Biomedical subjects

Kyong-Mi Chang

Publications and source records attributed to Kyong-Mi Chang.

6 recordsLinked to original sources

PubMed2026

Cross-Ancestry and Phenome-Wide Associations of Cancer-Specific Polygenic Risk Scores.

PURPOSE: Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited. METHODS: Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons. RESULTS: All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, P = 4.5 × 10-06) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease). CONCLUSION: Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.

Female↗

PubMed2026

A Common CD36 Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry.

IMPORTANCE: Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. OBJECTIVE: To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. DESIGN SETTING AND PARTICIPANTS: Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. EXPOSURE: Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). MAIN OUTCOMES AND MEASURES: Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. RESULTS: Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). CONCLUSIONS AND RELEVANCE: An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Journal Article↗

PubMed2025

Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.

IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.

Humans↗

PubMed2025

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Journal Article↗

PubMed2025

Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction.

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.

Humans↗

PubMed2025

Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.

Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.

Humans↗