European American Populations Research Articles

Association between the Number of Days/Week of Different Levels of Physical Activity and Chronic Pain in People of Different Races: A Mendelian Randomization Study.

Regular physical activity is beneficial for health, but the effect of the number of days/week of physical activity on chronic pain (CP) remains unclear, so we used a two-sample Mendelian randomization (MR) analysis to explore the relationship between the number of days/weeks of different levels of physical activity and chronic pain in people of different races. We obtained summary data from genome-wide association studies (GWASs) on the number of days/week of physical activity and multisite chronic pain in European, South Asian, East Asian, Middle Eastern, and African American populations. The single-nucleotide polymorphisms (SNPs) of the exposed data were visualized with a Manhattan plot via the R program. MR analysis was performed by the MR-Base platform. The results indicated that a higher number of days/week with ≥10 min of walking protects against CP in African American and Afro-Caribbean populations (inverse-variance weighting, IVW p < 0.05) but has little effect on people of different races (IVW p > 0.05). A higher number of days/week with ≥10 min of moderate physical activity increased the risk of CP in European and South Asia (IVW p < 0.05) but had little effect on people of different races (IVW p > 0.05). The number of days/week of ≥10 min of vigorous physical activity increased the risk of CP in Europeans (IVW p < 0.05) and protected against CP in African Americans and Afro-Caribbeans (IVW p < 0.05). A higher number of days/week of moderate and vigorous physical activity increased the risk of CP in Europeans; however, a higher number of days/week of walking and vigorous physical activity may protect against CP in African American and Afro-Caribbean individuals.

Convergent evolution of allele-specific gene expression that leads to non-small cell lung cancer in different human populations.

Phenotypical innovations during evolution are caused by novel mutations, which are usually heterozygous at the beginning. The gene expressions on two alleles of these mutation sites are not necessarily identical, leading to flexible allele-specific regulation in cell systems. We retrieve the transcriptome data of normal and non-small cell lung cancer (NSCLC) tissues from 47 African Americans (AA) and 50 European Americans (EA). We analyze the differentially expressed genes (DEGs) in NSCLC as well as the tumor-specific mutations. Expression and mutation profiles show convergent evolution in AA and EA populations. The tumor-specific mutations are poorly overlapped, but many of them are located in the same genes, mainly oncogenes and tumor suppressor genes. The DEGs in tumors are majorly caused by the mutated alleles rather than normal alleles. The relative expressions of mutated alleles are highly correlated between AA and EA. The differential expression in NSCLC is predominantly mediated by the mutated alleles on heterozygous sites. This molecular mechanism underlying NSCLC oncogenesis is conserved across different human populations, exhibiting convergent evolution. We present this novel angle that differential expression analysis should be performed separately for different alleles. Our ideas should greatly benefit the cancer community.

Reference intervals for carotid artery intima-media thickness measurements in the multi-ethnic Asian population: relationship with cardiometabolic risk factors

Abstract Background Carotid artery intima-media thickness (cIMT) is an intermediate surrogate marker for cardiovascular disease (CVD). It has been reported that although the distribution of cIMT values is very heterogeneous and values vary widely between different ethnicity, geographic location, and ultrasound protocol, the prediction of vascular events with study-specific cIMT values is consistent across all ethnicities and regions (1). Hence, Consensus Statement from the American Society of Echocardiography suggests that cIMT greater than or equal to 75th percentile for the patient’s age, sex, and ethnicity is indicative of increased CVD risk (2). Aims We aimed to establish age, sex, and ethnic-specific reference intervals in the multi-ethnic Asian population comprising Chinese, Malays, and Indians. Methods We analysed data from 8762 healthy individuals who had a 3D carotid ultrasonography done as part of the Health for Life in Singapore study. Carotid ultrasonography measurements were taken from the distal common carotid artery (CCA) at both the lateral and posterior angles bilaterally during the end-diastolic phase. The mean of all 4 measurements were taken as average cIMT (avgcIMT). For this analysis, we excluded individuals on treatment for diabetes, hypertension, hyperlipidemia, and ischemic heart disease to derive a healthy population subset comprising of 6522 individuals (Chinese: 69%, Malays: 14%, Indians: 17%). We then assessed the 75th percentile as a marker of cardiovascular risk in all individuals, by testing associations with Framingham risk scores (locally adapted) and with cardiometabolic risk factors (3). Results Ethnic- and sex-specific 75th percentiles (95% CI) of CIMT for our Asian populations are summarised in Table 1. Compared to reference intervals reported in European and African American populations, the 75th centiles are lower in all Asian ethnic subgroups (p&amp;lt;0.05). Framingham risk score, BMI, LDL-C, HbA1c and systolic blood pressure were higher in Asians with cIMT more than 75th percentile (p&amp;lt;0.001), compared to Asians with normal cIMT. Conclusions We estimated race- and sex-specific 75th percentiles of avgcIMT across age in the multi-ethnic Asian population. The thresholds for Asian populations are substantially lower than reported in European and African populations. The 75th centiles identify people with raised cardiovascular risk factors, supporting the validity of cIMT as marker of vascular risk in the population. The 75th centiles will be useful in interpretation of cIMT measures obtained both in research and clinical settings in different ethnic populations in Asia. Longitudinal evaluation is needed to determine the prediction of our Asian specific thresholds for predicting hard cardiovascular outcomes.

Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies.

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca2+) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.

Exploring adult-onset actinic prurigo in Thailand

Actinic prurigo (AP) is an uncommon photodermatosis. In European and native American populations, AP is more frequently found in young women and shows clinical improvement or remission in adulthood. The clinical symptoms of AP in Asians differ in that the condition usually occurs in adults (adult-onset AP) and is clinically persistent. The objective of this study is to investigate the characteristics and outcomes of patients with AP in Thailand. A total of 15 cases diagnosed AP were reviewed. All cases were adult-onset AP (mean age of onset was 45.5 years). Male predominated (66.7%). Mostly of them presented with papules on face and upper extremities. Mucositis was presented in 2 patients. Phototesting revealed decreased MED for UVA alone in 3 patients and decreased MED for both UVA and UVB in 3 patients. Nine patients who had normal MED were further performed photoprovocation test and showed positive UVA photoprovocation in 5 patients; positive both UVA and UVB photoprovocation in 4 patients. Systemic immunosuppressant was prescribed in 60% of patients. Median time to clinical improvement was 8.6 months. Complete clinical remission was found in only 3 patients. Adult-onset AP has different clinical features and responds differently to treatment, compared to classical AP.

Early electrophysiological study variants and their relationship with clinical presentation and outcomes of patients with Guillain-Barré syndrome

This study compared the clinical outcomes of the two main neurophysiological types of Guillain-Barré Syndrome (GBS). Sixty-two GBS patients were examined clinically at onset using Medical Research Council (MRC), Hughes disability scales (HDS), and nerve conduction studies were evaluated in four limbs. The Modified Erasmus GBS outcome score (MEGOS) was assessed 2 weeks after onset. Outcomes were measured after 3 months using MRC and HDS scores. According to electrophysiological data two main groups identified acute inflammatory demyelinating polyneuropathy (AIDP = 31 cases) or acute axonal GBS including inexcitable forms (26 cases). The number of days between onset of weakness and admission was significantly shorter, and gastrointestinal symptoms were significantly higher among the axonal type than AIDP. MRC sum scores at onset and at nadir were significantly worse in the axonal type than in AIDP. Neck muscle weakness, impaired cough reflex, the need for mechanical ventilation, hypoalbuminemia, and hypernatremia were more common in the axonal type. At outcome, 74% of the AIDP were healthy/minor symptoms versus 38.46% of the axonal type. There was a high prevalence of the axonal variant (41.9%) compared with European and North American populations. The axonal type had a significantly worse outcome than AIDP type.

The genus &lt;i&gt;Trichaptum&lt;/i&gt; in North Asia

It is shown that in North Asia (Urals, Siberia, Far East) the genus Trichaptum is represented by four widespread sympatric species (Trichaptum abietinum, T. biforme, T. fuscoviolaceum, T. laricinum) and T. quercinum found in the Far East. The geographic range of T. fuscoviolaceum, T. abietinum, T. biforme cover the whole of North Asia, whereas T. laricinum is absent in the Far East. The revealed sympatric nature of species is based on their predominant use of wood various coniferous (T. fuscoviolaceum, T. abietinum, T. laricinum) and deciduous (T. biforme) tree species. The widest trophic niche is in T. fuscoviolaceum and it overlaps by 70–80% with the niches of T. abietinum, T. laricinum. The narrowest trophic niche that does not overlap with other species of the genus is in T. biforme. The trophic spectra and preferences of all species in North Asia are close to those in Europe, and it shows stability and species specificity of these ecological characteristics. Phylogenetically, T. abietinum and T. fuscoviolaceum are the closest in ITS and LSU rDNA regions, while T. biforme and T. laricinum are strongly and equally distant from each other and from T. abietinum and T. fuscoviolaceum. During ITS and LSU clustering, the sequences are grouped in full accordance with the hymenophore structure of the fungi from which they were isolated; the same groups also include sequences of the corresponding fungi from Europe, China, and North America. This shows that in T. fuscoviolaceum, T. abietinum, T. biforme, T. laricinum, the structure of the hymenophore is a good diagnostic species character, and also that their North Asian populations do not show significant differences from European and North American populations. A database on diversity, distribution, ecology of fungi of the genus Trichaptum in North Asia has been uploaded to GBIF for public access.

214-LB: Plasma Proteomic Markers of Iron and Risk of Diabetes in a Biracial Cohort

Higher levels of iron have been linked to increased diabetes risk among European and European American (EA) populations; whether this is true for other populations where anemia is more common is unknown. Ferritin is an iron storage protein linked to diabetes risk; transferrin transports catalytic iron, reducing its oxidative damage. We tested whether proteomic measurements of ferritin and transferrin were associated with diabetes risk in a biracial cohort of current and former smokers. EA and African American (AA) participants from the COPDGene Cohort who were free of diabetes (n=4,671) at study baseline were followed for the incidence of diabetes. The Somascan was used on plasma measured at followup to determine relative amounts of proteins among participants. Logistic regression was used to calculate OR (95% CIs) of the cross-sectional relationship of natural log transformed ferritin and transferrin with diabetes risk. During an average of 5.6 years of follow-up, the incidence of diabetes was 7.9%. Ferritin was associated with increased diabetes risk (OR=1.29, 1.04-1.61), while higher transferrin linked with decreased risk (OR=0.19, 0.06-0.56) controlling for age, sex, BMI, hepcidin and smoking. When stratified by race, increased risk was associated with higher ferritin only among AA (OR=1.46, 1.07-2.01) and not for EA (OR=1.11, 0.81-1.52). Stratification by sex revealed that the relationship of ferritin was similar among AA men and women and EA women, with non-significant ORs ranging from 1.49-1.55; but null association among EA men (OR = 1.00, 0.65-1.52). Similarly, ORs for transferrin non-significantly ranged from 0.24-0.29 for AA men and women and EA women, but for EA men there was a significant 93% decreased risk for each natural long increase in transferrin (OR=0.07, 0.001-0.60). Our data suggest that higher body iron stores, as measured by ferritin, increases diabetes risk among both AA and EA. Ferritin may be a better marker for AA men and women and EA women while transferrin is a better marker for EU men. Disclosure R. B. Conway: None. K. Young: None. K. A. Pratte: None. G. L. Kinney: None. E. Austin: None. Y. Li: None. R. Bowler: None. D. A. Mcclain: None. J. Crappo: None. Funding National Heart, Lung, and Blood Institute (U01HL089897, U01HL089856); AstraZeneca; Bayer Pharmaceuticals; Boehringer Ingelheim; Genentech; GlaxoSmithKline; Novartis; Pfizer Inc.; Sunovion

Systemic lupus erythematosus and toll-like receptor 9 polymorphisms: A meta-analysis of genetic association studies.

This study aimed to examine whether polymorphisms in toll-like receptor 9 (TLR9) contribute to vulnerability to systemic lupus erythematosus (SLE). We searched the MEDLINE, Embase, and Web of Science databases for relevant articles. We conducted a meta-analysis to examine the association between the TLR9 rs187084, rs352139, rs352140, and rs5743836 polymorphisms and SLE risk. A total of 5447 patients with SLE and 6588 control participants across 26 trials from 24 articles were included. The TLR9 rs187084 T allele was significantly associated with SLE (odds ratio, 1.146; 95% confidence interval, 1.033-1.273; p = 0.010). In a meta-analysis, the TLR9 rs187084 T allele was associated with SLE in the Asian population but not in the Arab population, demonstrating the existence of ethnicity-specific effects. Using homozygote contrast and recessive models, the researchers also found that the TLR9 rs187084 T/C polymorphism was associated with SLE. The TLR9 rs352139 G allele was not associated with SLE in this meta-analysis. After accounting for ethnic differences, we found that the TLR9 rs352139 G allele was not associated with SLE in Asians and Arabs. Furthermore, homozygote contrast and dominant models found no association between the TLR9 rs352139 G/A polymorphism and SLE. TLR9 polymorphisms at rs352140 and rs5743836 were not associated with an increased risk of SLE in any genetic prediction model, including people of Asian, European, or Latin American ancestry. SLE susceptibility is associated with the TLR9 rs187084 polymorphism in the Asian population and the rs187084, rs352139, rs352140, and rs5743836 polymorphisms in the Asian, European, and Latin American populations, respectively.

Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome.

Restless Legs Syndrome (RLS) is a common sensorimotor and a sleep disorder that affects 2.5-10% of the European and North American populations. RLS is also often associated with periodic leg movements during sleep (PLMS). Despite ample evidence of genetic contributions, the underlying mechanisms that elicit the sensory and motor symptoms remain unidentified. Clinically, RLS has been correlated with an altered central iron metabolism, particularly in the brain. While several animal models have been developed to determine the outcome of an altered iron homeostasis on brain function, the potential role of an altered iron homeostasis on sleep and sensorimotor circuits has not yet been investigated. Here, we utilize a mouse model to assess the effects of an iron-deficient (ID) but non-anemic state on sleep time and episodes, and sensorimotor reflexes in male and female mice. We found that animals on the ID diet displayed an increased expression of the transferrin receptor in the spinal cord, confirming the results of previous studies that focused only on the impact of ID in the brain. We also demonstrate that the ID diet reduced hematocrit levels compared to controls but not into the anemic range, and that animals on the ID diet exhibited RLS-like symptoms with regard to sleep onset and spinal cord reflex excitability. Interestingly, the effects on the spinal cord were stronger in females than in males, and the ID diet-induced behaviors were rescued by the return of the animals to the control diet. Taken together, these results demonstrate that diet-induced ID changes to CNS function are both inducible and reversible, and that they mimic the sleep and sensorimotor RLS symptoms experienced in the clinic. We therefore propose replacing the commonly used phrase "brain iron deficiency" (BID) hypothesis in the RLS research field with the term "iron deficiency in the central nervous system" (ID-CNS), to include possible effects of altered iron levels on spinal cord function.

Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s disease

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

Genetic loci of beta-aminoisobutyric acid are associated with aging-related mild cognitive impairment

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)—the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value <5 × 10−8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants’ association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value <0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels.

Abstract 4201: Associations of pre-diagnostic serum liver enzymes levels with lung cancer risk: results from the Southern Community Cohort Study

Abstract Introduction: Lung cancer is the leading cause of cancer death in the United States (U.S.). Lung cancer disproportionately affects African Americans (AAs) more than other racial/ethnic groups. Previous studies have linked liver diseases to lung cancer risk; however, few studies have evaluated the associations of circulating liver enzyme levels with lung cancer risk. In this study, we evaluated the associations of the serum alanine transaminase (ALT) and alkaline phosphatase (ALP) levels with the risk of subsequently developing lung cancer. Methods: We conducted a nested case-control study within the Southern Community Cohort Study, a well-conducted prospective cohort study in the southern U.S. mainly consisting of low-income AAs and European Americans (EAs). We included 552 incident lung cancer cases and 1,039 controls individually matched on age, sex, recruitment sites, and date of blood draw. Baseline serum levels of ALT and ALP were measured using the Beckman Coulter clinical chemistry analyzer. Conditional logistic regression and generalized estimating models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for age, education, household income, body mass index (BMI), smoking status, pack-years, alcohol consumption, physical activity levels, history of chronic obstructive pulmonary disease, hypertension, and diabetes. Results: Higher serum levels of ALT were associated with a lower overall risk of lung cancer. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (Ptrend &amp;lt; 0.01). The inverse association was observed in both AAs and EAs. However, the inverse associations between serum ALT levels and lung cancer risk were more evident among men [ORT3 vs T1 = 0.36 (0.18-0.70)], current smokers [ORT3 vs T1 =0.65 (0.47-0.90)], participants with lower BMI [ORT3 vs T1=0.55 (0.38-0.79)], or lower physical activity [ORT3 vs T1 = 0.55 (0.37-0.83)]. Stratified analyses by time interval between blood collection and lung cancer diagnosis showed that the inverse associations were observed in both those diagnosed within [ORT3 vs T1 =0.48 (0.23-1.00)] and after [ORT3 vs T1 = 0.36 (0.19-0.69)] a median follow up time of 3 years. The serum ALT level was not associated with overall lung cancer; however, higher serum ALP levels were significantly associated with increased lung cancer risk among AA men [ORT3 vs T1 = 1.98 (1.18-3.34)]. Conclusion: Our results indicate that in a predominantly low-income AA and EA population, serum ALT levels may be related to a lower risk of lung cancer. Further studies are warranted to confirm our findings and elucidate the potential underlying mechanisms of the associations. Citation Format: Shuai Xu, Hui Cai, Jie Wu, Hyung-Suk Yoon, Regina Courtney, Xiao-Ou Shu, William J. Blot, Wei Zheng, Qiuyin Cai. Associations of pre-diagnostic serum liver enzymes levels with lung cancer risk: results from the Southern Community Cohort Study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4201.

Abstract P3-05-30: Survival after Development of Contralateral Breast Cancer

Abstract Purpose There are many studies reporting survival after development of contralateral breast cancer(CBC) but with inconsistent results. Also, many studies were based on European or North American population and few on Asian population. However, Korean breast cancer patients have different characteristics such as age distribution. Therefore, purpose of this study is to investigate whether development of CBC has influence on survival in Korean breast cancer population. Methods In this retrospective study, we included patients who were diagnosed with a first primary unilateral non-metastatic breast cancer at Asan Medical Center, Korea, between 1999-2013 followed through 2018. In this population, patients who delveloped CBC during the follow-up period were divided into the CBC cohort, and who did not into the non-CBC cohort. Survival of CBC cohort and non-CBC cohort was compared in the whole study population and in subgroup analysis by interval of CBC development, and breast cancer subtype. Results Over median follow-up of 107 months, 418 patients developed CBC out of 16,251 patients. Development of CBC did not influence overall survival or breast cancer-specific survival. In subgroup analysis by interval of CBC development, patients who developed CBC within one year after diagnosis of the first breast cancer had higher risk for overall death in CBC cohort (hazard ratio 2.58; 95% CI 1.28-5.18), and patients who developed CBC after one year showed no significant difference in survival compared with non-CBC cohort. In subgroup analysis by the subtype, patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative subtype for the first breast cancer showed higher risk for overall death in CBC cohort (hazard ratio 1.88; 95% CI 1.14-3.10) whereas patients with triple negative subtype for the first breast cancer showed lower risk for overall survival in CBC cohort (hazard ratio 0.42; 95% CI 0.19-0.95). Conclusion Development of CBC in Korean breast cancer patients did not have significant impact on survival. However, development of CBC early after diagnosis of first breast or having certain subtype of breast cancer may have affect on survival. Such information can be important information when counseling patients who are considering contralateral prophylactic mastectomy. Citation Format: Hakyoung Kim, Hee Jeong Kim, Yoon Tae In, Seonok Kim, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn. Survival after Development of Contralateral Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-30.

Sequencing-based fine-mapping and in silico functional characterization of the 10q24.32 arsenic metabolism efficiency locus across multiple arsenic-exposed populations.

Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.

Cephalometric comparison of Eastman standards among caucasians and saudi population in the Najran region.

Caucasian norms derived from the European-American population are often applied in the diagnosis and treatment planning of Saudi orthodontic patients. Minor differences in cephalometric values can be considered routine and normal, but significant differences indicate a structural deviation. The objective of this study was to establish the cephalometric norms of normal and pleasant soft tissue profiles of adult Saudi living in the Najran region of Saudi Arabia and compare them with the Eastman standards derived from the Caucasian population. A total of 60 lateral cephalometric radiographs (30 males and 30 females) of Najran adults aged between 18-30 years with pleasing, acceptable, harmonious and well-balanced soft tissue profile and Class I molar relationship with no history of previous orthodontic treatment, no crowding or spacing, normal overjet and overbite were selected for the study. Descriptive analysis and Student t-test were performed to evaluate the male and female gender differences and compare the Najran mean with Eastman standards. On evaluating the gender differences, Najran females tend to have more ANB angle and L1 to A-Pog linear distance than Najran males(p<0.05). On comparing with the Eastman Caucasian standards, the Najran population tends to have more SNA, ANB, UI to MxP and L1 to A-Pog (p<0.05). The U1 to L1 angle tends to be less in Najran population than the Caucasians (p<0.05). The Najran population has more protrusive skeletal bases, bimaxillary protrusion, more proclined upper and lower incisors and reduced interincisal angle than Caucasians. The Najran females have more protrusive skeletal bases and more proclined lower incisors compared to Najran males. The cephalometric findings of this study can be useful in the diagnosis and treatment planning of orthodontic patients belonging to the Najran region of Saudi Arabia.

IMPACTO DE LA ANCESTRÍA GENÉTICA EN LA DISTRIBUCIÓN DEL POLIMORFISMO DE INTERFERÓN-λ4 RS12979860 EN UNA POBLACIÓN GLOBAL DE BUENOS AIRES, ARGENTINA

Human interferon-λ4 is a cytokine involved in early stages of antiviral responses. Strikingly, some allelic variants with diminished antiviral activity reduce the susceptibility to viral infections, thus they would have suffered a positive selection pressure throughout the evolutionary history of the genus Homo. An intronic variant within the IFNλ4 locus (rs12979860, T˃C) emerged as one of the main gene determinants of the response to HCV and other viruses. The rs12979860-C allele has a differential frequency in African, European and Native American populations, though South American data are scarce. Here we characterize for the first time the distribution of rs12979860 genotypes in a sample of the global population of Buenos Aires, Argentina, assessing its association with European, Native American and African parental components. The rs12979860 genotypes were determined by PCR-RFLP in DNA samples from donors of a blood banks of Buenos Aires (n=96), whose genetic individual ancestry (European, African or Native American) had been previously determined using molecular markers. The distribution of rs12979860-CC, CT and TT was 29.17%, 50.0% and 20.83%, respectively. A significant increase in the frequency of CC among donors with a strong European contribution and a greater impact of the Native American component among donors carrying the T allele were observed. Native American and European components were associated to the rs12979860 distribution in a sample of the global population of Buenos Aires, while no differences were directly attributable to the African ancestry. Considering interferon´s key role in antiviral responses, our results may contribute to both bioanthropological and immunogenetic studies associated with infectious diseases. Key words: ancestry, Buenos Aires, IFNλ4 polymorphism, rs12979860 distribution.

Association between vitamin D receptor polymorphisms and vitiligo susceptibility: An updated meta-analysis.

Vitamin D receptor (VDR) polymorphisms may play an important role in the vitiligo susceptibility. There have been many studies looking at the associations between VDR polymorphisms and vitiligo risk, but the conclusions are still up for debate. This study aimed to determine whether polymorphisms in the VDR are associated to the susceptibility to vitiligo. Vitamin D receptor polymorphisms in vitiligo patients and controls were identified using PubMed/Medline and Embase databases. The relationships between the VDR ApaI, TaqI, BsmI, and TaqI polymorphisms and vitiligo were investigated using meta-analyses of all participants and Asian, Arab, European, and Latin American groups. This meta-analysis included 13 papers with 2034 patients and 2771 controls. In all individuals, there was no link between vitiligo and the VDR ApaI A allele (OR=0.889, 95% CI=0.713-1.109, p=0.298). However, in Asians (OR=0.721, 95% CI=0.553-0.940, p=0.016) but not in Europeans or Arabs, there was a link between the VDR ApaI A allele and vitiligo. Utilizing recessive, dominant, and homozygote contrast models, a link between vitiligo and the VDR ApaI polymorphism was discovered in Asians. Meta-analysis of the VDR BsmI polymorphism showed a significant association between vitiligo and the B allele (OR=0.812, 95% CI=0.686-0.961, p=0.015). In contrast, no connection between vitiligo and VDR polymorphisms was identified for TaqI and FokI polymorphisms. In the Asian population, ApaI and BsmI polymorphisms in VDR have been correlated to vitiligo susceptibility. However, TaqI and FokI polymorphisms in VDR are not associated with vitiligo susceptibility in European, Asian, Arab, and Latin American populations.

A sequence-based 163plex microhaplotype assay for forensic DNA analysis.

Novel genetic marker microhaplotype has led to an upsurge in forensic genetic research. This study established a 163 microhaplotype (MH) multiplex assay based on next-generation sequencing (NGS) and evaluated the assay’s performance and applicability. Our results showed that the 163 MH assay was accurate, repeatable and reliable, and could distinguish between African, European-American, Southern Asia and Eastern Asia populations. Among the 163 MH makers, 48 MHs with Ae > 3.0 in China Eastern Han were selected and confirmed to be highly polymorphic, with a combined power of discrimination of 1–8.26 × 10–44 and the combined power of exclusion in duos and trios of 1–1.26 × 10–8 and 1–8.27 × 10–16, respectively. Moreover, the mixture study demonstrated the realizability of the MHs in deconvoluting mixtures with different proportions of two to five-person. In conclusion, our findings support the use of this MH assay for ancestry inference, human identification, paternity testing and mixture deconvolution in forensic research.

Anatomical and Clinical Factors Associated With Valvulopathy and Aortopathy in Mexican Patients With Bicuspid Aortic Valves

The bicuspid aortic valve (BAV) is associated with significant aortic valve dysfunction. We aimed to study Mexican patients with BAV to assess phenotypic expressions of BAV, and associations of valvulopathy and aortopathy and their predictors. A cross-sectional, retrospective study was designed. The patients were divided according to (1) normally or minimally dysfunctional BAV, (2) predominant aortic regurgitation (AR), and (3) predominant aortic stenosis (AS). A total of 189 patients were included with a high prevalence of males (68%). The overall median age was 42 (23 to 52) years. The distribution of fused BAV phenotypes was right-left fusion (77%), right noncoronary fusion (17%) and left noncoronary fusion (6%). AS-predominant group was the oldest with a high prevalence of hypertension, type 2 diabetes mellitus (T2DM), and raphe. In multivariable analysis T2DM (odds ratio [OR] 10.5 [95% confidence interval (CI) 2.1 to 52], p <0.01) and presence of raphe (OR 2.58 [95% CI 1.02 to 6.52], p=0.04) were independently associated with AS. The AR-predominant group was composed mostly of males with significantly fewer cardiovascular risk factors. Male gender (OR 2.84 [95%CI 121 to 6.68], p=0.01) and aortic dilatation (OR 3.58 [95% CI 1.73 to 7.39], p <0.01) were associated with AR-predominance in multivariable analysis. Aortic dilatation was associated with age (OR 1.03 [95% CI 1.008 to 1.05], p <0.01) and AR (OR 4.31 [95% CI 2.05 to 9.06], p <0.01). Independent factors associated with the root phenotype were male gender (OR 12.4 [95% CI 1.6 to 95], p <0.01) and AR (OR 5.25 [95% CI 2.18 to 12.6], p <0.01).In conclusion, in a mestizo population, the distribution of BAV-fused phenotypes was similar to European and North American populations, the presence of raphe and T2DM were independently associated with AS-predominance, and male gender and aortic dilatation were independently associated with AR-predominance.