Publications by authors named "Nassir R"

Article Synopsis
  • Whole genome sequencing (WGS) helps identify rare genetic variants that may explain the missing heritability of coronary artery disease (CAD) by analyzing 4,949 cases and 17,494 controls from the NHLBI TOPMed program.
  • The study estimates that the heritability of CAD is around 34.3%, with ultra-rare variants contributing about 50%, especially those with low linkage disequilibrium.
  • Functional annotations show significant enrichment of CAD heritability, highlighting the importance of ultra-rare variants and specific regulatory mechanisms in different cells as major factors influencing genetic risk for the disease.
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Background: The Apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis.

Methods: Postmenopausal women (N=6,795) from the Women's Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included.

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  • Clonal hematopoiesis (CH) occurs when genetically identical blood cells expand, often influenced by genetic mutations linked to blood cancers; however, many cases happen without known driver mutations.
  • Researchers analyzed 51,399 genomes to study a specific type of CH (CH-LPMneg) without detectable leukemia-related mutations, developing a new method (GEM rate) to estimate mutation burden without paired samples.
  • Through their study, they identified seven genes linked to CH-LPMneg and found that alterations in hematopoietic stem cell (HSC) behavior may drive this mutation burden, while a broader analysis revealed relationships between GEM and the expression of 404 genes.
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Purpose: Long COVID-19 syndrome occurs in 10-20 % of people after a confirmed/probable SARS-COV-2 infection; new symptoms begin within three months of COVID-19 diagnosis and last > 8 weeks. Little is known about risk factors for long COVID, particularly in older people who are at greater risk of COVID complications.

Methods: Data are from Women's Health Initiative (WHI) postmenopausal women who completed COVID surveys that included questions on whether they had ever been diagnosed with COVID and length and nature of symptoms.

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  • * Researchers analyzed data from 52 studies, including nearly 31,000 CRC cases and over 41,000 controls, to explore the genetic interactions with regular aspirin/NSAID use.
  • * They found significant interactions with genetic variants in two specific regions (6q24.1 and 5p13.1), which could help uncover new targets for understanding how aspirin provides its protective effects against colorectal cancer.
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  • Menopausal hormone therapy (MHT) may lower the risk of colorectal cancer (CRC), especially in women with a higher genetic predisposition to the disease.
  • In a study of nearly 30,000 postmenopausal women, those in the highest genetic risk quartile saw a significantly greater reduction in CRC risk when using MHT compared to those in the lowest quartile.
  • The findings suggest that integrating genetic risk information could improve CRC risk predictions and inform the assessment of MHT benefits in postmenopausal women.
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  • - The study investigates how exonic variants (genetic changes within coding regions) are linked to traits (phenotypes) but can show variable effects (penetrance) among different individuals.
  • - Researchers found that mRNA splicing influenced by genetic factors affects the harmfulness of these exonic variants, showing a depletion of pathogenic alleles in highly expressed exons.
  • - By analyzing data from large genomic studies, the authors suggest that certain genetic variants might help mitigate the impact of rare harmful variants, particularly in relation to autism risk.
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Background: Racial and ethnic disparities in coronavirus disease 2019 (COVID-19) risk are well-documented; however, few studies in older adults have examined multiple factors related to COVID-19 exposure, concerns, and behaviors or conducted race- and ethnicity-stratified analyses. The Women's Health Initiative (WHI) provides a unique opportunity to address those gaps.

Methods: We conducted a secondary analysis of WHI data from a supplemental survey of 48 492 older adults (mean age 84 years).

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  • This study explores how genetics and body mass index (BMI) interact to influence colorectal cancer risk, analyzing data from over 84,000 participants.
  • The research identifies a significant genetic marker (rs58349661) in the FMN1/GREM1 gene region that shows a strong connection with increased cancer risk in individuals with higher BMI, particularly among those with a specific genotype.
  • Findings suggest that understanding this gene-environment interaction could help develop more tailored prevention strategies for colorectal cancer related to obesity.
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Importance: The best approach to identify younger postmenopausal women for osteoporosis screening is uncertain. The Fracture Risk Assessment Tool (FRAX), which includes self-identified racial and ethnic information, and the Osteoporosis Self-assessment Tool (OST), which does not, are risk assessment tools recommended by US Preventive Services Task Force guidelines to identify candidates for bone mineral density (BMD) testing in this age group.

Objective: To compare the ability of FRAX vs OST to discriminate between younger postmenopausal women who do and do not experience incident fracture during a 10-year follow-up in the 4 racial and ethnic groups specified by FRAX.

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Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population.

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  • The study investigates the role of a specific mutational signature (SBS88) in colorectal cancer (CRC), which is linked to a bacteria that produces a genotoxin called colibactin.
  • About 7.5% of the CRC cases studied were found to be SBS88-positive, with a notable prevalence in the distal colon and rectum, and demonstrated distinct somatic mutations associated with colibactin-induced DNA damage.
  • SBS88-positive CRCs were linked to better survival rates compared to negative cases, suggesting this mutational signature could help identify a unique subtype of CRC that may influence treatment and prevention approaches.
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This study aimed to conduct a methodological review of drug-related toxicological studies in Saudi Arabia. A systematic review and a methodological analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline and Embase were searched for all types of studies reporting toxicological studies in the English language published until January 10, 2022.

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Unlabelled: Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data.

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Article Synopsis
  • - Exonic variants are strongly associated with traits, but their harmful effects can vary between individuals, a phenomenon called variable penetrance.
  • - The study suggests that the way mRNA is spliced—controlled by genetic factors—can influence the pathogenic impact of these exonic variants.
  • - Analysis of data shows that common genetic variants affecting splicing may help mitigate the negative effects of rare pathogenic variants, particularly in the context of conditions like autism.
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This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.

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Article Synopsis
  • Tobacco smoking increases the risk of colorectal cancer, and certain genetic profiles may heighten this risk further.
  • A study involving over 33,000 colorectal cancer cases and nearly 44,000 controls identified specific genetic loci (on chromosomes 3p12.1, 6p21.33, and 8q24.23) that interact with smoking behaviors, potentially leading to a greater risk of developing the disease.
  • The research suggests that higher expression of specific genes is associated with a lower risk of colorectal cancer, emphasizing the role of these genetic factors in smoking-related cancer susceptibility and potential avenues for prevention.
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Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway.

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Perforation of the esophagus during dilatation is a rare complication that might cause mortality. We present the report of a 3-year-old girl who was diagnosed with B cell acute lymphoblastic leukemia at 17 months of age. She experienced a complicated clinical course after chemotherapy was initiated, which included mucositis and acute pericarditis.

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Background: Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk.

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Background: Although adherence to the American Cancer Society (ACS) Guidelines on Nutrition and Physical Activity for Cancer Prevention associates with lower risk of obesity-related cancer (ORC) incidence and mortality, evidence in Black and Latina women is limited. This association was examined in Black and Latina participants in the Women's Health Initiative (WHI).

Methods: Semi-Markov multistate model examined the association between ACS guideline adherence and ORC incidence and mortality in the presence of competing events, combined and separately, for 9301 Black and 4221 Latina postmenopausal women.

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Background: Hispanics are a heterogeneous population with differences in the prevalence of cardiovascular disease (CVD) and its related risk factors among ethnic sub-groups. This study evaluated the association of genetic admixture and CVD in self-identified Hispanic women from the Women's Health Initiative (WHI).

Methods: Data came from the WHI Observational Study and the Clinical Trial Components conducted among postmenopausal women.

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Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.

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Article Synopsis
  • The study explored how menopausal hormone therapy (MHT) interacts with genetic variants to affect the risk of colorectal cancer (CRC) in 28,486 postmenopausal women.
  • Results indicated that MHT use was linked to a lower risk of CRC, with specific genetic variants playing a significant role in this association.
  • The findings suggest that understanding these genetic interactions could lead to deeper insights into CRC development and potential therapeutic strategies.
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