Patients Of Other Ethnic Groups Research Articles

Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations.

Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately and accurately in highly-consanguineous Pakistani population. In the present discovery case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the analyses were stratified on the basis of age (≤40 years vs. >40 years) and ethnicity. The breast cancer gene panel assay was carried out by BROCA, which is a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (≤40 years) was higher in Sindhis (n = 12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grade III (50%), tumor size 2–5 cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients, which was not significantly associated with younger age or any particular ethnicity. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of hereditary-based preventive and treatment strategies against breast cancers in Pakistani population.

Abstract 3426: Genetic architecture of esophageal squamous cell carcinoma in African American veterans

Abstract Background: Esophageal carcinoma (EC) is one of the most common malignancies of the gastrointestinal tract worldwide and is unresponsive to therapy. Esophageal squamous cell carcinoma (ESCC) comprises the majority of EC in African Americans, Asians and other ethnic groups, while esophageal adenocarcinoma (EAC) predominates among Caucasians. Poor prognosis of EC in Caucasians and African Americans is reflected by five-year survival rates of 21% and 14 %, respectively. The aggressiveness and lower survival rate of African American ESCC patients than that from patients of other ethnic groups are evident even after adjusting for treatment modalities and socioeconomic factors. These characteristics suggest the existence of an ethnic- or race-dependent component of EC etiology. However, the genetic architecture of ESCC in AA is not well studied, and thus, mostly undefined. Our study aims to identify exonic mutations that may represent critical genetic changes in African American ESC carcinogenesis. Methods and Materials: Whole exome sequencing (WES) of matched tumor and normal tissue DNA from endoscopic biopsies from late-stage ESCC of nine African American Veteran male patients was conducted. This study was approved by the DC VAMC Institutional Review Board, and a written informed consent was obtained from each patient prior to biopsy. Biopsies were de-identified, freshly frozen and stored at -80 °C. To proceed to exon capture, we enriched our samples by using Agilent SureSelect XT Human All Exon V6+UTR. Paired-end sequencing at a read depth of 100X was performed on the exon libraries using the Illumina HiSeq 4000 sequencer. We applied Genome Analysis Toolkit's best practices WES pipeline to identify both germline and somatic variations in the dataset. The Seven Bridges Cancer Genomics Cloud platform was used for processing the data and annotating the variants. Variants were mapped to genomic regions and further aggregated at the gene level, pathways, and biological processes relevant to disease by using Reactome, Pathway Studio, and Ingenuity Variant Analysis. Results: In all samples, 27,586 variants consisted of 86% single nucleotide variation, 8.5% insertions and 5.5% deletions. Approximately half of the variants caused missense changes while 0.12% created nonsense mutations. High impact mutations occurred in genes that have a role in DNA damage repair, stress response, detoxification pathways, keratinization and immune surveillance. Conclusion: We found unique genomic variation in African American ESCC, that reveals a potential molecular signature for the aggressiveness and lethality of ESCC in this population. Future functional studies will be conducted to elucidate the role of these mutations in ESCC pathogenesis. Citation Format: Robert Wadleigh, Krithika Bhuvaneshwar, Gustavo Marino, Vincente Notario, Jack Lichy, Yuriy Gusev, Hayriye Verda Erkizan. Genetic architecture of esophageal squamous cell carcinoma in African American veterans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3426.

Gag-Specific CD4 and CD8 T-Cell Proliferation in Adolescents and Young Adults with Perinatally Acquired HIV-1 Infection Is Associated with Ethnicity - The ANRS-EP38-IMMIP Study.

The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty-nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care.

Whole-Exome Sequencing Identifies Novel Somatic Mutations in Chinese Breast Cancer Patients.

Most breast cancer genomes harbor complex mutational landscapes. Somatic alterations have been predominantly discovered in breast cancer patients of European ancestry; however, little is known about somatic aberration in patients of other ethnic groups including Asians. In the present study, whole-exome sequencing (WES) was conducted in DNA extracted from tumor and matched adjacent normal tissue samples from eleven early onset breast cancer patients who were included in the Shanghai Breast Cancer Study. We discovered 159 somatic missense and ten nonsense mutations distributed among 167 genes. The most frequent 50 somatic mutations identified by WES were selected for validation using Sequenom MassARRAY system in the eleven breast cancer patients and an additional 433 tumor and 921 normal tissue/blood samples from the Shanghai Breast Cancer Study. Among these 50 mutations selected for validation, 32 were technically validated. Within the validated mutations, somatic mutations in the TRPM6, HYDIN, ENTHD1, and NDUFB10 genes were found in two or more tumor samples in the replication stage. Mutations in the ADRA1B, CBFB, KIAA2022, and RBM25 genes were observed once in the replication stage. To summarize, this study identified some novel somatic mutations for breast cancer. Future studies will need to be conducted to determine the function of these mutations/genes in the breast carcinogenesis.

Ethnic Disparities in Trauma Mortality Outcomes

Ethnic disparities in trauma mortality outcomes have been demonstrated in the United States according to the US National Trauma Data Bank. The aim of this study was to determine the effect of race/ethnicity on trauma mortality in Singapore. This was a retrospective review of patients aged 18-64 years with an injury severity score (ISS) ≥ 9 in the Trauma Registry of Tan Tock Seng Hospital, a 1,300-bed trauma center in Singapore, from 2006 to 2010. Chinese, Malay, and Indian patients were compared with patients of other ethnic groups. Multiple logistic regression analyses determined differences in survival rates after adjusting for demographics, anatomic and physiologic ISS and revised trauma score, mechanism or type of injury. A total of 4,186 patients (66.4 % of the database) met the inclusion criteria. Most patients were male (76.3 %) and young (mean age 40 years). Using Chinese as the reference group, we found no statistically significant differences in unadjusted or adjusted mortality rates among the ethnic groups. Independent predictors of mortality included age [odds ratio (OR) 1.05, 95 % confidence interval (CI) 1.03-1.06, p < 0.0001], presence of severe head injury (OR 1.75, 95 % CI 1.13-2.69, p = 0.012), and increasing ISS (p < 0.0001). Ethnicity is not an independent predictor of trauma mortality outcomes in the Singapore population. Our findings contrast with those from the United States, where race/ethnicity (Black and Hispanic) remains a strong independent risk factor for trauma mortality. This study attests to the success of the Singapore health care/trauma system in delivering the same quality of care regardless of ethnicity.

The Prevalence of Autoantibodies in Saudis Patients with Type 1 Diabetes Mellitus

Background: Type 1 Diabetes mellitus (T1DM) results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. We designed this study to determine the prevalence of autoantibodies among Saudis patients with T1DM. Methods: Glutamic acid decarboxylase antibodies (GADA), antibodies to Islet cell (ICA) and Insulin (IAA) were measured in 171 Saudis patients with T1DM. Results: There were 171 patients with T1DM, 71 males (41.5%) and 100 females (58.5%). The mean age was 20.8 ± 6.6 and the mean diabetes duration was 7.7 ± 5.7. GADA, ICA and IAA were detected in 53.8%, 32.2% and 76% respectively. GADA, ICA and IAA were nonsignificantly more frequent in female and GADA and IAA were significantly more frequent in those younger than 20 years of age. Subjects testing positive for GADA had higher levels of ICA (42.4% vs. 20.3, p = 0.003) and IAA (79.3% vs. 72.2, p = 0.3) than those negative for GADA. Multiple antibodies (≥2) were observed more often in patients under the age of 20 years. There were nonsignificant differences in the prevalence of multiple antibodies between both genders. Multiple logistic regression analysis showed a significant independent positive relationship between the serum positivity of GADA, ICA and Multiple antibodies (≥2) with diabetes duration (0.02, p = 0.03, 0.02, p = 0.01 and 0.01, p = 0.04 respectively). Conclusions: The prevalence of autoantibodies in Saudi patients with T1DM is similar to those reported for diabetic patients in other ethnic groups.

Correspondence: Identification of TINF2 gene mutations in adult Japanese patients with acquired bone marrow failure syndromes

Mutations of the genes involved in human bone-marrow failure syndromes (BMFS) have been identified in components of the telomerase- and telomere-associated genes, including the TINF2 gene on chromosome 14q11·2, which encodes the 40 kDa TIN2 component of the telomere-associated shelterin protein complex (Calado & Young, 2008; Savage et al, 2008; Walne et al, 2008; Walne & Dokal, 2009). Clinically, it is very important to identify patients with pathogenic mutations in the telomere- or telomerase-associated genes, because these patients will probably exhibit refractoriness to conventional immunosuppressive therapy (IST) (Calado & Young, 2008). Several recent studies showed heterozygous TINF2 mutation in 1–5% of patients with acquired aplastic anaemia (AA) (Walne et al, 2008; Du et al, 2009). The subjects of these studies were Caucasian, Black and Hispanic. Analysis of the TINF2 gene among adult Asian populations of AA and myelodysplastic syndrome (MDS), to the best of our knowledge, had never been done. The largest controlled epidemiological study reported that the incidence of AA in the West was 2cases/million/year, but was about two- to three-fold higher in Asia (Issaragrisil et al, 2006). Therefore, we carried out an investigation to determine whether mutations in TINF2 could be found in our cohort of adult Japanese patients with acquired BMFS, and if so, at what frequency. We screened exon 6 of TINF2, as it was previously found to be a potential hotspot for disease-associated mutations (Walne et al, 2008; Du et al, 2009), among 142 Japanese patients who were diagnosed with acquired AA or MDS refractory anaemia between 1993 and 2006 at the Nippon Medical School Hospital. We excluded AA and MDS patients who were found to carry mutations in the telomerase TERC or TERT gene. We identified two AA patients (1·4%) with TINF2 heterozygous mutations, which were P283H and n865-866 di-nucleotide CC deletion (Fig 1A). The n865-866 di-nucleotide CC deletion in the TINF2 gene is a novel mutation that has not been previously identified. These mutations were not found in 300 healthy controls. Because of the lack of biological sample from the relatives of the patients as well as other tissues of the patients, it was not possible to determine whether these were segregational or germline mutations. Using Southern blotting technique, we compared the length of telomeres of mononuclear cells in AA patients who carried the TINF2 mutations to those of healthy age-matched controls. As shown in Fig 1B, AA patients with TINF2 mutations (Patients 1 and 2) showed much shorter telomere lengths than those of healthy age-matched controls. The clinical characteristics of these two patients with TINF2 mutation are shown in Table I. Both of the patients with TINF2 mutations were diagnosed with severe AA with no physical features of Dyskeratosis Congenita or its severe variant Hoyeraal-Hreidarsson syndrome (HH) (Walne et al, 2008) and showed no clinical response to IST. We attempted treatment of our patients with TINF2 mutations with metenolone, which is a dihydrotestosterone (DHT)-based anabolic steroid with androgenic properties, but they did not show any favourable clinical responses, unlike a previous report of favourable haematological response in BMFS patients with TERT mutations upon androgen treatment (Calado et al, 2009). In summary, we report here for the first time TINF2 natural mutations in 2/142 Japanese patients with acquired BMFS, which is at about the same frequency (1·4%) as reported in patients of other ethnic groups (Caucasian, Black and Hispanic) (Walne et al, 2008; Du et al, 2009). Identification of TINF2 mutations and telomere length measurements. (A) Gene mutations identified by direct sequencing. In the case of the n865-866 di-nucleotide CC deletion (Patient 2), the TINF2 PCR product was sub-cloned into pCR2·1-TOPO expression vector and sequenced. (B) telomere lengths of patients with TINF2 mutations. Patient 1: 3·1 kb, Patient 2: 4·9 kb. HY was the principal investigator and takes primary responsibility for the paper. HY, KI, JT, HT and KD recruited the patients. HY, KI, YM and FK performed the laboratory work for this study. HY, HL and KD analyzed the data and wrote the paper. The authors reported no potential conflicts of interest. This work was supported in part by grants from the American Cancer Society (RSG-06-162-01-GMC) and the AA&MDSIF to H.L.

Different Natural History of Ulcerative Colitis (UC) in Hispanic and Caucasian Patients with Ileal Pouch-Anal Anastomosis (IPAA)

Purpose: Inflammatory bowel disease is becoming increasingly recognized in ethnic and racial minorities. IPAA has become the treatment of choice for patients with UC requiring surgery. Few studies have characterized UC and pouch outcomes in the Hispanic American population. The aim of the study was to characterize natural history and outcome of IPAA in a Hispanic population. Methods: Hispanic ethnicity was designated by self-report and the Hispanic patients with UC and IPAA were identified from the prospectively maintained pouch database. Demographics, clinical characteristics and pouch outcomes in Hispanic population were compared to those in a random sample of Caucasian patients (1:2 ratio). Exclusion criteria were patients with a preoperative diagnosis of Crohn's disease, indeterminate colitis, or familial adenomatous polyposis, and patients of other ethnic groups. Results: 33 Hispanic patients with IPAA were identified. Gender distribution, family history of IBD, smoking history, preoperative immunomodulator use, extent of UC, toxic megacolon or fulminant colitis, pouch configuration, stage of pouch, presence of extraintestinal manifestation, autoimmune disorders, primary sclerosing cholangitis, or significant comorbidities were similar between the two groups. Current pouch conditions including normal pouch, irritable pouch syndrome, acute pouchitis, chronic pouchitis, cuffitis, surgical complications, and anismus were also similar. However, when compared with Caucasian controls (n=66), Hispanic patients were younger at UC diagnosis and at colectomy, and they were more likely to have colectomy for dysplasia. The interval between diagnosis and colectomy was comparable. No Hispanic patients received biologic agents for UC before colectomy or pouch disease while 10.3% and 11.8% of Caucasian patients had biologics for underlying UC or for pouch diseases, respectively (Table). Conclusion: The natural history of UC differed between the two ethnic groups before colectomy, but similar after colectomy and IPAA. Biosocioeconomical factors may lead to these differences, which warrants further investigation.Table 1: Comparison of clinical characteristics between Hispanic and caucasian populations

Future Treatment for Non-Aids-Defining Cancers in HIV-Infected Patients

ISSN 1758-4310 10.2217/HIV.09.14 © 2009 Future Medicine Ltd HIV Ther. (2009) 3(4), 311–314 at higher risk for some cancers compared with African–Americans and patients of other ethnic groups [7]. Additional risk factors include behavioral aspects, such as an increased use of tobacco and alcohol in patients with HIV [8]. Research has demonstrated that HIV itself may have direct effects that contribute to the development of NADC. For example, the HIV Tat protein may cause transactivation of protooncogenes [9]. Other genes within the HIV virus may inhibit tumor suppressor genes, including p53. HIV infection may cause microsatellite gene instability and genetic alterations leading towards onco genesis. Tissue infection with HIV may make these t issues more sensitive to the effects of carcinogens from the environment. Finally, HIV infection can cause endothelial abnormalities including pro angiogenesis, which may enhance the development of tumor growth and metastasis [1]. There have been conflicting data regarding whether HAART is associated with the risk of developing NADCs. Some studies have demonstrated a decreased risk of developing a NADC while patients are on HAART, compared with patients who are not receiving antiretroviral therapy or are only on single agent or dual agent antiretroviral therapy [7]. Other studies have demonstrated a possible increased risk if patients are on HAART [4], and specifically if they are on a non-nucleoside reverse transcriptase inhibitorbased therapy [5]. A concerning, recent finding in the large Phase III trial that led to the approval of raltegravir (an integrase inhibitor also known as Isentress [Merck] and MK-0518) was that during the period of the study, patients on raltegravir had a higher risk of developing a NADC compared with those taking placebo [10]. Clearly more research is needed to elucidate the role of antiretroviral therapy, immune reconstitution and the relative risk of developing NADCs. Editorial

A Genetic Basis for Adult Onset TTP?.

Thrombotic thrombocytopenic purpura (TTP) presents in childhood or adult life and is caused by a deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity. Several mutations and polymorphisms have been reported in ADAMTS13 in congenital TTP. The study aim was to elucidate whether a mutation(s) may be linked to adult onset TTP, which may be precipitated by infection, pregnancy or oestrogen-containing preparations and is associated with antibodies to ADAMTS13. We investigated 58 adult onset TTP patients (median age 39 (range 16–74) years) with ADAMTS13 activity levels <5% of pooled normal plasma when tested pre-treatment during the acute phase of their TTP episode. Initial screening using WAVE® technology detected a novel sequence change in exon 24 of ADAMTS13 in 2/14 of these patients (both heterozygous). Gene sequencing identified this nucleotide change as C3178T which results in the significant amino acid substitution arginine to tryptophan (R1060W) in the terminal thrombospondin type 1 (TSP1-8) domain of ADAMTS13. We confirmed this C3178T nucleotide change using a specific PCR and restriction enzyme digest and studied the remaining 44 cases, identifying one homozygote (T3178T) and three additional heterozygous patients, giving a total of 6/58 (10.3%). Fifty-eight healthy normal subjects (median age 33 (range 22–57) years) were also screened for this C3178T nucleotide change and all had the wild-type (C3178C) genotype. There was a significant difference in prevalence of the C3178T missense mutation between the TTP patient and normal control groups (p=0.0072, χ2 test, odds ratio (OR) = 0.00, 95% confidence intervals (CI) = 0.00–0.67). The mutation was only detected in Caucasian patients (n = 6/41). It was not found in any of the Afro-Caribbeans (n = 8), Asians (n = 5) or patients in other ethnic groups (n = 4). The difference in prevalence remained significant amongst the Caucasian contingent (p=0.0024, χ2 test, OR = 0.00, 95% CI = 0.00–0.52). IgG antibodies to ADAMTS13 (found in 37/58 (63.8%) patients) were demonstrated in three of the five heterozygous C3178T TTP patients, but not in the homozygous patient. The C3178T mutation was also detected in the mother of one of these three heterozygous patients and the daughter of the homozygous patient, neither of whom have had TTP. In conclusion, the novel C3178T missense mutation appears to be associated with adult onset TTP and in some instances, antibodies to ADAMTS13. This raises the possibility that adult onset TTP may arise as a result of an interaction between genetic and acquired factors.

Autoantibodies to GAD and IA‐2 in Saudi Arabian diabetic patients

To determine the prevalence of autoantibodies in sera of Saudi diabetic patients including Type 1 and Type 2 diabetes mellitus (DM) and gestational diabetes mellitus (GDM) living in Jeddah, Saudi Arabia. Apart from data on the prevalence of islet-cell antibodies in patients in Ryhadh (Al-Attas et al. Frequency of islet cell antibodies in adult newly diagnosed diabetic patients. Ann Saudi Med 1990; 10: 369-373) immunological markers of autoimmune diabetes have not been explored in Saudi Arabians. Autoantibodies to GAD65 (GADA) and IA-2 (IA-2A) were determined using radio-immunoprecipitation assays. In Type 1 DM patients, 54% were GADA+ and 27% were IA-2A+. A greater negative effect of disease duration was noted for IA-2A than for GADA positivity. Autoantibodies were more prevalent with younger age of onset. GADA were slightly more common in female Type 1 DM patients. In Type 2 DM, 8/99 patients were GADA+, and three of these patients with shorter disease duration were also IA-2A+. GADA, and particularly IA-2A, were associated with a younger age of onset of Type 2 DM and all the autoantibody-positive Type 2 DM patients were insulin-treated. GADA were detected in 2.2% of GDM patients, but none of these patients possessed IA-2A. The prevalence and associations of autoantibodies in Saudi diabetic patients are very similar to those reported for diabetic patients in other ethnic groups.

Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel ( r = −0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.

Diverticular disease of the colon: ethnic differences in frequency.

Colonic diverticular disease is more common in Western populations than in developing countries. To determine whether the frequency of colonic diverticular disease is different in British patients of Indian-subcontinent Asian origin compared with other ethnic groups. All colonoscopies performed over a 3-year period in a London hospital were studied. Patients of Indian-subcontinent Asian origin were identified by name. Five of 134 Indian-subcontinent Asian males (4%) had colonic diverticular disease, compared with 278 of 1268 patients of other ethnic groups (22%; P < 0.001). Five of 91 Indian-subcontinent Asian females (6%) had colonic diverticular disease, compared with 333 of 1486 patients of other ethnic groups (23%; P < 0.001). Although patients of Indian-subcontinent Asian origin (54.8 +/- 15.8 years) were younger than those of other ethnic groups (60.3 +/- 17.8 years; P < 0.0001), the ethnic difference in the frequency of diverticular disease persisted even when age was taken into account. There is a lower frequency of colonic diverticular disease in Indian-subcontinent Asians presenting for colonoscopy, compared with other ethnic groups. This cannot be explained by sex or age differences. Our findings require confirmation, but may provide opportunities for research into the aetiology of colonic diverticular disease.

Differences in recurrent COL7A1 mutations in dystrophic epidermolysis bullosa: ethnic-specific and worldwide recurrent mutations.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the gene encoding type VII collagen (COL7A1). Although most COL7A1 mutations are unique to individual families, small numbers of mutations are recurrent. The recurrent mutations R578X, 7786delG, and R2814X seem to be exclusive to a specific ethnic group, the British population. The mutations 5818delC, 6573+1G-->C, and E2857X are present only in individuals of Japanese ethnic origin. On the other hand, the mutations 425A-->G and G2043R have been found in several different ethnic groups. The purpose of this study was to clarify whether these recurrent mutations are also found in patients of other ethnic groups with DEB, mainly Asian patients. We demonstrated the absence of the recurrent mutations R578X, 7786delG, and R2814X in 42 non-British patients with DEB and detected the mutations 425A-->G in a French patient and G2043R in Japanese and Chinese patients with DEB. The mutations 5818delC, 6573+1G-->C, and E2857X were detected in 11 Japanese patients (13 alleles) with DEB. Our results confirm that R578X, 7786delG, and R2814X mutations are specifically limited to British patients, and the mutations 5818delC, 6573+1G-->C, and E2857X are frequent in Japanese patients. On the other hand, the mutations 425A-->G and G2043R can be found in different ethnic groups. In conclusion, our results further support the notion that recurrent mutations can be classified into two types, ethnic-specific mutation and worldwide mutation.

Severe bone marrow failure associated with the use of alternating steroid with chlorambucil in lupus membranous nephropathy in Chinese.

Severe pancytopenia associated with the use of alternating steroid with chlorambucil regimen was described in six patients with nephrotic syndrome secondary to lupus membranous nephropathy (WHO class V). We believe this is the first report describing the life-threatening degree of marrow toxicity associated with this regimen of alternating steroid with chlorambucil in a Chinese population. Our data suggests that the susceptibility to marrow toxicity with the use of chlorambucil may only be applicable to Chinese patients with underlying systemic lupus erythematosus as a similar degree of toxicity has neither been reported in lupus patients of other ethnic groups nor in non-lupus patients of Chinese origin.

Application of DNA-based tests for diagnosis of spinal muscular atrophy in Saudi Arabia

We examined the deletion of the survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in patients with spinal muscular atrophy (SMA) using polymerase chain reaction followed by restriction site assay methods. The study included 16 Saudi patients (9 SMA type I and 7 SMA type II) and 6 healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene, and exon 5 of the NAIP gene were found in all SMA type I patients. Exons 7 and 8 of telomeric SMN were deleted in all SMA type II patients. However, exon 5 of NAIP was deleted in three of the seven cases. All control volunteers and all family members of the patients had normal SMN and NAIP. The incidence of NAIP deletion was higher in the more severe SMA cases and the dual deletion of the SMN and NAIP genes was more common in Saudi SMA type I patients compared with patients of other ethnic groups.

Molecular analysis of the SMN and NAIP genes in Saudi spinal muscular atrophy patients.

In this study we examined the deletion of the SMN and NAIP genes in 14 Saudi families (16 patients and 38 relatives of the patients, including parents and siblings) and six healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene and exon 5 of the NAIP gene were found in seven out of eight spinal muscular atrophy (SMA) type-I patients. In seven SMA type-II patients, exons 7 and 8 of telomeric SMN were deleted in six cases and exon 5 of NAIP was deleted in three cases. Three patients with SMA diagnosis did not show either of the above deletions. All control Saudi volunteers and all but two family members of the patients had both normal SMN and NAIP genes. Our results show that the incidence of NAIP deletion is higher in the more severe SMA cases and the dual deletions of the SMN and NAIP genes are more common in Saudi SMA type-I patients compared to patients of other ethnic groups.

Prevalence and significance of pancreatic acinar metaplasia at the gastroesophageal junction.

Pancreatic acinar metaplasia (PAM), defined as nodules of glandular tissue forming acini composed of cells with coarse apical eosinophilic granules, with or without mucous cells, was recently recognized in gastric mucosa, but its significance is not known. As part of a study on intestinal metaplasia at the gastroesophageal junction (GEJ), we evaluated the prevalence and clinical and histologic correlates of PAM in biopsy specimens from the gastroesophageal squamocolumnar junction. All adult patients having elective upper gastrointestinal endoscopy over a 6-month period were invited to participate. Clinical data and endoscopic findings were recorded. Biopsy specimens, obtained from both sides of the apparent squamocolumnar junction, were processed routinely and reviewed (without knowledge of the clinical data) to evaluate types of epithelium, types and degree of inflammation, and the presence of PAM. The presence or absence of PAM was then correlated with the other histologic findings and with the clinical and endoscopic data. The study comprised 155 patients (79 women, 76 men; 139 white patients, nine black patients, and seven patients of other ethnic groups). Their mean age was 52 years (range: 18-89 years). PAM was present in 37 patients (24%). PAM was not associated with any of the reported symptoms, endoscopic evidence of esophagitis or columnar epithelium in the distal esophagus, or any of the histologic features evaluated, including active esophagitis, intestinal metaplasia at the GEJ, active and chronic gastritis, intestinal metaplasia in the stomach, and Helicobacter infection. Although PAM is present in a considerable proportion (24%) of patients with mucosal biopsy specimens from the squamocolumnar junction, it appears to be an incidental finding unrelated to clinical or histologic abnormalities. We therefore suggest a congenital, rather than an acquired, origin for this entity.

The Changing Profile of Homozygous β-Thalassemia: Demography, Ethnicity, and Age Distribution of Current North American Patients and Changes in Two Decades

Background. The age of patients with homozygous β-thalassemia is increasing because of better treatment and decreased births. A countering influence is immigration of ethnic groups with a high prevalence of thalassemia. Methods. A questionnaire sent to 48 North American centers requested information about current patients with homozygous β-thalassemia: age, clinical severity, and ethnicity. An 83% response was obtained. Twelve reference hospitals that participated in similar surveys in 1972 and 1984 were included. Results. Five hundred eighteen patients with homozygous β-thalassemia represent most North American patients. Four hundred forty-three (86%) of these had transfusion-dependent thalassemia major (TM); 75 (14%) had thalassemia intermedia (TI). Sixty-two percent were of Greek and Italian ancestry. There were approximately equal numbers of patients with TM in 5-year intervals between 0 and 25 years of age. Thereafter, the number of patients fell sharply. The mean age (±SD) of the patients with TM was 16.1 ± 9.2 years. Striking differences were seen in Italian and Greek patients compared with those of other ancestries. Sixty-six percent of the 271 Italian and Greek patients with TM were older than 16 years of age, whereas 77% of the 172 patients of other ethnic groups with TM were younger than 15 years of age. The mean age of the 75 patients with TI was greater than that of the patients with TM. Seventy-three percent of African-American patients with thalassemia had TI, compared with 0% of Southeastern Asian patients. Comparisons of patients with TM from the 12 reference hospitals for two decades show increasing mean ages of TM patients (1973, 11.4 ± 6.7 years; 1985, 14.2 ± 7.3 years; and 1993, 16.1 ± 9.2 years). Conclusions. There are probably only 750 to 1000 patients with homozygous β-thalassemia in North America. Only about 15 to 20 new cases are diagnosed each year. The increasing mean age and age distribution indicate that modern therapies are effective, but immigration of non-Mediterranean ethnic groups with thalassemia has resulted in more, younger patients. TM is increasingly becoming a disease of young adults.

No apparent association between HLA and multiple sclerosis in southern Chinese.

HLA-A, -B and -DR antigens have been studied in 34 Chinese patients with multiple sclerosis and 100 normal healthy controls. Unlike patients of other ethnic groups in whom multiple sclerosis is associated with HLA-DR2, there was no obvious association with any HLA antigen in the Chinese patients, although the overall distribution of antigens did not appear typical of the southern Chinese population from which the patients were drawn.