Publications by authors named "Alexander G Bick"

43 Publications

Distinction of lymphoid and myeloid clonal hematopoiesis.

Nat Med 2021 Oct 18. Epub 2021 Oct 18.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
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http://dx.doi.org/10.1038/s41591-021-01521-4DOI Listing
October 2021

Expanding approaches to detect clonal hematopoiesis.

Haematologica 2021 Sep 30. Epub 2021 Sep 30.

Division of Genetic Medicine, Department of Medicine Vanderbilt University School of Medicine and Vanderbilt University Medical Center Nashville, TN 37232.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.279818DOI Listing
September 2021

is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.

Blood Cancer Discov 2021 Sep 14;2(5):500-517. Epub 2021 Jul 14.

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462124PMC
September 2021

Clonal Hematopoiesis of Indeterminate Potential: an Expanding Genetic Cause of Cardiovascular Disease.

Curr Atheroscler Rep 2021 09 1;23(11):66. Epub 2021 Sep 1.

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Ave S, Nashville, TN, USA.

Purpose Of Review: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease-which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP.

Recent Findings: The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.
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http://dx.doi.org/10.1007/s11883-021-00966-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543762PMC
September 2021

Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry.

JAMA Netw Open 2021 Aug 2;4(8):e2119084. Epub 2021 Aug 2.

Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York.

Importance: Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown.

Objective: To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry.

Design, Setting, And Participants: This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm.

Main Outcomes And Measures: Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components.

Results: This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations.

Conclusions And Relevance: This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.19084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339934PMC
August 2021

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

J Am Coll Cardiol 2021 07;78(1):42-52

Department of Epidemiology, Brown University, Providence, Rhode Island, USA; Care New England, Center for Primary Care and Prevention, Pawtucket, Rhode Island, USA; Department of Family Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. Electronic address:

Background: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

Objectives: This study sought to evaluate whether CHIP is associated with incident HF.

Methods: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

Results: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

Conclusions: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
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http://dx.doi.org/10.1016/j.jacc.2021.04.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313294PMC
July 2021

Publisher Correction: Germline risk of clonal haematopoiesis.

Nat Rev Genet 2021 Sep;22(9):619

Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.

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http://dx.doi.org/10.1038/s41576-021-00384-2DOI Listing
September 2021

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Nat Med 2021 06 7;27(6):1012-1024. Epub 2021 Jun 7.

Institute for Molecular Medicine Finland, Helsinki, Finland.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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http://dx.doi.org/10.1038/s41591-021-01371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245201PMC
June 2021

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Aging Cell 2021 06 29;20(6):e13366. Epub 2021 May 29.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10 ) to 3.08 years (EEAA, p < 3.7 × 10 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.
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http://dx.doi.org/10.1111/acel.13366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208788PMC
June 2021

Germline risk of clonal haematopoiesis.

Nat Rev Genet 2021 09 13;22(9):603-617. Epub 2021 May 13.

Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.
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http://dx.doi.org/10.1038/s41576-021-00356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117131PMC
September 2021

Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential: Results From the Women's Health Initiative.

J Am Heart Assoc 2021 02 23;10(5):e018789. Epub 2021 Feb 23.

Division of Preventive Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA.

Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57-0.88] and 0.83 [95% CI, 0.68-1.01], respectively; -trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.
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http://dx.doi.org/10.1161/JAHA.120.018789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174283PMC
February 2021

Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer.

medRxiv 2020 Nov 16. Epub 2020 Nov 16.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood . Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality . Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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http://dx.doi.org/10.1101/2020.11.12.20230821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685330PMC
November 2020

Increased CHIP Prevalence Amongst People Living with HIV.

medRxiv 2020 Nov 7. Epub 2020 Nov 7.

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n=600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n=8,111) from blood DNA-derived exome sequences. We observed that HIV is associated with increased CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p=0.005). Additionally, unlike in ARIC, ASXL1 was the most commonly implicated mutated CHIP gene. We propose that CHIP may be one mechanism through which PLWH are at increased risk for CAD. Larger prospective studies should evaluate the hypothesis that CHIP contributes to the excess cardiovascular risk in PLWH.
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http://dx.doi.org/10.1101/2020.11.06.20225607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654930PMC
November 2020

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Circulation 2021 Feb 9;143(5):410-423. Epub 2020 Nov 9.

Cardiology Division (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.

Methods: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.

Results: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; =0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; =0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; =0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; <0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; =0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; =0.005).

Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911856PMC
February 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.

Nature 2020 10 14;586(7831):769-775. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
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http://dx.doi.org/10.1038/s41586-020-2786-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606745PMC
October 2020

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.

Nat Commun 2020 08 20;11(1):3635. Epub 2020 Aug 20.

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.
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http://dx.doi.org/10.1038/s41467-020-17374-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441381PMC
August 2020

Proteomic Profiling in Biracial Cohorts Implicates DC-SIGN as a Mediator of Genetic Risk in COVID-19.

medRxiv 2020 Jun 11. Epub 2020 Jun 11.

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses, as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine. Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.
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http://dx.doi.org/10.1101/2020.06.09.20125690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302224PMC
June 2020

Parenting While in Training: A Comprehensive Needs Assessment of Residents and Fellows.

J Grad Med Educ 2020 Apr;12(2):162-167

Background: Parenting issues can affect physicians' choice of specialty or subspecialty, as well as their selection of individual training programs, because of the distinctive challenges facing residents and fellows with children. Specific information about how residents perceive these challenges is limited.

Objective: We sought to better understand the challenges associated with parenting during residency and fellowship training in order to inform policy and research.

Methods: In 2017, a voluntary online questionnaire was distributed to all 2214 Partners HealthCare graduate medical education trainees across 285 training programs. The survey queried attitudes of and about trainees with children and assessed needs and experiences related to parental leave, lactation, and childcare. Responses were compared between subgroups, including gender, surgical versus nonsurgical specialty, parental status, and whether the respondent was planning to become a parent.

Results: A total of 578 trainees (26%) responded to the questionnaire. Of these, 195 (34%) became parents during training. An additional 298 (52%) planned to become parents during training. Respondents overwhelmingly agreed that their institution should support trainees with children (95%) and that doing so is important for trainee wellness (98%). However, 25% felt that trainees with children burden trainees without children. Childcare access, affordability, and availability for sufficient hours were identified as key challenges, along with issues related to parental leave, lactation facilities, and effect on peers.

Conclusions: This survey highlights trainees' perspectives about parenting during their clinical training, signaling parental leave, lactation facilities, and childcare access and affordability as particular challenges and potential targets for future interventions.
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http://dx.doi.org/10.4300/JGME-D-19-00563.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161335PMC
April 2020

Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis.

Circulation 2020 01 11;141(2):124-131. Epub 2019 Nov 11.

Cardiovascular Research Center (A.G.B., J.P.P., P.N.), Massachusetts General Hospital, Boston.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as or . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.

Methods: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with or CHIP. We used the p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by p.Asp358Ala.

Results: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], =0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], <0.001). p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29-0.73], <0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89-1.01], =0.08; =0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by p.Asp358Ala (=0.036).

Conclusions: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008855PMC
January 2020

Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD: JACC Review Topic of the Week.

J Am Coll Cardiol 2019 07;74(4):578-586

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address:

The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.
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http://dx.doi.org/10.1016/j.jacc.2019.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662618PMC
July 2019

Association of Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Circulation 2019 09 24;140(12):1031-1040. Epub 2019 Jul 24.

Massachusetts General Hospital, Boston (A.G.B., D.K., P.N., S.K.).

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 () risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between risk alleles and cardiovascular disease (CVD) that is independent of the effects of on kidney disease. We sought to test the association of G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program.

Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.

Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; =0.031). When both cardiovascular and renal outcomes were modeled, was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets.

Conclusions: risk variants display a modest association with CVD, and this association is likely mediated by the known association with chronic kidney disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754626PMC
September 2019

Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure.

Am J Hum Genet 2018 10 13;103(4):461-473. Epub 2018 Sep 13.

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of hypertension (1.38 OR; 95% CI, 1.27-1.50 per 1 SD predicted increase in albuminuria, p = 7.01 × 10). We then examined bidirectional associations of albuminuria with blood pressure which suggested that genetically elevated albuminuria led to higher blood pressure (2.16 mmHg systolic blood pressure; 95% CI, 1.51-2.82 per 1 SD predicted increase in albuminuria, p = 1.22 × 10) and that genetically elevated blood pressure led to more albuminuria (0.005 SD; 95% CI 0.004-0.006 per 1 mmHg predicted increase in systolic blood pressure, p = 2.45 × 10). These results support the existence of a feed-forward loop between albuminuria and blood pressure and imply that albuminuria could increase risk of cardiovascular disease through blood pressure. Moreover, they suggest therapies that target albuminuria-increasing processes could have antihypertensive effects that are amplified through inhibition of this feed-forward loop.
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http://dx.doi.org/10.1016/j.ajhg.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174360PMC
October 2018

modifies -induced kidney disease risk.

Proc Natl Acad Sci U S A 2018 03 12;115(13):3446-3451. Epub 2018 Mar 12.

Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with We performed an admixture mapping study to identify genetic modifiers of -associated kidney disease. Individuals with two risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the locus correlates with lower levels of expression. In cell-based experiments, the disease-associated alleles (known as G1 and G2) lead to increased abundance of mRNA but to decreased levels of protein. gene expression inversely correlates with G1 and G2 -mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both and , which interact in a functionally important manner. UBD appears to mitigate -mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in and expression appear to modify the -associated kidney phenotype.
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http://dx.doi.org/10.1073/pnas.1716113115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879665PMC
March 2018

Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.

Proc Natl Acad Sci U S A 2017 10 9;114(43):E9096-E9104. Epub 2017 Oct 9.

Department of Genetics, Harvard Medical School, Boston, MA 02115;

Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of , a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if expression was cardioprotective, we produced and characterized mice. Mutant mice had left atrial enlargement and cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor ( vs. wild type, = 7.8 × 10), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that mice recapitulate features of diastolic heart disease and define previously unappreciated roles for in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.
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http://dx.doi.org/10.1073/pnas.1711303114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664535PMC
October 2017

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.

N Engl J Med 2017 07 21;377(2):111-121. Epub 2017 Jun 21.

From the Department of Medicine, Division of Hematology, Brigham and Women's Hospital (S.J., A.J.S., M.M.) and Harvard Medical School (B.L.E.), the Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital (E.S.) and Harvard Medical School (G.K.S., P.L.), the Department of Pathology (S.J.) and the Center for Genomic Medicine (P.N., S.K.), Massachusetts General Hospital, the Department of Medicine, Division of Cardiology, and Cardiovascular Research Center (P.N., S.K.), and the Department of Medicine (A.G.B.), Massachusetts General Hospital and Harvard Medical School, and the Departments of Medical Oncology (C.J.G.) and Biostatistics and Computational Biology (D.N.), Dana-Farber Cancer Institute, Boston, and the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., A.G.B., N.G., S.G., S.K.) - all in Massachusetts; the Department of Cardiology, University Hospital, Parma, Italy (D.A.); the Department of Medicine, Division of Cardiology, Mt. Sinai School of Medicine, New York (U.B., R.M., V.F.); Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid (V.F.); Medical Research Council-British Heart Foundation Cardiovascular Epidemiology Unit and National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, and the British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge (J.D.), and the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (J.D.) - both in the United Kingdom; the Center for Non-Communicable Diseases, Karachi, Pakistan (P.F., D.S.); the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S.); and the Department of Clinical Sciences Malmö, Lund University, Lund, Sweden (O.M.).

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.

Methods: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.

Results: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.

Conclusions: The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1701719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717509PMC
July 2017

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

PLoS One 2017 15;12(3):e0172995. Epub 2017 Mar 15.

Department of Medecine and Genetics Harvard Medical School, Boston, MA, United States of America.

Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.

Methods And Results: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here.

Conclusion: We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351854PMC
September 2017

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

J Am Coll Cardiol 2016 Dec;68(25):2761-2772

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Background: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.

Objectives: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD.

Methods: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.

Results: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.

Conclusions: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.
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http://dx.doi.org/10.1016/j.jacc.2016.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328146PMC
December 2016
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