Publications by authors named "Yesha M Patel"

11 Publications

  • Page 1 of 1

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

Aging (Albany NY) 2021 01 19;13(2):1692-1717. Epub 2021 Jan 19.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization . Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880332PMC
January 2021

Genetic analyses of diverse populations improves discovery for complex traits.

Nature 2019 06 19;570(7762):514-518. Epub 2019 Jun 19.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785182PMC
June 2019

Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations.

Clin Epigenetics 2018 08 23;10(1):110. Epub 2018 Aug 23.

Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.

Background: Lung cancer is the leading cause of cancer-related death. While cigarette smoking is the primary cause of this malignancy, risk differs across racial/ethnic groups. For the same number of cigarettes smoked, Native Hawaiians compared to whites are at greater risk and Japanese Americans are at lower risk of developing lung cancer. DNA methylation of specific CpG sites (e.g., in AHRR and F2RL3) is the most common blood epigenetic modification associated with smoking status. However, the influence of internal smoking dose, measured by urinary nicotine equivalents (NE), on DNA methylation in current smokers has not been investigated, nor has a study evaluated whether for the same smoking dose, circulating leukocyte DNA methylation patterns differ by race.

Methods: We conducted an epigenome-wide association study (EWAS) of NE in 612 smokers from three racial/ethnic groups: whites (n = 204), Native Hawaiians (n = 205), and Japanese Americans (n = 203). Genome-wide DNA methylation profiling of blood leukocyte DNA was measured using the Illumina 450K BeadChip array. Average β value, the ratio of signal from a methylated probe relative to the sum of the methylated and unmethylated probes at that CpG, was the dependent variables in linear regression models adjusting for age, sex, race (for pan-ethnic analysis), and estimated cell-type distribution.

Results: We found that NE was significantly associated with six differentially methylated CpG sites (Bonferroni corrected p < 1.48 × 10-7): four in or near the FOXK2, PBX1, FNDC7, and FUBP3 genes and two in non-annotated genetic regions. Higher levels of NE were associated with increasing methylation beta-valuesin all six sites. For all six CpG sites, the association was only observed in Native Hawaiians, suggesting that the influence of smoking dose on DNA methylation patterns is heterogeneous across race/ethnicity (p interactions < 8.8 × 10-8). We found two additional CpG sites associated with NE in only Native Hawaiians.

Conclusions: In conclusion, internal smoking dose was associated with increased DNA methylation in circulating leukocytes at specific sites in Native Hawaiian smokers but not in white or Japanese American smokers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-018-0543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108111PMC
August 2018

Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer.

Cancer Epidemiol Biomarkers Prev 2017 07 14;26(7):1034-1042. Epub 2017 Mar 14.

Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk. We measured the levels of BD metabolites, 1- and 2-(-acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) and -acetyl--(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism. We found that mean urinary MHBMA concentrations differed significantly by ethnicity ( = 4.0 × 10). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by gene copy number ( < 0.0001); conditional on , no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups ( = 3.3 × 10), but were not affected by copy number ( = 0.226). gene deletion has a strong effect on urinary MHBMA levels, and therefore BD metabolism, in smokers. Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained by genotype. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-16-0838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500389PMC
July 2017

Isotope Dilution nanoLC/ESI-HRMS Quantitation of Urinary N7-(1-Hydroxy-3-buten-2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3-Butadiene.

Chem Res Toxicol 2017 02 17;30(2):678-688. Epub 2017 Jan 17.

Division of Biostatistics, Keck School of Medicine and Children's Cancer Group, University of Southern California , Los Angeles, California 90089, United States.

1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a known human carcinogen. Occupational exposure to BD in the polymer and monomer industries is associated with an increased incidence of lymphoma. BD is present in automobile exhaust, cigarette smoke, and forest fires, raising concern about potential exposure of the general population to this carcinogen. Following inhalation exposure, BD is bioactivated to 3,4-epoxy-1-butene (EB). If not detoxified, EB is capable of modifying guanine and adenine bases of DNA to form nucleobase adducts, which interfere with accurate DNA replication and cause cancer-initiating mutations. We have developed a nanoLC/ESI-HRMS methodology for N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts in human urine (limit of detection: 0.25 fmol/mL urine; limit of quantitation: 1.0 fmol/mL urine). This new method was successfully used to quantify EB-GII in urine of F344 rats treated with 0-200 ppm of BD, occupationally exposed workers, and smokers belonging to two different ethnic groups. EB-GII amounts increased in a dose-dependent manner in urine of laboratory rats exposed to 0, 62.5, or 200 ppm of BD. Urinary EB-GII levels were significantly increased in workers occupationally exposed to 0.1-2.2 ppm of BD (1.25 ± 0.51 pg/mg of creatinine) as compared to administrative controls exposed to <0.01 ppm of BD (0.22 ± 0.08 and pg/mg of creatinine) (p = 0.0024), validating the use of EB-GII as a biomarker of human exposure to BD. EB-GII was also detected in smokers' urine with European American smokers excreting significantly higher amounts of EB-GII than African American smokers (0.48 ± 0.09 vs 0.12 ± 0.02 pg/mg of creatinine, p = 3.1 × 10). Interestingly, small amounts of EB-GII were observed in animals and humans with no known exposure to BD, providing preliminary evidence for its endogenous formation. Urinary EB-GII adduct levels and urinary mercapturic acids of BD (MHBMA, DHBMA) were compared in a genotyped multiethnic smoker cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.chemrestox.6b00407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515386PMC
February 2017

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

Cancer Res 2016 10 3;76(19):5768-5776. Epub 2016 Aug 3.

Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768-76. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050097PMC
http://dx.doi.org/10.1158/0008-5472.CAN-16-0446DOI Listing
October 2016

The Impact of Risk-Based Care on Early Childhood and Youth Populations.

J Calif Dent Assoc 2016 Jun;44(6):367-77

This quality improvement project explored dental caries risk among children residing in El Monte, Calif., a low-income area 16 miles east of Los Angeles. In an attempt to decrease oral health disparities, Western University of Health Sciences, College of Dental Medicine established school-based oral health centers in El Monte and implemented a modified caries risk assessment protocol. Results showed a statistically significant decrease in caries risk following disease management interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2016

Metabolites of the Polycyclic Aromatic Hydrocarbon Phenanthrene in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer.

PLoS One 2016 8;11(6):e0156203. Epub 2016 Jun 8.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, United States of America.

Results from the Multiethnic Cohort Study demonstrated significant differences in lung cancer risk among cigarette smokers from five different ethnic/racial groups. For the same number of cigarettes smoked, and particularly among light smokers, African Americans and Native Hawaiians had the highest risk for lung cancer, Whites had intermediate risk, while Latinos and Japanese Americans had the lowest risk. We analyzed urine samples from 331-709 participants from each ethnic group in this study for metabolites of phenanthrene, a surrogate for carcinogenic polycyclic aromatic hydrocarbon exposure. Consistent with their lung cancer risk and our previous studies of several other carcinogens and toxicants of cigarette smoke, African Americans had significantly (p<0.0001) higher median levels of the two phenanthrene metabolites 3-hydroxyphenanthrene (3-PheOH, 0.931 pmol/ml) and phenanthrene tetraol (PheT, 1.13 pmol/ml) than Whites (3-PheOH, 0.697 pmol/ml; PheT, 0.853 pmol/ml) while Japanese-Americans had significantly (p = 0.002) lower levels of 3-PheOH (0.621 pmol/ml) than Whites. PheT levels (0.838 pmol/ml) in Japanese-Americans were not different from those of Whites. These results are mainly consistent with the lung cancer risk of these three groups, but the results for Native Hawaiians and Latinos were more complex. We also carried out a genome wide association study in search of factors that could influence PheT and 3-PheOH levels. Deletion of GSTT1 explained 2.2% of the variability in PheT, while the strongest association, rs5751777 (p = 1.8x10-62) in the GSTT2 gene, explained 7.7% of the variability in PheT. These GWAS results suggested a possible protective effect of lower GSTT1 copy number variants on the diol epoxide pathway, which was an unexpected result. Collectively, the results of this study provide further evidence that different patterns of cigarette smoking are responsible for the higher lung cancer risk of African Americans than of Whites and the lower lung cancer risk of Japanese Americans, while other factors appear to be involved in the differing risks of Native Hawaiians and Latinos.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156203PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898721PMC
July 2017

Benzene Uptake and Glutathione S-transferase T1 Status as Determinants of S-Phenylmercapturic Acid in Cigarette Smokers in the Multiethnic Cohort.

PLoS One 2016 9;11(3):e0150641. Epub 2016 Mar 9.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55105, United States of America.

Research from the Multiethnic Cohort (MEC) demonstrated that, for the same quantity of cigarette smoking, African Americans and Native Hawaiians have a higher lung cancer risk than Whites, while Latinos and Japanese Americans are less susceptible. We collected urine samples from 2,239 cigarette smokers from five different ethnic groups in the MEC and analyzed each sample for S-phenylmercapturic acid (SPMA), a specific biomarker of benzene uptake. African Americans had significantly higher (geometric mean [SE] 3.69 [0.2], p<0.005) SPMA/ml urine than Whites (2.67 [0.13]) while Japanese Americans had significantly lower levels than Whites (1.65 [0.07], p<0.005). SPMA levels in Native Hawaiians and Latinos were not significantly different from those of Whites. We also conducted a genome-wide association study in search of genetic risk factors related to benzene exposure. The glutathione S-transferase T1 (GSTT1) deletion explained between 14.2-31.6% (p = 5.4x10-157) and the GSTM1 deletion explained between 0.2%-2.4% of the variance (p = 1.1x10-9) of SPMA levels in these populations. Ethnic differences in levels of SPMA remained strong even after controlling for the effects of these two deletions. These results demonstrate the powerful effect of GSTT1 status on SPMA levels in urine and show that uptake of benzene in African American, White, and Japanese American cigarette smokers is consistent with their lung cancer risk in the MEC. While benzene is not generally considered a cause of lung cancer, its metabolite SPMA could be a biomarker for other volatile lung carcinogens in cigarette smoke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784986PMC
August 2016

Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity.

Carcinogenesis 2016 Mar 27;37(3):269-279. Epub 2016 Jan 27.

Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, University of Minnesota , 2231 6th Street SE, 2-127 CCRB, Minneapolis, MN 55455 , USA.

Genetic variation in cytochrome P450 2A6 (CYP2A6) gene is the primary contributor to the intraindividual and interindividual differences in nicotine metabolism and has been found to influence smoking intensity. However, no study has evaluated the relationship between CYP2A6 genetic variants and the CYP2A6 activity ratio (total 3-hydroxycotinine/cotinine) and their influence on smoking intensity [total nicotine equivalents (TNE)], across five racial/ethnic groups found to have disparate rates of lung cancer. This study genotyped 10 known functional CYP2A6 genetic or copy number variants in 2115 current smokers from the multiethnic cohort study [African Americans (AA) = 350, Native Hawaiians (NH) = 288, Whites = 413, Latinos (LA) = 437 and Japanese Americans (JA) = 627] to conduct such an investigation. Here, we found that LA had the highest CYP2A6 activity followed by Whites, AA, NH and JA, who had the lowest levels. Adjusting for age, sex, race/ethnicity and body mass index, we found that CYP2A6 diplotypes were predictive of TNE levels, particularly in AA and JA (P trend < 0.0001). However, only in JA did the association remain after accounting for cigarettes per day. Also, it is only in this population that the lower activity ratio supports lower TNE levels, carcinogen exposure and thereby lower risk of lung cancer. Despite the association between nicotine metabolism (CYP2A6 activity phenotype and diplotypes) and smoking intensity (TNE), CYP2A6 levels did not correlate with the higher TNE levels found in AA nor the lower TNE levels found in LA, suggesting that other factors may influence smoking dose in these populations. Therefore, further study in these populations is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgw012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014092PMC
March 2016

The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations.

Cancer Epidemiol Biomarkers Prev 2015 Jan 7;24(1):119-27. Epub 2014 Oct 7.

Department of Biochemistry, Molecular Biology, and Biophysics and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

Background: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism.

Methods: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined.

Results: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10(-43)) was in high LD (r(2) = 0.99) with rs115765562.

Conclusions: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose.

Impact: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-14-0815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294952PMC
January 2015