Arab Ancestry Research Articles

KEMUDI’s Pursuance of Muslim Identity and its Implications to Malaysian Muslims

KEMUDI or Persatuan Kesedaran Melayu dan Islam (The Malay and Islamic Awareness Association) is a Malaysian based non-governmental organization (NGO) established in 2013. The organization aims to embrace and uphold a discreet Malay-Arab Muslim identity believed as being degraded by colonialism that introduces liberal democracy and capitalism to replace Malay monarchy. This qualitative study involves data collection from social media platforms, library research and semi-structured interviews. The descriptive analytical approach is applied within the organizational framework of Objective, Leadership Structure, Membership, Resource, Strategy and Tactic. The aim is to investigate KEMUDI’s origin, strategy and tactic as well as its variant of Muslim identity. It follows that KEMUDI’s pursuit of Muslim identity incorporates upholding a hybrid Arab ancestry (read: prophetic, ahl al-baytness) as the prerogative of Malay Muslim identity using strategical alliances and tactical series of lectures, publications as well as cultural activities. The Malay Arab Muslim identity is being pursued and maintained, symbiotically, as religiously significant and ethnically privileged to serve political, religious and social pursuits. The implication of KEMUDI’s ethno-religious identity to Malaysian Muslims focuses on three sectors of the National Integrity Plan (NIP); politics, civil society organization (CSO) and religion. It is found that the discreet dual Malay Arab Muslim identity adopted by KEMUDI has its share of commendatory and condemnatory implications on Malaysian Muslims.

Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort

AbstractNeutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Abstract 2222: Knowledge of risk factors and symptoms of head and neck cancers among Arab-Americans

Abstract Background: In 2023, approximately 66000 patients with head and neck cancers (HNC) will be diagnosed in the United States (U.S.). There are approximately 3.7 million Arab-Americans living in the U.S., with large concentration in Michigan (MI). For example, Dearborn, MI has the largest percentage of Arab-Americans (40% of people having Arab ancestry). Smoking, alcohol, and human papillomavirus (HPV) are the main causes of HNC. Common symptoms of HNC are lump in the neck/mouth, nonhealing ulcers, dysphagia or odynophagia, and change in voice. Currently, there is a scarcity of research on knowledge of HNC risk factors and symptoms among Arab-Americans. We examined knowledge of risk factors and symptoms of HNC among Arab-Americans residing in MI. Methods: This was a cross-sectional study of adult Arab-Americans (≥18 years) conducted between March and July 2023. Survey questions were adapted from the National Cancer Institute and Centers for Disease Control and Prevention and offered in English and Arabic depending on respondent preference. Awareness of the symptoms of HNCs were assessed using 14 questions while risk factors were assessed using 10 questions. The questions were in the form of “Do you know that the following can be symptoms/risk factors of HNC?” Respondents selected “yes,” “no,” or “don’t know/not sure” for each answer choice. Results: Of the 295 Arab-Americans survey respondents, the mean age ± SD was 37.9 ± 14.6, and most were female (60.7%), had at least a college degree (57.6%), private health insurance (56.7%), and usual place of receiving care (70.7%). Majority had no history of cigarette use (81.7%) or alcohol use (91.6%). Regarding HNC symptoms knowledge, only 40-50% knew about most common HNC symptoms: nonhealing ulcers (41%), dysphagia or odynophagia (51.4%), and voice changes (48.6%); while 60.6% knew about swelling or lump in neck/throat. About half of respondents knew of persistent mass or lesion on the tongue (53.3%) and bleeding in the mouth or throat (50.3%) as symptoms of HNC. About a third knew these as HNC symptoms: teeth loosening (31.7%), ill-fitting dentures (25.9%), otalgia (37.8%), and nasal obstruction/congestion (34.9%). For HNC risk factors knowledge, tobacco smoking, chewing, and second-hand smoking were the most common recognized risk factors, identified by 78.9%, 72.8% and 66.8%, respectively. However, less than half knew HPV (40.6%) and Epstein-Barr virus (35.4%) as risk factors. Conclusion: While there is higher knowledge about tobacco as a risk factor for HNC, knowledge about HPV as a risk factor is very low. Similarly, knowledge about HNC symptoms is suboptimal in the Arab-American community, which could result in late-stage presentation and thus lower survival. Educational programs designed for this community are needed to help close this gap and improve HNC related health outcomes among culturally and ethnically distinct Arab-Americans. Citation Format: Eric Adjei Boakye, Reem F. Siddiqui, Nada Al-Antary, Marissa Gilbert, Lamis Fakhoury, Milkie Vu, Farzan Siddiqui. Knowledge of risk factors and symptoms of head and neck cancers among Arab-Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2222.

(266) Examining the Experience of Sexual Dysfunction and Spiritual Abuse among Cisgender Muslim Women in North America

Abstract Introduction Muslim women are an underrepresented and underserved population in North America who often do not seek care for their sexual traumas and sexual difficulties. In order to better serve this population with minimal bias, it is important for healthcare providers to understand their vast experiences with spiritual abuse and sexual dysfunction, as well as reasons for not seeking healthcare related to sexual dysfunction. Objective To understand the experiences of cisgender Muslim women in North America with regards to sexual function, sexual abuse and spiritual abuse. Methods To investigate these topics, a survey was administered to 771 Muslims between the ages of 18–45 who live in the US and Canada 2020. The majority of respondents were heterosexual females, were part of the Sunni sect of Islam, had a bachelor’s degree or higher, and were of South Asian, Asian, Middle Eastern, or Arab ancestry. Aspects of sexual functioning such as the frequency of sexual desire, arousal during sexual intercourse, achievement of orgasm, and pain during or after vaginal penetration were assessed. Results Of the 158 respondents who reported having experienced sexual pain, only 34.4% sought healthcare for this problem. The most commonly cited reasons included fear or shame, unawareness, doubt that the situation would improve, and resolution of the pain on its own. 530 participants were asked if religion or spirituality have been used to: force them to make decisions they are opposed to (76.4%), force them to engage in a non-consensual sexual act (14.6%), isolate from others (57.9%), minimize the abuse they experienced (48.7%), or prevent them from speaking out against abuse (53.9%). Conclusions This data provides insight into a Muslim cohort’s frequency of sexual burdens which include dysfunction and abuse. Understanding how spiritual abuse can influence patients’ familial, romantic, and sexual relationships may help providers to administer culturally competent care to Muslim patients. Disclosure No.

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals.

Background: The current study explores the genetic underpinnings of cardiac arrhythmia phenotypes within Middle Eastern populations, which are under-represented in genomic medicine research. Methods: Whole-genome sequencing data from 14,259 individuals from the Qatar Biobank were used and contained 47.8% of Arab ancestry, 18.4% of South Asian ancestry, and 4.6% of African ancestry. The frequency of rare functional variants within a set of 410 candidate genes for cardiac arrhythmias was assessed. Polygenic risk score (PRS) performance for atrial fibrillation (AF) prediction was evaluated. Results: This study identified 1196 rare functional variants, including 162 previously linked to arrhythmia phenotypes, with varying frequencies across Arab, South Asian, and African ancestries. Of these, 137 variants met the pathogenic or likely pathogenic (P/LP) criteria according to ACMG guidelines. Of these, 91 were in ACMG actionable genes and were present in 1030 individuals (~7%). Ten P/LP variants showed significant associations with atrial fibrillation p < 2.4 × 10-10. Five out of ten existing PRSs were significantly associated with AF (e.g., PGS000727, p = 0.03, OR = 1.43 [1.03, 1.97]). Conclusions: Our study is the largest to study the genetic predisposition to arrhythmia phenotypes in the Middle East using whole-genome sequence data. It underscores the importance of including diverse populations in genomic investigations to elucidate the genetic landscape of cardiac arrhythmias and mitigate health disparities in genomic medicine.

(004) Examining the Experience of Sexual Dysfunction and Spiritual Abuse among cis-Gender Muslim Women In North America

Abstract Introduction Unwanted sexual advances and sexual contact can lead to a lifetime of trauma. The NSVIS survey demonstrates that 43.6% of women (nearly 52.2 million) experienced some form of unwanted sexual contact sexual in their lifetime in the United States and 21.3% or an estimated 25.5 million women in the U.S. reported completed or attempted rape at some point in their lifetime (Smith et al., 2018). Additionally, prevalence rates for sexual pain for women in the U.S. vary and can be as high as 40% depending on the study. Muslim women are an underrepresented and underserved population in North America who often do not seek care for their sexual traumas and sexual difficulties. There are likely many factors involved and in order to better serve them with minimal bias, it is important for healthcare providers to understand their vast experiences in spiritual abuse and sexual dysfunction and reasons for not seeking care. Objective To understand the experiences of cis-gender Muslim women in North America with regards to sexual pain and spiritual trauma, along with looking at barriers to treatment and how to better serve this population. Methods A cross-sectional, IRB approved, online and anonymous survey was implemented in the United States and Canada for self-identified Muslim responders ages 18-45 in 2020. Survey was 151 questions that were based on validated survey instruments and implemented on Qualtrics. Snowball and purposive sampling was utilized to identify a total of 771 self-identified Muslims between the ages of 18-45. Participants were recruited via social media, listserv outreach, office visits and community partners. Demographics were assessed as well as religiosity, sexual function and dysfunction, sexual abuse and treatments. Descriptive statistics were utilized for analysis. Results The majority of respondents were heterosexual females, were part of the Sunni sect of Islam, had a bachelor’s degree or higher, and were of South Asian, Asian, Middle Eastern, or Arab ancestry. Aspects of sexual functioning such as the frequency of sexual desire, arousal during sexual intercourse, achievement of orgasm, and pain during or after vaginal penetration were assessed. Of the 158 respondents who reported having experienced sexual pain, 65.0% did not seek treatment for it. The main reasons included a sense of fear or shame, unawareness, disbelief that the situation would improve, and resolution of the pain on its own. 530 participants were asked if religion or spirituality have been used to: force them to make decisions they are opposed to (76.4%), force them to engage in a non-consensual sexual act (14.3%), isolate from others (57.9%), minimize the abuse they experienced (48.7%), or prevent them from speaking out against abuse (54.0%) Conclusions This data provides insight into a Muslim cohort’s frequency of sexual burdens which include dysfunction and abuse. Sexual abuse and sexual pain are common among cis-gender Muslim women in North America and it is underreported. Most of the patients who reported abuse and pain, did not seek treatment. Barriers to treatment may include cultural stigmas around sex, lack of cultural competence among providers, implicit bias, lack of awareness of it being a problem or there being solutions, and costs. Understanding how spiritual abuse can influence patients’ familial, romantic, and sexual relationships may help providers to administer culturally competent care to Muslim patients. Disclosure No

ABU HASAN KRUENG KALEE: THE CHARISMATIC ULAMA OF ACEH

Abu Hasan Krueng Kalee is one of Aceh's charismatic scholars who teaches religious knowledge and other sciences. Abu Hasan Krueng Kalee has an important role in the sustainability of education, politics, and religion in Aceh. The research location that the author examined was Siem Village, Darussalam Sub-District. In this study, the authors used historical research methods, namely investigations that apply scientific solutions to the historical perspective of a problem with the steps of data collection, source criticism, interpretation, and writing method. The author draws a number of conclusions concerning Teungku Hasan bin Teungku Muhammad Hanafiyyah bin Teungku Shaykh 'Abbas bin Teungku Muhammad Fadhil based on the findings of the investigation. Muhammad Hasan was given the first name when he was born on 13 Rajab 1303 H, which corresponds to 18 April 1886 AD, in Gampong Langgoe Meunasah Keutumbu Village, Sangeue, Pidie. Teungku Haji Muhammad Hanafiyah bin Teungku Sheikh Abbas, often known as Teungku Chik Krueng Kalee One or Teungku Haji Muda Krueng Kalee, is the father of Abu Hasan Krueng Kalee. Nya'Ti Hafsah bint Teungku Ismail, the mother of Abu Hasan Krueng Kalee, was of Arab ancestry and migrated through Pase. Teungku Syekh Abdul Wahab and Asiah, two brothers of Abu Hasan Krueng Kalee.. Abu Hasan Krueng Kalee's contributions to religion and the country have been made in the areas of politics, education, and religion. Additionally, works of Abu Hasan Krueng Kalee might be used to instruct students. The writings include “Risalah Latifah Fi Adabi’z_Zikry” as well as “Jawahiru’I-‘ulum Fi kasyfi’I-ma’lum, An’amatu’I-fa-idatu fi isti’mali qa’odati’r-rabitat, ­Siraju’s-Salikin’ala minhaju’I-‘abidin.

Whole-Exome Sequencing Reveals Migraine-Associated Novel Functional Variants in Arab Ancestry Females: A Pilot Study.

Migraine, as the seventh most disabling neurological disease with 26.9% prevalence in Saudi females, lacks studies on identifying associated genes and pathways with migraines in the Arab population. This case control study aims to identify the migraine-associated novel genes and risk variants. More than 1900 Arab ancestry young female college students were screened: 103 fulfilled the ICHD-3 criteria for migraine and 20 cases confirmed in the neurology clinic were included for the study with age-matched healthy controls. DNA from blood samples were subjected to paired-end whole-exome sequencing. After quality control, 3365343 missense, frameshift, missense splice region variants and insertion-deletion (indels) polymorphisms were tested for association with migraine. Significant variants were validated using Sanger sequencing. A total of 17 (p-value 9.091 × 10-05) functional variants in 12 genes (RETNLB, SCAI, ADH4, ESPL1, CPT2, FLG, PPP4R1, SERPINB5, ZNF66, ETAA1, EXO1 and CPA6) were associated with higher migraine risk, including a stop-gained frameshift (-13-14*SX) variant in the gene RETNLB (rs5851607; p-value 3.446 × 10-06). Gene analysis revealed that half of the significant novel migraine risk genes were expressed in the temporal lobe (p-value 0.0058) of the cerebral cortex. This is the first study exploring the migraine risk of 17 functional variants in 12 genes among Saudi female migraineurs of Arab ancestry using whole-exome sequencing. Half of the significant genes were expressed in the temporal lobe, which expands migraine pathophysiology and early identification using biomarkers for research possibilities on personalised genetics.

Patterns and distribution of de novo mutations in multiplex Middle Eastern families

While de novo mutations (DNMs) are key to genetic diversity, they are also responsible for a high number of rare disorders. To date, no study has systematically examined the rate and distribution of DNMs in multiplex families in highly consanguineous populations. Leveraging WGS profiles of 645 individuals in 146 families, we implemented a combinatorial approach using 3 complementary tools for DNM discovery in 353 unique trio combinations. We found a total of 27,168 DNMs (median: 70 single-nucleotide and 6 insertion-deletions per individual). Phasing revealed around 80% of DNMs were paternal in origin. Notably, using whole-genome methylation data of spermatogonial stem cells, these DNMs were significantly more likely to occur at highly methylated CpGs (OR: 2.03; p value = 6.62 × 10−11). We then examined the effects of consanguinity and ethnicity on DNMs, and found that consanguinity does not seem to correlate with DNM rate, and special attention has to be considered while measuring such a correlation. Additionally, we found that Middle-Eastern families with Arab ancestry had fewer DNMs than African families, although not significant (p value = 0.16). Finally, for families with diseased probands, we examined the difference in DNM counts and putative impact across affected and unaffected siblings, but did not find significant differences between disease groups, likely owing to the enrichment for recessive disorders in this part of the world, or the small sample size per clinical condition. This study serves as a reference for DNM discovery in multiplex families from the globally under-represented populations of the Middle-East.

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman.

Familial hypertriglyceridemia (F-HTG) is an autosomal disorder that causes severe elevation of serum triglyceride levels. It is caused by genetic alterations in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. The mutation spectrum of F-HTG in Arabic populations is limited. Here, we report the genetic spectrum of six families of F-HTG of Arab ancestry in Oman. Methods: six Omani families affected with triglyceride levels >11.2 mmol/L were included in this study. Ampli-Seq sequencing of the selected gene panels was performed. Whole-exome sequencing and copy number variant analysis were also performed in cases with negative exome results. Three novel pathogenic missense variants in the LPL gene were identified, p.M328T, p.H229L, and p.S286G, along with a novel splice variant c.1322+15T > G. The LPL p.H229L variant existed in double heterozygous mutation with the APOA5 gene p.V153M variant. One family had a homozygous mutation in the LMF1 gene (c.G107A; p.G36D) and a heterozygous mutation in the LPL gene (c.G106A; p.D36N). All affected subjects did not have a serum deficiency of LPL protein. Genetic analysis in one family did not show any pathogenic variants even after whole-exome sequencing. These novel LPL and APOA5 mutations are not reported in other ethnic groups. This suggests that patients with F-HTG in Oman have a founder effect and are genetically unique. This warrants further analysis of patients of F-HTG in the Middle East for preventative and counseling purposes to limit the spread of the disease in a population of high consanguinity.

Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study

ObjectivesTo determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received...

Impact of Endometriosis in Women of Arab Ancestry on: Health-Related Quality of Life, Work Productivity, and Diagnostic Delay.

Introduction: Endometriosis has a negative effect on health-related quality of life (HRQoL), wellbeing and daily functioning. Endometriosis is an under-researched condition within non-western populations. Cultural representations are needed to understand the relative roles of societal norms, traditional factors, and religious sensitivities on the impact of endometriosis on HRQoL in various populations. In particular, there is a lack of emphasis placed in understanding the association of HRQoL on endometriosis in Arab women.Method: In this prospective case-control study, 2,610 Arab ancestry women in the United Arab Emirates were recruited to investigate the impact of endometriosis on HRQoL, diagnostic delay, psychological co-morbidities, work productivity, and physical activity. Participants completed the following standardized, validated questionnaires: Short Form-36 version 2 questionnaire, the World Endometriosis Research Foundation EPHect minimum clinical questionnaire version, and Work Productivity and Activity Impairment questionnaire. Translations to the Arabic language, validated using the forward-backward translation method, of the questionnaires were utilized.Results: HRQoL scores were significantly impaired in women with endometriosis, as demonstrated in the Physical Composite Scores and Mental Composite Scores in the symptomatic control group (p = 0.001; p = 0.003, respectively) and the asymptomatic control group (p < 0.001; p < 0.001, respectively). Susceptibility and severity of multiple pain syndromes and infertility in women with endometriosis was the main indicator of lower HRQoL. Anxiety (p = 0.007) and depression (p = 0.005) were significantly associated with endometriosis, in comparison to symptomatic controls. The average diagnostic delay was 11.61 years, however single women experience 15.81 years of diagnosis delay, with approximately 18% (n = 15) of the single women experiencing more than a 20-year delay in diagnosis. The intensity of physical activity was not associated with endometriosis, when compared to symptomatic (p = 0.405) or asymptomatic controls (p = 0.144).Conclusion: For the first time, we provide evidence from a combined hospital, clinic, and population-based study that Arab women with endometriosis experience significant impacts on HRQoL, substantial diagnostic delay after the onset of symptoms, significant association to psychological disorders (anxiety and depression), and a negative impact on work productivity. Future research must focus on understanding the personal and culturally centered beliefs of Arab women to ensure a positive HRQoL trajectory by improving diagnosis and management strategies.

Transient Neonatal Diabetes Mellitus with the Rare Association of Nonsuppurative Sialadenitis and Genetic Defects in 6q24

Background Transient neonatal diabetes mellitus (TNDM) is the most common cause of diabetes in the first week of life, with an overall incidence of 1 in 90,000 to 160,000 live births. TNDM occurs soon after birth and undergoes spontaneous remission during infancy; however, it may relapse to a permanent form of diabetes mellitus in childhood or adolescence. We report a case of TNDM due to hypomethylation on chromosome 6q24, associated with a rare clinical finding of nonsuppurative submandibular sialadenitis managed by subcutaneous insulin, and who underwent remission by three months of age. Case Presentation. We report a male neonate of Arab ancestry delivered by caesarean section at 37 weeks of gestation. He had intrauterine growth retardation with a birth weight of 2.099 kg. He presented with hyperglycemia on the first day of life, which was managed with parenteral insulin infusion. Blood glucose control was initially difficult to achieve due to difficulties in preparing such small doses of insulin and the significant variations in blood glucose concentrations, without ketosis. Blood tests revealed low serum insulin and C-peptide levels. Genetic analysis revealed multiple loci hypomethylation of the PLAGL1/HYMAI-DMR in the TNDM region in chromosome 6q24 and two pathogenic heterozygous variants in the ZFP57 gene. Segregation analysis showed that both parents were heterozygous carriers of familial ZFP57 variants. The clinical course was associated with bilateral nonsuppurative sialadenitis, which is extremely rare among newborns. Conclusion Sialadenitis is a well-known phenomenon that is rarely diagnosed in neonates. To the best of our knowledge, this is the first case report to describe the exceedingly rare association of nonsuppurative submandibular sialadenitis in a neonate with TNDM due to multiple loci hypomethylation of the PLAGL1/HYMAI-DMR in the TNDM region in 6q24 and heterozygous pathogenic variants in the ZFP57 gene.

Hepatitis B and C among patients with hidradenitis suppurativa: a population-based study.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition related to multiple systemic diseases and infections. This retrospective cross-sectional study from 1999 to 2015 used the database of Clalit Health Services, the largest managed care organization in Israel, to explore the association between HS and hepatitis B and C. Sociodemographic and clinical information was compared using χ2 tests for sex and socioeconomic status and t-tests for age. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to compare the odds of hepatitis B and C in those with and without HS. In multivariate analysis controlling for sex, age as a continuous variable, Arab ancestry, and history of drug abuse, HS was associated with a 1.87-fold increased odds (95% CI 1.11-3.17, P = 0.019) of hepatitis B (HBV). HS was also associated with HCV in multivariate analysis controlling for sex, age per year, Arab ancestry, alcohol use, and drug use, with a 1.74-fold increased odds (95% CI 1.05-2.89, P = 0.032) of hepatitis C (HCV) among those with HS as compared to controls. This study demonstrated an association between HS and both hepatitis B and hepatitis C.

Ancestry-associated transcriptomic profiles of breast cancer in patients of African, Arab, and European ancestry

Breast cancer largely dominates the global cancer burden statistics; however, there are striking disparities in mortality rates across countries. While socioeconomic factors contribute to population-based differences in mortality, they do not fully explain disparity among women of African ancestry (AA) and Arab ancestry (ArA) compared to women of European ancestry (EA). In this study, we sought to identify molecular differences that could provide insight into the biology of ancestry-associated disparities in clinical outcomes. We applied a unique approach that combines the use of curated survival data from The Cancer Genome Atlas (TCGA) Pan-Cancer clinical data resource, improved single-nucleotide polymorphism-based inferred ancestry assignment, and a novel breast cancer subtype classification to interrogate the TCGA and a local Arab breast cancer dataset. We observed an enrichment of BasalMyo tumors in AA patients (38 vs 16.5% in EA, p = 1.30E − 10), associated with a significant worse overall (hazard ratio (HR) = 2.39, p = 0.02) and disease-specific survival (HR = 2.57, p = 0.03). Gene set enrichment analysis of BasalMyo AA and EA samples revealed differences in the abundance of T-regulatory and T-helper type 2 cells, and enrichment of cancer-related pathways with prognostic implications (AA: PI3K-Akt-mTOR and ErbB signaling; EA: EGF, estrogen-dependent and DNA repair signaling). Strikingly, AMPK signaling was associated with opposing prognostic connotation (AA: 10-year HR = 2.79, EA: 10-year HR = 0.34). Analysis of ArA patients suggests enrichment of BasalMyo tumors with a trend for differential enrichment of T-regulatory cells and AMPK signaling. Together, our findings suggest that the disparity in the clinical outcome of AA breast cancer patients is likely related to differences in cancer-related and microenvironmental features.

Tracing the mutated HTT and haplotype of the African ancestor who spread Huntington disease into the Middle East

PurposeWe aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East. MethodsWe performed genetic and genealogical analyses to establish the ancestral origin of the HTT pathgenic variant from a large kindred from Oman (hereafter called the OM-HD-01 pedigree) by single-nucleotide polymorphism and dense haplotype analysis genotyping. ResultsWe traced the oldest ancestry of the largest, eight-generation, OM-HD-01 pedigree (n=302 subjects, with 54 showing manifest HD) back to sub-Saharan Africa and identified a unique HD haplotype carried by all pedigree members, which consisted of portions of the C6 and C9 haplotypes and was carried by all affected members. Such a unique HD haplotype was of African origin and appeared to be associated with large CAG repeat expansions on average and high frequency of juvenile-onset HD. Three other families from the same area were also identified and found carrying a Caucasian HD haplotype A, also shared by most families of Arab ancestry. ConclusionMutated HTT spread into Middle East with a unique haplotype of African origin, appeared to be associated with juvenile-onset, a HD condition frequently occurring in Black Africans, and may have a significant impact on further development of novel targeted genetic therapies.

The Role of Polymorphisms in Vitamin D-Related Genes in Response to Vitamin D Supplementation.

Background. Vitamin D deficiency represents a major healthcare problem. Vitamin D status is influenced by genetic and environmental determinants. Several observational studies have evaluated the association of single-nucleotide polymorphisms (SNPs) in vitamin D-related genes and vitamin D levels. Nevertheless, little is known about the role of these SNPs in the response to vitamin D supplementation. We conducted an interventional study to define the association between SNPs in vitamin D-related genes and the response to vitamin D supplementation in 100 self-reported healthy women of Arab ancestry for the majority. Methods. A total of 100 healthy female subjects received a weekly oral dose of 50,000 IU vitamin D for 12 weeks. Serum vitamin D concentration and metabolic profiles were measured at baseline and 12 weeks post-vitamin D supplementation. The genotypes of 37 SNPs selected from previously reported vitamin D-related genes have been assessed by Fluidigm genotyping assay. Results. Rs731236 (VDR gene) and rs7116978 (CYP2R1 gene) showed a significant association with vitamin D status. The rs731236 GG genotype and the rs7116978 CC genotype were associated with a “vitamin D sufficiency” state. Rs731236 GG and rs7116978 CC genotypes showed a higher response to vitamin D supplementation. Transcription factor binding site prediction analysis showed altered binding sites for transcription factors according to the different rs7116978 alleles. Interestingly, the 37 SNPs previously established to play a role in vitamin D-related pathways explained very little of the response to vitamin D supplementation in our cohort, suggesting the existence of alternative loci whose number and effect size need to be investigated in future studies. Conclusion. In this paper, we present novel data on vitamin D-related SNPs and response to vitamin D supplementation demonstrating the feasibility of applying functional genomic approaches in interventional studies to assess individual-level responses to vitamin D supplementation.

1647-P: Rare Disruptive Loss of Function Mutations in the Cluster of Differentiation 36 (CD36) Gene Overwhelmingly Cause a Metabolic Syndrome in Multiple Members of an Inbred Pedigree from One Village in Northern Israel

The metabolic syndrome consisting of type 2 diabetes (T2DM), obesity, dyslipidemia and arterial hypertension, is a complex disorder whose molecular basis is largely unknown. The cluster of differentiation 36 (CD36), a multifunctional class B scavenger receptor, has been acknowledged as a promising candidate for T2DM and its complications. More than a decade ago, a rare nonsense mutation, namely c.1079T&amp;gt;G (p.L360X) was identified in one Caucasian pedigree presenting with autosomal dominant diabetes (Hum mutation 2004). Recent studies however, have disputed the contribution of rare coding mutations in CD36 to T2DM and additional metabolic complications (Scientific Reports 2019). In an extended pedigree of Israeli Muslim Arab ancestry from a single village in northern Israel multiple members (n=33) with T2DM, obesity, dyslipidemia and arterial hypertension were investigated. Three affected individuals from three nuclear inbred families, originating from an extended Arab Muslim clan, underwent whole-exome sequencing that displayed several disruptive rare mutations in CD36 namely c.1011_1014delins26; p.(Arg337Serfs*23); c.1079T&amp;gt;G; p.(Leu360*); and c.1202_1205delTATT; p.(Val401Glufs*4). Sanger sequencing was thereafter employed to show that these mutations segregated in 30 additional affected individuals from the same clan. Our findings substantiate that CD36 plays a pivotal role in glucose homeostasis and lipid metabolism. Mutations in this gene prompt insulin resistance, obesity and dyslipidemia in humans. A rare nonsense mutation (p.L360X) in CD36 was previously found in a French pedigree presenting with autosomal dominant diabetes. Here we provide evidence that other than the p.L360X mutation, rare loss-of-function coding mutations in CD36 evoke impaired fatty acid metabolism, glucose intolerance, type 2 diabetes and arterial hypertension. Disclosure N. Zuckerman Levin: None. D. Bercovich: None. I. Pasternak: None. R. Gershoni-Baruch: None. N. Shehadeh: None.

Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.

The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.

First description of the molecular and clinical characterization of hereditary factor V deficiency in Saudi Arabia: report of four novel mutations.

Coagulation factor V plays a significant role in the blood coagulation cascade as part of the prothrombinase complex. Factor V deficiency (FVD) is a rare autosomal recessive bleeding disorder with a variable phenotypic expression which varies from being asymptomatic-to-severe bleeding episodes. The aim of this study was to perform molecular and clinical characterization of FVD in patients originating from Saudi Arabia. Eleven patients (two males and nine females) with confirmed FVD were recruited in the study with ages ranging between 5 and 53 years. A next-generation sequencing-based hematology panel encompassing 393 known genes was used. A total of six sequence variations in F5 gene were identified, including four missense mutations (p.Pro189Leu, p.Trp2004Arg, p.Met2148Thr, p. Arg2202Cys), a deletion (p.Arg872Lysfs*12) and a splicing variant (c.1118+5G>T). Four variants were identified for the first time in this study. Three patients were homozygous for their respective mutations and seven patients were heterozygous. We were not able to identify a pathogenic variant in one patient of the cohort. In-silico and three-dimensional structural analyses were performed to predict the possible impact and functional consequences of the identified variants. To our knowledge, this is the first study addressing factor V mutations in patients with Arab ancestry. Results have helped in providing a definitive diagnosis to the patients and carrier detection in extended family members. Overall, the hematology panel assay was an efficient platform, demonstrating a formidable approach for the molecular diagnosis of other suspected bleeding disorders.