Publications by authors named "Pankratz N"
Background: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.
Methods: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk.
Article Synopsis
- Genetic studies have highlighted the need for more diverse research on plasma fibrinogen levels, as previous studies largely focused on Europeans, leading to gaps in understanding and missing heritability.
- By analyzing data from whole-genome sequencing and genotype data from large cohorts, researchers identified 18 genetic loci related to fibrinogen levels, some of which are more common in African populations and include variants that may impact protein function.
- The study's findings indicate a connection between fibrinogen levels and various health conditions, emphasizing the importance of whole-genome sequencing in discovering genetic factors in diverse populations and enhancing knowledge about fibrinogen regulation.
African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs).
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- Venous thromboembolism (VTE) poses significant health risks, with a notable difference in incidence rates between Black and White Americans.
- Researchers developed polygenic risk scores (PRSs) for VTE using data from both European and African-ancestry populations to enhance predictive capability.
- Results showed that multi-ancestry PRSs slightly outperformed ancestry-specific ones in predicting VTE risk, indicating potential benefits in using diverse data for better risk assessment across populations.
Article Synopsis
- Genome-wide association studies (GWAS) have successfully identified genes linked to telomere length, but previous research hadn't validated these findings until now.
- In a large analysis involving over 211,000 people, the study discovered five new signals linked to telomere length and highlighted the importance of blood/immune cells in this area.
- The researchers confirmed that the genes KBTBD6 and POP5 truly affect telomere length by demonstrating that manipulating these genes can lengthen telomeres and that their regulation is crucial for understanding telomere biology.
Article Synopsis
- Inflammation biomarkers offer crucial insights into the inflammatory processes linked to various diseases, and their sequencing can help reveal the genetic makeup of these traits.
- A study analyzed 21 inflammation biomarkers from around 38,465 individuals, discovering 22 significant associations across 6 inflammatory traits after considering existing findings.
- The research combined single-variant and rare variant analyses, identifying additional significant associations and highlighting the complexity and diversity of genetic influences on inflammation traits across different ancestries.
Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood.
View Article and Find Full Text PDFAfrican American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n=58) and low (n=60) TAC troughs (N=515 AA KTRs).
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- * Discovery of 7 new genetic loci associated with FVIII and 1 new locus for VWF, supporting their roles in thrombotic outcomes via Mendelian randomization.
- * Functional testing revealed that silencing genes like B3GNT2 and CD36 impacted FVIII and VWF release from endothelial cells, indicating their potential regulatory roles.
Article Synopsis
- Venous thromboembolism (VTE) significantly affects health outcomes and shows disparities in incidence between Black and White Americans, necessitating improved risk assessment methods.* -
- Polygenic risk scores (PRSs) derived from diverse ancestry data performed better than traditional PRSs, indicating their potential for accurately identifying high-risk individuals for VTE in both European and African ancestries.* -
- The study found that using multi-ancestry PRSs could enhance risk stratification, with individuals in the highest risk category having a substantially increased likelihood of VTE, suggesting a path towards personalized treatment approaches.*
Background And Objectives: Nearly all genetic analyses of Parkinson disease (PD) have been in populations of European ancestry. We sought to test the ability of a machine learning method to extract accurate PD diagnoses from an electronic medical record (EMR) system, to see whether genetic variants identified in European populations generalize to individuals of African and Hispanic ancestries, and to compare the rates of PD across ancestries.
Methods: A machine learning method using natural language processing was applied to EMRs of US veterans participating in the VA Million Veteran Program (MVP) to identify individuals with PD.
Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood.
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- Megabase-scale mosaic chromosomal alterations (mCAs) in blood can indicate the risk of various human diseases, and this study analyzes whole-genome sequencing data from 67,390 individuals to better understand mCA rates across different genetic backgrounds.
- The research found that whole-genome sequencing is more effective than traditional methods for detecting mCAs, revealing that individuals of European ancestry have higher rates of autosomal mCAs and lower rates of chromosome X mCAs compared to those of African or Hispanic ancestry.
- The study identifies three genetic loci linked to chromosome X loss and associates rare variants in specific genes (DCPS, ADM17, PPP1R16B, and TET2) with autosomal mCAs
Article Synopsis
- A study on a Pakistani family revealed that two daughters suffered from severe schizophrenia, while other family members were unaffected, suggesting a possible autosomal recessive inheritance pattern.
- Genetic analysis pinpointed a rare variant in the non-catalytic deubiquitinase gene, linked to schizophrenia, along with evidence supporting its role in the glutamate hypothesis of the disorder through significant protein interactions in the brain.
Article Synopsis
- Abdominal aortic aneurysm (AAA) has a significant genetic component, with a study identifying 141 genetic associations, including 97 that were previously unknown.
- The research highlighted key biological pathways related to AAA, such as lipid metabolism, vascular development, and inflammation, indicating how these factors contribute to the disease's progression.
- The study also suggests that lowering non-high-density lipoprotein cholesterol could be beneficial for AAA patients, advocating for the use of PCSK9 inhibitors based on evidence from a mouse model where PCSK9 loss prevented AAA development.
Article Synopsis
- * Findings validate previous associations, revealing that lower mtDNA CN correlates with a higher risk of coronary heart disease but within the context of no causal relationship established in either direction.
- * Strong evidence suggests that high low-density lipoprotein cholesterol influences mtDNA CN levels, indicating it may play a key role in the relationship between mtDNA CN and cardiovascular health.
Article Synopsis
- Mitochondria have their own circular DNA, and problems with this DNA are linked to aging-related diseases.
- A study of nearly 195,000 UK Biobank participants reveals that higher levels of mitochondrial DNA variation (heteroplasmy) increase the risk of dying by 1.5 times.
- Specific mutations in mitochondrial DNA may indicate a higher risk for cancer, particularly leukemia, suggesting that these mutations could be useful for cancer prognosis.
Article Synopsis
- Inflammation biomarkers play a crucial role in understanding diseases and can reveal insights into genetic traits through whole-genome sequencing studies.
- A comprehensive analysis of 21 inflammation biomarkers in over 38,000 individuals found 22 significant single-variant associations across six different inflammatory traits, indicating the complexity and diversity of these biomarkers.
- The study also included rare variant analyses, identifying 19 additional significant associations, which highlights the importance of using multiple analytical approaches to enhance the understanding of inflammation-related traits across different ancestries.
Background: Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution.
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- * The study employs genetic analysis methods (polygenic risk score and Mendelian randomization) to explore the relationship between genetically predicted leukocyte telomere length and the risk of AML and MDS.
- * A significant association was found: a higher predicted telomere length increases the risk of AML, with various genetic instruments showing different odds ratios for this relationship.
Article Synopsis
- Genetic studies on plasma fibrinogen levels primarily focused on Europeans, revealing numerous associated regions, but there are gaps in understanding due to missing heritability and representation of non-Europeans.
- The researchers utilized whole genome sequencing (WGS) and array-based genotyping data from large cohorts to identify 18 new genetic loci linked to fibrinogen levels, with some variants more common in African populations.
- The study highlights the importance of WGS in discovering genetic variations across diverse populations, linking fibrinogen polygenic risk scores to increased risk for thrombotic and inflammatory diseases like gout.
Successful treatment of endogenous Cushing disease (CD) is often followed by a period of adrenal insufficiency (AI). We performed an exploratory study on genetic factors potentially involved in the hypothalamic-pituitary-adrenal (HPA) axis recovery in patients with CD after remission. We identified 90 patients who achieved remission after surgery and had a minimum of 3 months follow-up.
View Article and Find Full Text PDFBackground: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.
Methods: The 3793 cases and 7834 controls (11.
Background: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development.
Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies.