Ethnic Differences In Susceptibility Research Articles

Abstract 18998: Deletion of the Duffy Antigen Receptor for Chemokines Impairs Blood Flow Recovery in the Mouse Hindlimb Ischemia Model: Role of CCL11

Introduction: Peripheral Artery Disease (PAD) is characterized by obstruction of the arteries in the lower extremities. Impaired angiogenesis plays a major role in the progression of PAD. Pro-angiogenic and anti-angiogenic chemokines are modulated by binding to the Duffy antigen receptor for chemokines (DARC), a non-signaling receptor expressed primarily on erythrocytes. Incidence and severity of PAD is greater in Blacks, ~70% of whom do not express DARC on their erythrocytes due to a common gene variant. Here, we tested the hypothesis that hematopoietic-specific deletion of DARC impairs blood flow recovery in mouse hindlimb ischemia model. Methods: Twelve week old female DARC Flox/Vav1-Cre+ (DARC HKO ) and littermate Vav1-Cre- (wild type, WT) mice underwent unilateral femoral artery ligation and excision. Ischemic muscle tissue and plasma were analyzed at early ischemic phase (day three post ligation) and late ischemic phase (day fourteen post ligation). Blood flow recovery was measured weekly via laser Doppler imaging. Results: DARC HKO mice had poor blood flow recovery compared to WT mice (p<0.05), along with reduced capillary formation and increased inflammation, necrosis and fibrosis in the ischemic gastrocnemius muscles. Amongst the various DARC-bound chemokines assayed, levels of CCL11 (a pro-angiogenic strong DARC-bound chemokine) were significantly reduced in the plasma of DARC HKO mice, both at early and late ischemic phases (p<0.01). CCL11 levels strongly correlated with capillary formation in ischemic hindlimb. CCL11 levels in ischemic muscle tissue were significantly reduced in the DARC HKO mice in the early, but not late, ischemic phase. Conclusions: Loss of DARC on hematopoietic cells has a negative impact on the recovery of perfusion and angiogenesis in the murine hindlimb ischemia model, possibly due to reduced levels of CCL11 consequent to DARC deletion. These findings may be relevant to ethnic differences in susceptibility to PAD and suggest that therapies directed towards increasing CCL11 may be beneficial in Blacks with PAD.

Abstract 18831: The Protective Effect of Duffy Antigen Receptor for Chemokines Gene Deletion on Abdominal Aortic Aneurysm Formation: Role of Lysyl Oxidase

Introduction: Epidemiologic studies indicate that Blacks are protected against abdominal aortic aneurysm (AAA), despite similar risk factors as Caucasians. Approximately 70% of Blacks harbor a variant in the Duffy Antigen Receptor for Chemokines (DARC), a non-signaling receptor expressed primarily on erythrocytes which binds and regulates inflammatory chemokines. Since chemokines play a critical role in AAA, we tested the hypothesis that lack of DARC expression on erythrocytes protects against AAA, and we investigated the mechanisms. Methods: Mice lacking DARC on hematopoietic cells were created by mating DARC flox/flox mice with Vav1-Cre mice. At 10-14 weeks of age, both Vav1-Cre positive (DARC HKO ) and Vav1-Cre - mice [wild type (WT) littermate controls] received PCSK9 adeno-associated virus injection and were started on high fat diet. After 1 week, mice were infused with angiotensin II (AngII, 1,000 ng/kg/min) via osmotic minipump for 26 days to induce AAA. Results: Compared to WT, there was no difference in blood pressure or cholesterol levels in AngII-infused DARC HKO mice, which were confirmed to lack DARC on erythrocytes by flow cytometry. Aortic diameter and AAA incidence were significantly decreased in DARC HKO compared to WT mice (n=16-20, p=0.0257), in conjunction with reduced elastin degradation and macrophage infiltration. We did not find differences in levels of DARC-bound chemokines that could account for the protection against AAA. Interestingly, we found that the level and activity of lysyl oxidase (LOX), a cytokine-like enzyme that crosslinks extracellular matrix proteins and protects against AAA, were higher in DARC HKO mice compared to WT mice. Conclusions: Loss of DARC on hematopoietic cells protects against AAA formation, likely by upregulating aortic LOX. These findings provide novel insight into ethnic differences in susceptibility to AAA.

Exclusion of Patients Living with Chronic Viral Infections and Underrepresentation of Ethnic Minorities in Diffuse Large B-Cell Lymphoma Clinical Trials

Introduction There is a substantial underrepresentation of ethnic minorities within oncology studies. Specifically, Black, Asian and Hispanic patients have a low participation rate in US based randomized clinical trials (RCT). Furthermore, patients living with HIV (PLWH) or chronic viral hepatitis are often systematically excluded from these studies. Diffuse large B-cell lymphoma (DLBCL) is one of the most common malignancies associated with HIV and viral hepatitis. Given these characteristics, it is imperative that studies reporting on safety and efficacy of new treatments mirror real-world populations. Objective: The primary objective of our study was to describe the demographic characteristics of patients who have participated in DLBCL phase II and III randomized US clinical trials; evaluating each group's enrollment fraction compared to US DLBCL prevalence. The secondary objective was analyzing the inclusion of PLWH and chronic viral hepatitis in US based DLBCL RCT. Methods and Measures: We queried PubMed, ClinicalTrials.gov, as well as ASCO and ASH meeting abstracts for phase II and III RCTs on DLBCL from 2000 to 2020, including chimeric antigen receptor T cells (CAR-T) therapy studies. Trials that did not report race and ethnicity or recruited outside of the US were excluded. We analyzed enrollment data and compared to DLBCL prevalence demographics obtained from the SEER 18 Registries. Enrollment fraction (EF) is defined as the number of trial enrollees divided by the estimated US prevalence of DLBCL. Results: We identified 51 trials between 2000 and 2020 with only 25 (49%) studies reporting race and ethnicity. Only 9 trials enrolled solely in the US which comprised of 763 patients. Compared with an EF of 1.88% among Non-Hispanic whites, lower EF was noted in Blacks (1.08%; P=0.0009), Hispanics (0.71; P=<0.0001) and Asian patients (0.71%; P=<0.0001). The EF of patients < 65 years old was significantly higher than those aged 65 or more (1.2 vs 0.79%, P=<0.0001). The EF of males and females was 1.8 vs 1.4%, respectively (P=0.001). PLWH and/or chronic viral hepatitis were excluded in 89% and 67% of the clinical trials analyzed (Table 1). Conclusions: US based clinical trials for DLBCL have significant underrepresentation of Hispanic, Black and Asian patients. Moreover, despite being commonly associated with HIV and chronic viral hepatitis, patients with these comorbidities are typically excluded from clinical trials. Pharmacoethnicity, ethnic differences in susceptibility to the effects of therapy, remains a challenge in oncology because clinical trials have significant underrepresentation of minorities. Efforts are needed to address the ascertainment bias and improve external validity of RCTs in DLCBL. Reasons for clinical trial underrepresentation are complex and multifactorial including lack of access, cultural differences and healthcare system mistrust. Healthcare professionals must address the inequalities through awareness and education with the objective of increasing enrollment of minorities in clinical trials. Although there have been efforts to increase enrollment of patients with HIV and chronic viral hepatitis in clinical trials, it remains inadequate. In accordance to recent recommendations by the FDA, investigators should consider having a predefined plan for inclusion of such patients. Disclosures Sandoval-Sus: Massive Bio: Consultancy; Janssen: Consultancy; MorphoSys US: Consultancy; Celgene: Speakers Bureau.

Abstract MP154: Deletion of the Duffy Antigen Receptor for Chemokines (DARC) Confers Protection Against Abdominal Aortic Aneurysm (AAA) Formation

Introduction: Abdominal aortic aneurysms (AAA) are characterized by inflammation and matrix metalloproteinase (MMP)-mediated degradation of extra cellular matrix proteins leading to aortic dilation and potentially rupture. Inflammatory chemokines that promote AAA are modulated by binding to the Duffy antigen receptor for chemokines (DARC), a non-signaling receptor expressed primarily on erythrocytes. Interestingly, African Americans exhibit reduced frequency of AAA, and the majority of African descendent individuals do not express DARC on their erythrocytes. Here, we tested the hypothesis that DARC gene deletion protects against the development of AAA. Methods: The induction of AAA was performed using both angiotensin II (AngII) infusion and calcium chloride (CaCl 2 ) application models. Eight week old LDLR knockout (KO, control) and LDLR KO/DARC KO mice were infused with AngII via osmotic mini-pumps for four weeks. For the CaCl 2 application model, twelve week old DARC KO and WT control mice underwent laparotomy and 0.5 mol/L CaCl 2 was applied to the infrarenal aorta. Aortic dilation and AAA formation was assessed using ultrasound, mice were then euthanized and tissues were harvested for analysis. Results: The aortic diameter of LDLR KO/DARC KO mice was significantly lower relative to control mice after AngII infusion (P=0.02). There was no difference in the pressor response to AngII between groups. Furthermore, IL-6 levels were significantly reduced in the aortas of LDLR KO/DARC KO mice compared to control mice (P=0.001). Expression of MCP-1, which has strong affinity for DARC, tended to be higher in aortas from LDLR KO/DARC KO mice compared to control (P=0.063). In contrast, plasma IL-6 levels were similar in both LDLR KO/DARC KO and control mice, while MCP-1 tended to be lower in the plasma of LDLR KO/DARC KO (P=0.07). DARC KO mice likewise exhibited a trend toward reduced aortic dilation in the CaCl 2 application model compared to controls (P=0.09). Conclusions: DARC KO mice are protected against AAA formation, perhaps through differential regulation of aortic chemokine trafficking. Understanding the mechanisms by which loss of DARC confers protection from AAA formation may be relevant to ethnic differences in susceptibility to AAA.

Deletion of the Duffy Antigen Receptor for Chemokines (DARC) Confers Protection Against Abdominal Aortic Aneurysm (AAA) Formation

IntroductionAbdominal aortic aneurysms (AAA) are characterized by inflammation and matrix metalloproteinase (MMP)‐mediated degradation of extra cellular matrix proteins leading to aortic dilation and potentially rupture. Inflammatory chemokines that promote AAA are modulated by binding to the Duffy antigen receptor for chemokines (DARC), a non‐signaling receptor expressed primarily on erythrocytes. Interestingly, African Americans exhibit reduced frequency of AAA, and greater than 70% of individuals of African descent do not express DARC on their erythrocytes due to evolutionary pressure from malaria. Here, we tested the hypothesis that DARC gene deletion protects against the development of AAA.MethodsThe induction of AAA was performed using both angiotensin II (AngII) infusion and calcium chloride (CaCl2) application models. In brief, eight week old LDLR knockout (KO, control) and LDLR KO/DARC KO mice were infused with angiotensin II via osmotic minipumps for four weeks at a rate of 1,000 ng/kg/min. For the CaCl2 application model, 12 week old WT and DARC KO mice underwent laparotomy and 0.5 mol/L was applied to the infrarenal aorta. For both models, aortic dilation and AAA formation was assessed using ultrasound, mice were then euthanized and tissues were harvested for histology and biochemical analysis.ResultsLDLR KO/DARC KO mice were protected from the formation of AngII‐induced AAA, as only ~20% developed an aneurysm compared to ~80% in the control group. Concordantly, the aortic diameter of LDLR KO/DARC KO mice was significantly lower relative to control mice after AngII infusion (P=0.02). There was no difference in the pressor response to AngII between groups, but LDLR KO/DARC KO mice exhibited reduced macrophage infiltration, and aortic dilation compared to the control group. Furthermore, IL‐6 levels were significantly reduced in the aortas of LDLR KO/DARC KO mice compared to control mice (P=0.001). Interestingly, however, expression of MCP‐1, which has strong affinity for DARC, tended to be higher in aortas from LDLR KO/DARC KO mice compared to control (P=0.063). In contrast, plasma IL‐6 levels were similar in both LDLR KO/DARC KO and control mice, while MCP‐1 tended to be lower in the plasma of LDLR KO/DARC KO (P=0.07). Interestingly, DARC appears to be upregulated in the aortas of mice in response to AngII. Furthermore, DARC KO mice likewise exhibited reduced aortic dilation in the CaCl2 application model compared to controls.ConclusionsDARC KO mice are protected against AAA formation, perhaps through differential regulation of aortic chemokine trafficking. Understanding the mechanisms by which loss of DARC confers protection from AAA formation may be relevant to ethnic differences in susceptibility to AAA.Support or Funding InformationThis study was supported by the AHA [19PRE34400043 to T.W.B] and the National Institutes of Health [HL124097, HL126949, HL134354 and AR070029 to N.L.W].

The incidence and survival of melanoma and nonmelanoma skin cancer in patients with vitiligo: a nationwide population-based matched cohort study in Korea.

While studies report a lower incidence of skin cancer in white patients with vitiligo compared with controls, the skin cancer incidence in Asian patients with vitiligo is unknown. To quantify the incidence of melanoma and nonmelanoma skin cancer (NMSC) in Korean patients with vitiligo and compare it with matched nonvitiligo controls. A retrospective matched cohort study was performed with 131245 incident vitiligo cases and 2624900 age- and sex-matched (1:20) controls at index date, who were selected from the Korean National Health Insurance database between January 2005 and December 2017. Stratified Cox proportional hazards regression (stratified by sex, birth year and index year) was used to calculate the hazard ratio (HR) of skin cancer in patients with vitiligo. Patients with vitiligo were followed up for a mean duration of 6·34 years compared with a follow-up period of 6·27 years for matched controls. Ultraviolet (UV) treatment-adjusted HR for melanoma in patients with vitiligo was 3·32 [95% confidence interval (CI) 2·29-4·81] and 1·29 (95% CI 1·06-1·56) for NMSC. The HRs for melanoma and NMSC in the vitiligo population without a history of UV treatment were 3·37 (95% CI 2·32-4·90) and 1·35 (95% CI 1·11-1·64), respectively. In contrast to white patients with vitiligo, the risk of skin cancer was increased in the Korean vitiligo population. However, it is noteworthy that the skin cancer incidence in Korean patients with vitiligo was lower than that of their white counterparts. Owing to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted for race. What's already known about this topic? Prior studies have reported a lower incidence of melanoma and nonmelanoma skin cancer (NMSC) in white patients with vitiligo compared with nonvitiligo controls. The skin cancer incidence in Asian patients with vitiligo is unknown. What does this study add? In contrast to white patients, the risk of both melanoma and NMSC was increased in Korean patients with vitiligo compared with controls. Owing to possible ethnic differences in susceptibility to skin cancer, skin cancer surveillance in the vitiligo population should be adjusted for race.

Diabetes: Leveraging the Tipping Point of the Diabetes Pandemic.

Diabetes is one of the fastest growing public health problems in the world, with significant variations in its prevalence and in the major risk factors for type 2 diabetes among ethnic groups. In this issue of Diabetes , the Perspective by Unnikrishnan et al. (1) focuses on the global prevalence of diabetes, ethnic differences in susceptibility to diabetes, and major determining factors for type 2 diabetes. A major concern today is the increasing number of people with type 2 diabetes in middle-income and low-income countries, such as China and India. Vulnerability to diabetes among immigrants from Korea, the Pacific Islands, South Asia, and the Philippines to the U.S. or Europe compared with the Caucasian population is highlighted. Although obesity and its correlate insulin resistance, as well as genetic factors, have been considered the established determining factors for type 2 diabetes risk, recent evidence shows that early loss of β-cell function plays a much more important role in the pathogenesis of type 2 diabetes, especially in nonobese individuals of southern and eastern Asian origin. The results from the China National Diabetes Survey have indicated that the prevalence of diabetes in Chinese adults aged ≥20 years increased from 1% in 1980 (2) to 9.7% in 2007–2008 (3) and 11.6% in 2010 (4). One recent pooling of data from 751 studies including 4,372,000 adults from 146 of 200 countries estimated that the number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014, while the global age-standardized diabetes prevalence increased from 4.3% in 1980 to 9.0% in 2014 in men and from 5.0% to …

990P - Comparison of the toxicity and response of a novel outpatient weekly CDFLEM (cisplatin, docetaxel, fluorourcil, leucovorin, epirubicin, methotrexate) induction chemotherapy versus triweekly TPF or PF in locally advanced SCCHN

Triweekly TPF and PF induction chemotherapy (IndCT) are the most popular and effective regimen for locally advanced squamous cell carcinoma of the head and neck (SCCHN). However, significant ethnic differences in susceptibility to the effects and toxicities exist. We designed a novel weekly CDFLEM IndCT and compared treatment outcome with TPF/PF from literature in locally advanced SCCHN. A four-drug regimen (C-D-FL-EM) consisting of (1) cisplatin 60 mg/m2, day 1, (2) docetaxel 50 mg/m2, day 8, (3) 5-fluorouracil 2500 mg/m2 + leucovorin 250 mg/m2, day 15, (4) epirubicin 30 mg/m2 + methotrexate 30 mg/m2, day 22, were alternatively delivered once per week, 4 weeks per cycle. From September 2011 to December 2013, 78 patients with stage III/IV SCCHN received 3-4 cycles IndCT of CDFLEM, followed by local therapy (including surgery, radiotherapy, concurrent chemoradiotherapy, or bio-radiotherapy). Baseline characteristics of 78 patients are as follows: primary of oral cavity/oropharynx/hypophayrnx/larynx = 23/26/24/5; stage III/IV = 10/68; median age = 51 (range 33-77); male/female = 73/5; performance status ECOG 0-1/2 = 75/3. Synchronous second or triple primary tumors were also noted in 10 patients. We obtained an overall response rate of 97.3% (CR 39.2% + PR 58.1%) for 74 evaluable patients. The Overall response rate in the TAX-323 trial was 53.6% (CR 6.6% + PR 47.0%) for the PF and 67.8% (CR 8.5% + PR 59.3%) for the TPF regimens, respectively. The corresponding figures in the TAX-324 trial was 64% (CR 15% + PR 49%) and 72% (CR 17% + PR 55%), respectively. Gr 3/4 mucositis occurred in 7.7% for our weekly CDFLEM, 11.2% and 4.6% for PF and TPF in the TAX-323, 27% and 22% for PF and TPF in the TAX-324. Gr 3/4 leucopenia was 38.4% for our CDFLEM, 22.9% and 41.6% for PF and TPF in the TAX-323, 56% and 83% for PF and TPF inf the TAX-324. IndCT with our weekly CDFLEM regimen has a higher response rate and a lower Gr 3/4 mucositis/neutropenia than triweekly PF/TPF in patients with locally advanced SCCHN.

A global multicenter study on reference values: 2. Exploration of sources of variation across the countries

ObjectivesThe intent of this study, based on a global multicenter study of reference values (RVs) for serum analytes was to explore biological sources of variation (SVs) of the RVs among 12 countries around the world. MethodsAs described in the first part of this paper, RVs of 50 major serum analytes from 13,396 healthy individuals living in 12 countries were obtained. Analyzed in this study were 23 clinical chemistry analytes and 8 analytes measured by immunoturbidimetry. Multiple regression analysis was performed for each gender, country by country, analyte by analyte, by setting four major SVs (age, BMI, and levels of drinking and smoking) as a fixed set of explanatory variables. For analytes with skewed distributions, log-transformation was applied. The association of each source of variation with RVs was expressed as the partial correlation coefficient (rp). ResultsObvious gender and age-related changes in the RVs were observed in many analytes, almost consistently between countries. Compilation of age-related variations of RVs after adjusting for between-country differences revealed peculiar patterns specific to each analyte. Judged fromthe rp, BMI related changes were observed for many nutritional and inflammatory markers in almost all countries. However, the slope of linear regression of BMI vs. RV differed greatly among countries for some analytes. Alcohol and smoking-related changes were observed less conspicuously in a limited number of analytes. ConclusionThe features of sex, age, alcohol, and smoking-related changes in RVs of the analytes were largely comparable worldwide. The finding of differences in BMI-related changes among countries in some analytes is quite relevant to understanding ethnic differences in susceptibility to nutritionally related diseases.

Induction chemotherapy with dose-modified docetaxel, cisplatin, and 5-fluorouracil in Asian patients with borderline resectable or unresectable head and neck cancer.

Significant ethnic differences in susceptibility to the effects of chemotherapy exist. Here, we retrospectively analyzed the safety and efficacy of induction chemotherapy (ICT) with dose-modified docetaxel, cisplatin, and 5-fluorouracil (TPF) in Asian patients with borderline resectable or unresectable head and neck squamous cell carcinoma (HNSCC). Based on the incidence of adverse events that occurred during daily practice, TPF90 (90% of the original TPF dosage; docetaxel 67.5mg/m2 on Day 1, cisplatin 67.5mg/m2 on Day 1, and 5-fluorouracil 675mg/m2 on Days 1-5) was used for HNSCC patients who were scheduled to receive ICT TPF. Between March 2011 and May 2014, 52 consecutive patients with borderline resectable or unresectable HNSCC were treated with ICT TPF90 followed by concurrent chemoradiotherapy. Forty-four patients (84.6%) received at least three cycles of ICT TPF90. The most commonly observed Grade 3-4 adverse events included neutropenia (35%), anemia (25%), stomatitis (35%), diarrhea (16%), and infections (13.5%). In an intention-to-treat analysis, the complete and partial response rates after ICT TPF90 were 13.5% and 59.6%, respectively. The complete and partial response rates following radiotherapy and salvage surgery were 42.3% and 25.0%, respectively. The estimated 3-year overall survival and progression-free survival rates were 41% [95% confidence interval (CI): 25-56%] and 23% (95% CI: 10-39%), respectively. The observed median overall survival and progression-free survival were 21.0months (95% CI: 13.3-28.7months) and 16.0months (95% CI: 10.7-21.3months), respectively. TPF90 is a suitable option for Asian patients with borderline resectable or unresectable HNSCC who are scheduled for ICT.

Smoking, drinking, and pancreatitis: a population-based cohort study in Taiwan.

In Western population, smoking is a dose-dependent risk factor for pancreatitis, whereas a threshold of 5 drinks per day may exist for alcohol to increase pancreatitis risk. Given ethnic differences in tobacco and alcohol metabolism, we examined the associations between smoking, alcohol, and pancreatitis in Asians. A population-based cohort was assembled using participants of the National Health Interview Survey in Taiwan. Information on drinking and smoking was collected by in-person interview at baseline. Incident cases of pancreatitis were identified through data linkage with National Health Insurance claims database. During 94,601 person-years of follow-up, 66 incident cases of pancreatitis occurred. Neither current nor ever smoking was associated with the incidence of pancreatitis (adjusted hazard ratio [aHR] 1.13; 95% confidence interval [CI], 0.62-2.06; and aHR, 1.14; 95% CI, 0.63-2.06, respectively). Dose-response analysis also showed no association between smoking and pancreatitis. By contrast, regular (aHR, 3.09; 95% CI, 1.51-6.30) and heavy alcohol drinking (aHR, 6.46; 95% CI, 3.07-13.60) were associated with an increased incidence of pancreatitis compared with abstinence. In this Asian population-based cohort, alcohol was associated with pancreatitis in a dose-dependent way, but smoking was not associated with pancreatitis. These results support for ethnic differences in susceptibility to smoking- and alcohol-related pancreatitis.

Ethnic differences in susceptibility to movie smoking

Ethnic differences in susceptibility to movie smoking

Polymorphisms of the GSTM1, GSTT1, and CYP2D6 xenobiotic biotransformation genes, which are possible risk markers of cancer in populations of indigenous ethnic groups and Russians of North Siberia

The CYP2D6, GSTM1, and GSTT1 xenobiotic biotransformation genes are involved in processes of carcinogenesis in humans due to the presence of mutant variants that decrease or block the expression of genes. Since the middle of the 20th century, there has been an extensive increase in cancer morbidity in human populations, including indigenous ethnic groups of Siberia. The problem of ethnic differences in susceptibility to cancer is still pressing. The study of polymorphisms of the CYP2D6 (CYP2D6*3 and CYP2D6*4 alleles), GSTM1, and GSTT1 (GSTM1 0/0 and GSTT1 0/0 “null” genotypes) genes (which are considered as genetic markers of the risk of cancer) was conducted for the first time in practically healthy representatives of the Samoyedic ethnic groups (Selkups, Forest Nenets, and Nganasans) and Russians from Siberia. A significant variability in the CYP2D6*4 and GSTM1 0/0 frequency distribution in northern populations was detected. At the same time, there are no significant differences in frequencies of the CYP2D6*3 and GSTT1 0/0 variants among indigenous populations of the Selkups, Forest Nenets, and Nganasans. In the CYP2D6*4 allele frequencies, indigenous ethnic groups are intermediate between Russians of Siberia and Mongolians of China. However, frequencies of the null GSTM1 0/0 and GSTT1 0/0 genotypes in indigenous ethnic groups are significantly lower than in populations of Russians of Siberia and Mongoloids of China (p < 0.05). Generally, according to all four studied polymorphic variants, it is possible to predict a decreased risk of cancer in indigenous Samoyedic ethnic groups, as compared with Russians of Siberia. The Forest Nenets population, with an increased frequency of the GSTM1 0/0 genotypes, is an exception; this can be caused by the originality of their marriage structure and increased inbreeding coefficient. The results we obtained can also be important in predicting the probability of complications and a positive response to drugs that are metabolized by the GSTM1, GSTT1, and CYP2D6 enzymes.

Ethnic Differences in Susceptibility to Smoking and Intention to Smoke on Smoking Behavior among Adolescents

Ethnic Differences in Susceptibility to Smoking and Intention to Smoke on Smoking Behavior among Adolescents

Ethnic Differences in Susceptibility to Smoking and Intention to Smoke on Smoking Behavior among Adolescents

Objectives: This quantitative study examined the differences in susceptibility to smoking and intention to smoke on smoking behavior among adolescents of different ethnic groups. Methods: The study utilized secondary data from the 2007 National Survey on Drug Use and Health (NSDUH). The study population included 18,314 persons in the ages 12-17 years, both smokers and nonsmokers and representing the races: White, African American, Hispanic, Asian, Multi-Racial, American Indian and Native Hawaiian. The theory of reasoned action by Ajzen and Fishbein formed the basis of this study. Results: A statistically significant positive relationship was found between participants’ susceptibility to smoking and their intentions to smoke (r = .57, p < .01). Additionally, Hispanics demonstrated a significantly higher intention to smoke in the next 12 months than the White participants. More specifically, a significant difference was found among ethnic groups on smoking intentions and among age groups on susceptibility to smoking. Discussion: The constructs of susceptibility to smoking and intention to smoke can be targeted by health education interventions in primary and secondary interventions to reduce smoking behavior in different ethnic groups.

Retinal microvascular calibre and risk of incident diabetes: The multi-ethnic study of atherosclerosis

AimTo prospectively examine the association of retinal microvascular signs with incident diabetes and impaired fasting glucose (IFG) in a multi-ethnic population-based cohort. MethodsThe multi-ethnic study of atherosclerosis comprised Caucasians, African-Americans, Hispanics and Chinese aged 45–84years. Retinal vascular calibre and retinopathy were quantified from baseline retinal photographs. Incident diabetes and IFG were ascertained prospectively. ResultsAfter a median follow-up of 3years, 243 (4.9%) people developed diabetes and 565 (15.0%) developed IFG. After adjusting for known risk factors, participants with wider retinal arteriolar calibre had a higher risk of developing diabetes [HR: 1.60; 95% CI: 1.12–2.29, p=0.011 comparing highest with lowest arteriolar calibre tertile]. In ethnic subgroup analysis, the association between wider retinal arteriolar calibre and incident diabetes was stronger and statistically significant only in Caucasians [HR: 2.78; 95% CI: 1.37–5.62, p=0.005]. Retinal venular calibre and retinopathy signs were not related to risk of diabetes or IFG. ConclusionWider retinal arteriolar calibre is independently associated with an increased risk of diabetes, supporting a possible role for early arteriolar changes in diabetes development. This effect was largely seen in Caucasians, and not in other ethnic groups, and may reflect ethnic differences in susceptibility to diabetes from microvascular pathways.

Ion channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing

Schizophrenia is a complex genetic disorder. Gene set-based analytic (GSA) methods have been widely applied for exploratory analyses of large, high-throughput datasets, but less commonly employed for biological hypothesis testing. Our primary hypothesis is that variation in ion channel genes contribute to the genetic susceptibility to schizophrenia. We applied Exploratory Visual Analysis (EVA), one GSA application, to analyze European-American (EA) and African-American (AA) schizophrenia genome-wide association study datasets for statistical enrichment of ion channel gene sets, comparing GSA results derived under three SNP-to-gene mapping strategies: (1) GENIC; (2) 500-Kb; (3) 2.5-Mb and three complimentary SNP-to-gene statistical reduction methods: (1) minimum p value (pMIN); (2) a novel method, proportion of SNPs per Gene with p values below a pre-defined α-threshold (PROP); and (3) the truncated product method (TPM). In the EA analyses, ion channel gene set(s) were enriched under all mapping and statistical approaches. In the AA analysis, ion channel gene set(s) were significantly enriched under pMIN for all mapping strategies and under PROP for broader mapping strategies. Less extensive enrichment in the AA sample may reflect true ethnic differences in susceptibility, sampling or case ascertainment differences, or higher dimensionality relative to sample size of the AA data. More consistent findings under broader mapping strategies may reflect enhanced power due to increased SNP inclusion, enhanced capture of effects over extended haplotypes or significant contributions from regulatory regions. While extensive pMIN findings may reflect gene size bias, the extent and significance of PROP and TPM findings suggest that common variation at ion channel genes may capture some of the heritability of schizophrenia.

Incidence of celiac disease among second-generation immigrants and adoptees from abroad in Sweden: evidence for ethnic differences in susceptibility

Background and aims. The incidence of celiac disease (CD) shows large, worldwide variation. However, whether its causes are environmental (gluten-containing diet) or genetic (specific haplotype) have not been established. The aim of the present study is to examine the incidence of CD among second-generation immigrants and adoptees from abroad to disentangle genetic/ethnic versus environmental influences (assuming that immigrants have similar gluten exposures to native Swedes, and thus differ from them only in terms of their genetic background). Methods. Second-generation immigrants and adoptees from abroad were identified in the MigMed 2 Database and were followed until diagnosis of CD, death, or the end of study. Standardized incidence ratios (SIRs) were calculated among these immigrants with native Swedes as the reference group. Results. A total of 1,050,569 children were defined as second-generation immigrants and the overall SIR of CD (SIR = 0.89, 95% confidence interval 0.84–0.94) was significantly lower than that of native Swedes. The incidence of CD among children with parents from Western, Eastern, and Northern European countries was similar to that in native Swedes, but was lower for those with parents from low-prevalence countries, especially Eastern and Southeast Asian countries. A total of 51,557 children born in foreign countries were adopted by Swedes. Adoptees from Eastern Asia had a significantly decreased SIR of CD. Conclusions. The decreased incidence of CD in second-generation immigrants and some groups of adoptees from abroad strongly suggests that ethnic genetic heterogeneity may contribute to the worldwide variation in CD incidence.

Cancer Pharmacoethnicity: Ethnic Differences in Susceptibility to the Effects of Chemotherapy

A long-term goal of pharmacogenomics research is the design of individualized therapy based on the genomic sequence of the patient, in order to maximize response and minimize adverse drug reactions. Pharmacoethnicity, or ethnic diversity in drug response or toxicity, is becoming increasingly recognized as an important factor accounting for interindividual variation in anticancer drug responsiveness. Although pharmacoethnicity is determined by genetic and nongenetic factors, there is rapidly accumulating clinical evidence about ethnic differences in the frequencies of polymorphisms within many of the important cancer drug-related genes. This article reviews the current clinical evidence for ethnic differences in anticancer drug disposition and sensitivity while highlighting the challenges, and potential solutions, to acquiring such knowledge. The discovery of "ethnic-specific genetic signatures," representing unique sets of drug susceptibility-governing polymorphisms, may be the outcome of such work. Ultimately, such understanding will further the lofty goal of individualization of chemotherapy based on a person's unique genetic make-up to improve the tolerability and effectiveness of chemotherapy for all patients.

Ethnic Differences in the Risks of Adverse Reactions to Drugs Used in the Treatment of Psychoses and Depression

Factors such as age, sex and disease state alter a patient's susceptibility to adverse drug reactions (ADRs). Ethnicity may also alter the risk of an ADR. To review the evidence for ethnic differences in susceptibility to adverse reactions to drugs used to treat psychoses and depression. We searched MEDLINE (from 1951), EMBASE (from 1974), and PsycINFO (from 1950) to March 2006. Studies were included if there was a mention of ethnicity, ethnic or racial groups and a description of a procedure to investigate ADRs specifically or a description of ADRs that were a result of drugs in therapeutic use. Studies selected by any two reviewers were retained if they referred to drugs used in the treatment of psychoses and related disorders or antidepressant drugs. Of 124 studies describing ADRs to antipsychotics or antidepressants, 51 reported data from different ethnic groups. Data were extracted independently from those studies selected for inclusion by two reviewers, using a standard data extraction form. Studies were assessed for bias in order to determine the quality of the study. In a pooled analysis of patients treated with antipsychotics, the relative risk (RR) of tardive dyskinesia in Black compared with White patients was 1.03 (95% CI 0.85, 1.24); the RR of extrapyramidal symptoms in East Asian compared with non-East Asian patients was 1.38 (95% CI 1.11, 1.72); the RR of hyperglycaemia in Black compared with non-Black patients was 1.55 (95% CI 0.95, 2.53); and the RR of diabetes mellitus in non-White compared with White patients was 1.35 (95% CI 0.95, 1.92). It was impossible to perform pooled analysis of data from studies investigating antidepressants due to insufficient data. We found limited evidence of ethnic differences in the risk of ADRs. The clinical implications of these results remain unclear because of confounding factors. Further progress will require improved recruitment of patients from different ethnic groups and an established consensus on how to define ethnicity.