters of Indian faces and compare them with the studies found in the literature, in an endeavor to help in preoperative planning in rhinoplasty while maintaining their ethnicity. This was a hospital-based cross-sectional study of 500 subjects. A total of 21 standard measurements were noted directly from the faces, and 11 proportional values calculated. Mean values with standard deviations were statistically used for comparisons with studies in the literature. There were significant differences between male and female subjects of our study in 16 variables. The proportional indices calculated also revealed significant differences statistically in 6 out of 11 measurements between male and female subjects. Significant differences were found in most of the parameters when our data were compared with Indian American, North American white population, Korean, Chinese, and African American. Facial measurements in the Indian population are different from those of other races, such as nasal index: (al-al×100/n-sn), sn-prn x 100/ al-al index, and sn-prn x 100/n-Sn index, and it is important to have own set of parameters to act as standards guiding esthetic nasal surgeries while maintaining ethnicities. Our study is an attempt at the same. However, because of the huge diversity of the Indian population, it requires larger studies from different regions to achieve the final aim to create standards for cosmetic rhinoplasties.

Skeleto-dental features among a sample of Saudi female children compared to North American standards: A cephalometric study.

This cross-sectional observational retrospective study aimed at assessing the cephalometric skeleto-dental features of class I, II, and III skeletal relationships of Saudi female school children samples and comparing the results to the established North American Caucasian cephalometric standards. The sample consisted of 205 retrospective lateral cephalometric radiographs of female school children. The age range of the subjects was between 10 and 13 years with a mean age of 11 ± 1 years. Several cephalometric and constructed points were identified. Angular, linear, and proportional measurements were obtained and analyzed. The skeleto-dental features of class II and class III were compared to class I of this sample then compared with the established North American Caucasian population. Different angular, linear, and proportional variables were investigated. Descriptive statistics and student t-test were used for data analysis. The distribution of the skeletal relationship revealed that 68.3% of the sample showed class I relationship, 16.1% class II, and 15.6% class III. The result indicates significant differences between the different classes. A greater tendency towards class II facial pattern and more convex profile among Saudis were detected in the present study compared to Caucasians. Furthermore, The dentoalveolar relationship results showed more Bi-maxillary protrusion among Saudi females compared to the North American Caucasians. The results obtained can be of great value in distinguishing the various skeleto-dental features in the different skeletal classes among the Saudi females and in the clinical diagnosis and treatment planning. Furthermore, the results of the study can also serve as a base-line for future investigations in Saudi Arabia.

Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss

Specific killer cell immunoglobulin-like receptor (KIR) in women with recurrent pregnancy loss (RPL) and HLA ligands in couples invoke a susceptibility to RPL. However, the relationship between KIR2DL2 and its cognate ligand HLA-C1 has not been explored. In this prospective cohort study, 160 Caucasian women with RPL and 99 partners were included. KIR/HLA-C typing, NK assay, Th1/Th2 intracellular cytokine ratios, 25-(OH)-vitamin D level, and the presence of autoantibodies were analyzed. KIR2DL2 positive women (P = 0.023) and their partners (P = 0.017) had lower allele frequencies of HLA-C1 than those of KIR2DL2 negative women. KIR2DL2 positive women had significantly lower genotype frequency of HLA-C1C1 as compared to the North American Caucasian population controls (P < 0.05). In the partners of KIR2DL2 positive women, there was a substantially higher frequency of HLA-C2C2 than controls (P = 0.016). Besides, KIR2DL2 negative women had a higher prevalence of anti-ssDNA antibody as compared with that of KIR2DL2 positive women (P = 0.043). There were no differences in the distribution of HLA-C genotypes based on KIR2DL2, regardless of pregnancy outcome in women with RPL and their partners while on immunomodulation treatment. In conclusion, decreased ligands for inhibitory KIRs (inhKIR) could lead to insufficient inhibition of maternal uterine NK cells toward the trophoblast, thereby contributing to the pathogenesis of RPL. Specific KIR and HLA-C genotyping may predict the reproductive outcome of women with RPL.

Molecular characterization of prostate cancer in Middle Eastern population highlights differences with Western populations with prognostic implication.

To investigate the incidence and prognostication of ERG, PTEN and SPINK1 protein expressions in prostate cancer cohort of Middle Eastern descent in comparison to published data from Western population. Immunohistochemistry for ERG, PTEN and SPINK1 was performed in a cohort of localized PCA (n = 340). The data were correlated to pathological and clinical outcomes and compared to Western populations. ERG expression and PTEN loss were noted in 123/288 (42.7%) and 91/297 (30.6%) of patients, respectively. SPINK1 expression was assessed in a subset of cases, noted in 6/150 (4%) of patients. Only ERG expression was associated with grade groups, being more common in the lower grade groups (1-3 vs 4-5; p = 0.04). In contrast to the Western population, PTEN loss foci were more likely to be ERG negative, observed in 81% of tumor foci and patients with PTEN neg/ERG pos were more likely to exhibit biochemical recurrence (OR 2.831; 95% CI 1.10-726, p = 0.03). This association remained significant in multivariate analysis (OR 2.68; 95% CI 0.98-7.33, p = 0.05), after adjusting for GG, path stage and surgical margin. This study documents significant differences in key molecular events in PCA in Middle Eastern population compared to Western populations that could explain differences in PCA incidence, progression and prognostication. ERG, PTEN and SPINK1 genomic alteration occur less frequently and the enrichment of ERG for PTEN loss is not observed. Additionally, patients with combined PTEN loss/ERG positive are at highest risk for BCR vs North American Caucasian population where PTEN loss alone seems to be associated with the worst clinical outcome. The data presented here further support differences in clonal evolution between Middle Eastern and Western population in relation to PCA and add further insight to understanding PCA molecular pathways.

Association of Hypomorphic P2X7 Receptor Genotype With Age.

One of the main risk factors for brain diseases is aging. Recent studies have shown that aging is a progressive degenerative process associated with chronic low-level inflammation. The ATP-gated P2X7 receptor (P2X7R) plays an important role in inflammation and has been associated with different brain (e.g., Alzheimer’s and Parkinson’s) or other age-related (osteoporosis, arthritis, cancer) diseases. Several single nucleotide polymorphisms (SNPs) in the P2RX7 gene have been identified, including the loss-of-function 1513A>C and 1405A>G SNPs, and the gain-of-function 489C>T and 1068G>A SNPs. We carried out a literature analysis to verify an association between P2RX7 SNPs’ frequency and age. In 34 worldwide eligible studies (11.858 subjects) no correlation between 1513CC genotype frequency and age emerged. On the contrary, analysis of European Caucasian cohorts (7.241 subjects) showed a significant increase in 1513CC frequency with age (P = 0.027). In agreement with these findings, analysis of two publicly available datasets, including USA Caucasian cohorts, unveiled an increased frequency of 1513CC and 489CC genotypes with age (P = 0.0055 and P = 0.0019, respectively). Thus, hypomorphic P2RX7 genotypes may be positively selected with age in European and North American Caucasian populations. We hypothesize that Caucasian individuals bearing an anti-inflammatory P2X7R phenotype and living in high-income countries may have a longer life expectancy.

Long non-coding RNA expression analysis during mouse testis development using the FANTOM5 data

Specific killer cell immunoglobulin-like receptor (KIR) in women with recurrent pregnancy loss (RPL) and HLA ligands in couples invoke a susceptibility to RPL. However, the relationship between KIR2DL2 and its cognate ligand HLA-C1 has not been explored. In this prospective cohort study, 160 Caucasian women with RPL and 99 partners were included. KIR/HLA-C typing, NK assay, Th1/Th2 intracellular cytokine ratios, 25-(OH)-vitamin D level, and the presence of autoantibodies were analyzed. KIR2DL2 positive women (P = 0.023) and their partners (P = 0.017) had lower allele frequencies of HLA-C1 than those of KIR2DL2 negative women. KIR2DL2 positive women had significantly lower genotype frequency of HLA-C1C1 as compared to the North American Caucasian population controls (P < 0.05). In the partners of KIR2DL2 positive women, there was a substantially higher frequency of HLA-C2C2 than controls (P = 0.016). Besides, KIR2DL2 negative women had a higher prevalence of anti-ssDNA antibody as compared with that of KIR2DL2 positive women (P = 0.043). There were no differences in the distribution of HLA-C genotypes based on KIR2DL2, regardless of pregnancy outcome in women with RPL and their partners while on immunomodulation treatment. In conclusion, decreased ligands for inhibitory KIRs (inhKIR) could lead to insufficient inhibition of maternal uterine NK cells toward the trophoblast, thereby contributing to the pathogenesis of RPL. Specific KIR and HLA-C genotyping may predict the reproductive outcome of women with RPL.

Female breast shape categorization based on analysis of CAESAR 3D body scan data

In this study we explore the variation in female breast shape across the younger (age: 18–45), non-obese (BMI &lt; 30) North American Caucasian population, a population that has not previously been well-represented in studies of breast shape. A method of classifying breast shape was developed based on multiple data-mining techniques. Forty-one relative measurements (i.e., ratios and angles) were constructed from 66 raw measurements (circumferences, depths, widths, etc.), extracted from 478 CAESAR (Civilian American and European Surface Anthropometry Resource) scans, using self-developed Matlab® programs. Seventy subjects were regarded as outliers and were removed. The remaining data were transformed and standardized to ensure robust analysis. To judge results, an algorithm was developed to visualize clustering outcomes in the form of side profiles of breasts. The results of three clustering methods, namely hierarchical, K-means, and K-medoids clustering, were compared. Finally, breast shapes were categorized into three and five groups by two different cluster number selection criteria proposed by the study: (1) based on misclassification rate; (2) based on the goodness-of-fit of the model. Several of the relative body measurements were identified to be critical in defining breast shape. The findings and the proposed methods of this study can contribute to the development of improved shape and sizing systems of bra products that work for both manufacturers and consumers. The new methodology developed in this study can also be applied to other types of intimate apparel products where an understanding of body shape plays a key role in body support, comfort, and fit.

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality.

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

Management of patients with difficult autoimmune hepatitis

Autoimmune hepatitis (AIH) is characterized by a T-cell rich infiltrate associated with lobular and interface hepatitis, hypergammaglobulinemia and production of autoantibodies. Genetic risk is linked to the HLA particularly DRB1*0301 and DRB1*0401 alleles in North American and European Caucasian populations. It has recently been suggested that functional deficiencies in CD4(+)CD25(+)CD127(low)FOXP3(+) regulatory T cells contribute to the breakdown of immune tolerance that results in AIH. Most patients respond to immunosuppressive therapy with corticosteroids and can be maintained in remission by low-dose corticosteroid treatment and/or azathioprine. For those who progress to end-stage disease liver transplantation is an effective treatment although it is associated with recurrence. In the future it is likely that biological therapies will allow more targeted therapy designed to switch the balance to immune regulation and thereby restore immune homeostasis. Although treatment for many cases is relatively straightforward and successful problems are encountered in those who fail to respond to standard treatment, are unable to tolerate it or relapse. In such cases alternative therapies should be considered. In addition treatment is complicated in some patients by comorbidity and special care is required during and after pregnancy. We will discuss the current and future therapeutic options for patients with difficult to treat AIH.

Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force

Search terms included: Transfusion-associated graft-versus-host disease, Transfusion-associated graft-versus-host, TA-GvHD. The last guideline covering this topic was published in 1996 (British Committee for Standards in Haematology (BCSH) Blood Transfusion Task Force, 1996. The writing group produced the new draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology and Blood Transfusion Task Forces of the BCSH. The guideline was then reviewed by a sounding board of approximately 100 UK haematologists, the BCSH and the committee of the British Society for Haematology and amended, again by consensus. Criteria used to quote levels and grades of evidence are according to the GRADE system (Guyatt et al, 2006). Strong recommendations (grade 1, ‘recommended’) are made when there is confidence that the benefits either do or do not outweigh the harm and burden and costs of treatment. Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation (‘suggested’) is made. Grade 1 recommendations can be applied uniformly to most patients whereas grade 2 recommendations require judicious application. The quality of evidence is graded as A (high quality randomized clinical trials), moderate (B) or low (C). This publication reports the key recommendations of the Writing Group. It is also accessible at http://www.bcshguide lines.com.

GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients

Parkinson disease (PD) is one of the most common neurodegenerative disorders with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. At least thirteen gene loci responsible for PD or parkinsonism have been found and nine causative genes have been identified. Recently, Asn56Ser or Asn457Thr mutations in the Grb10-Interacting GYF Protein-2 gene ( GIGYF2) were found to occur in about 2.4% familial PD Italian and French patients. We conducted genetic examination of Asn56Ser or Asn457Thr mutations, but none was found in 310 PD patients from North America. We did identify a non-disease-associated polymorphism Pro460Thr. Our results suggest that the GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population.

Lack of mutations in the PVRL3 gene in North American caucasians with non-syndromic cleft lip/palate

Cleft lip with or without cleft palate (CLP) is one of the most common birth defects. In about 70% of cases, CLP occurs as an isolated anomaly, denoted non-syndromic CLP (nsCLP). Genetic linkage and association studies have implicated many loci in susceptibility to nsCLP, including some members of the nectin gene family. We performed mutation screening of the PVRL3 gene that encodes nectin-3 in 73 unrelated Caucasian nsCLP patients and 105 unrelated controls from North America. We detected no sequence variants in the PVRL3 gene in either the nsCLP patients or the controls. These data suggest that PVRL3 is not an important susceptibility gene for nsCLP in the North American Caucasian population.

Dentatorubral pallidoluysian atrophy in South Wales

Background:Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration...

CYP2C9 , CYP2C19 and CYP2D6 Allele Frequencies in the Ashkenazi Jewish Population

To determine and compare the cytochrome P450 (CYP)2C9, CYP2C19 and CYP2D6 allele and genotype frequencies in the Ashkenazi Jewish (AJ) population with other populations. CYP2C9, CYP2C19 and CYP2D6 genotypes were determined in 250 anonymous, unrelated, healthy AJ individuals from the greater New York (USA) metropolitan area. Genotyping was performed using the Tag-Ittrade mark Mutation Detection system and the recently redefined CYP2D6*41A allele was identified by a restriction fragment length polymorphism assay. Among the 250 AJ individuals, the CYP2C9*1, *2, *3 and *5 allele frequencies were 0.772, 0.140, 0.086 and 0.002, respectively, and the genotypes were distributed into extensive- (60.8%), intermediate- (32.8%) and poor- (6.4%) metabolizer phenotypes. The CYP2C19*1, *2 and *4 allele frequencies were 0.830, 0.152 and 0.018, respectively, and the genotypes were distributed into extensive (69.2%), intermediate (27.6%) and poor (3.2%) metabolizers. The most common CYP2D6 alleles identified were *1, *2A, *4 and *41A, and their frequencies were 0.286 0.152 0.226 and 0.140, respectively. The CYP2D6 genotypes were distributed into ultrarapid- (8.8%), extensive- (70.0%), intermediate- (16.0%) and poor- (5.2%) metabolizer phenotypes. Although the CYP2C9 allele and genotype frequencies in the AJ subjects were similar to those in other North American Caucasian populations, genotyping the CYP2C19*4 and CYP2D6*41A alleles in the AJ population resulted in the clinically relevant reclassification of the predicted metabolizer phenotypes. Inclusion of CYP2C19*4 reclassified individuals from either extensive- or intermediate- to the intermediate- or poor-metabolizer phenotypes, respectively. Inclusion of the redefined CYP2D6*41A allele increased the ultrarapid-, intermediate- and poor-metabolizer phenotype combined frequencies to 30%, indicating that approximately one in three AJ individuals may benefit from genotype-based drug selection and dosage. In addition, the ultrarapid CYP2D6 genotype frequency in the AJ population (8.8%) was approximately twofold higher than that in other North American Caucasians.

Startle modulation in Caucasian-Americans and Asian-Americans: a prelude to genetic/endophenotypic studies across the ???Pacific Rim???

Deficient prepulse inhibition (PPI) of startle in schizophrenia patients and unaffected family members may be a useful endophenotype in studies seeking to identify vulnerability genes for schizophrenia. Before expanding such studies to include Pacific Rim populations with distinct genetic origins compared with North American Caucasian populations, we examined PPI and related startle measures in normal North American Caucasian and Asian men. One hundred and seventy-four consecutive carefully screened right-handed male 18-35 year olds completed tests of startle and PPI using bilateral electromyography measures of orbicularis oculi. Subjects identified their racial background. Startle in Caucasian subjects was of significantly larger magnitude and shorter latency compared with Asian subjects; the percent PPI was significantly greater in Asian versus Caucasian subjects at 60 and 120 ms prepulse intervals. Group differences in PPI but not reflex latency were eliminated when groups were matched for startle magnitude on pulse alone trials. Caucasian-American and Asian-American groups did not differ significantly in resting blink rate, resting electromyography activity, or startle reflex habituation. Robust phenotypic differences in acoustic startle magnitude and latency between Caucasian-American and Asian-American populations must be considered in studies using startle and PPI as endophenotypes across these populations.

Genetic Analysis of Large Data Sets of North American Black, Caucasian, and Hispanic Populations at 13 CODIS STR Loci

Genetic Analysis of Large Data Sets of North American Black, Caucasian, and Hispanic Populations at 13 CODIS STR Loci

Molecular and functional bases of self-antigen recognition in long-term persistent melanocyte-specific CD8+ T cells in one vitiligo patient.

Vitiligo patients possess high frequencies of circulating CD8+ T lymphocytes specific for the melanocyte differentiation antigen Melan-A/MART-1. These self-specific T cells exhibit intact functional properties and their T cell receptors are selected for a narrow range of high affinities of antigen recognition, suggesting their important role in the pathogenesis of vitiligo. In order to understand the molecular base for this unexpected, optimal T cell receptor recognition of a self-antigen, a tetramer-guided ex vivo analysis of the T cell receptor repertoire specific for the Melan-A antigen in a patient affected by vitiligo is reported. All T cell receptors sequenced corresponded to different clonotypes, excluding extensive clonal expansions and revealing a large repertoire of circulating Melan-A-specific T lymphocytes. A certain degree of T cell receptor structural conservation was noticed, however, as a single AV segment contributed to the alpha chain rearrangement in 100% of clones and a conserved amino acid sequence was found in the beta chain complementarity determining region 3 of various high affinity cells. We suggest that the conserved alpha chain confers self-antigen recognition, necessary for intrathymic selection and peripheral homeostasis, to many synonymous T cell receptors, whereas the beta chain fine tunes the T cell receptor affinity of the specific cells. In addition, we demonstrate that many high avidity T cell clones from this patient were capable of specifically lysing normal, HLA-matched melanocytes. These autoreactive clones persisted for more than 3 y in the patient's peripheral blood. These data, together with the skin-homing potential of the clones, directly point to the in vivo pathogenic role of melanocyte-specific cytotoxic T lymphocytes in vitiligo.

Frequency of thiopurine S‐methyltransferase genetic variation in Thai children with acute leukemia

Background Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation (inactivation) of mercaptopurine, azathioprine, and thioguanine, and exhibits genetic variation. About 11% of Caucasians have intermediate TPMT activity because of heterozygosity, and about 1 in 300 inherits TPMT deficiency as an autosomal codominant trait. If patients who have intermediate or deficient TPMT activity receive the standard dose of thiopurine medications, they can accumulate excessive thiopurine nucleotides in hematopoietic tissue, which could lead to severe and possibly fatal myelosuppression. There is very little information about TPMT genetic variation among Asian populations. We investigated the frequency of TPMT genetic variation among Thai children with acute leukemia. Procedure Fresh whole blood was obtained from 75 Thai children with acute leukemia at the time of remission. Genomic DNA was isolated from total peripheral white blood cells. We performed polymerase chain reaction (PCR) to detect 3 types of variant of the human TPMT gene. Results Among 75 patients, the frequency of heterozygotes for the TPMT gene among Thai children with acute leukemia was ∼11%. However, the TPMT*3C was the only variant TPMT allele found among Thai children. This is different from the North American Caucasian populations, in which TPMT*3A is the predominant variant allele, and TPMT*3C is rare (∼5% of variant alleles). Conclusions There is no difference in the frequency of this genetic variation between Asian and North American Caucasian populations. Determination of the TPMT genotype by PCR method before antileukemic therapy is practical and may have clinical relevance. This knowledge could be applied towards organ transplant recipients who require these medications for immunosuppression. Med. Pediatr. Oncol. 35:410–414, 2000. © 2000 Wiley-Liss, Inc.