Five common gene variants identify elevated genetic risk for coronary heart disease

Bare, Lance A.; Morrison, Alanna C.; Rowland, Charles M.; Shiffman, Dov; Luke, May M.; Iakoubova, Olga A.; Kane, John P.; Malloy, Mary J.; Ellis, Stephen G.; Pankow, James S.; Willerson, James T.; Devlin, James J.; Boerwinkle, Eric

doi:10.1097/gim.0b013e318156fb62

Cited by 90 publications

(93 citation statements)

References 36 publications

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“…MYH15 has previously been identified as a sarcomeric myosin gene, but little information is available about its expression and function (28). MYH15 has previously been found to be expressed in extraocular muscles but not in leg or heart muscle (29), but polymorphisms in MYH15 have been linked to coronary heart disease and to noncardioembolic stroke (30)(31)(32). We report the novel gene expression of MYH15 in human lung tissue.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Hansel¹,

Paré

Rafaels

et al. 2015

Am J Respir Cell Mol Biol

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Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P , 9.57 3 10 28 ). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 3 10 28 , P < 4.6 3 10 26 ). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 3 10 29 ) and MYH15 (P = 1.62 3 10 26 ), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.Keywords: COPD; airway reactivity; bronchial responsiveness; eQTL; d-sarcoglycan

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Hansel¹,

Paré

Rafaels

et al. 2015

Am J Respir Cell Mol Biol

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“…Обсуждение В исследование корпорации Celera были включены наиболее информативные в отношении риска разви-тия ИБС полиморфизмы генов на момент исследова-ния: rs20455 гена KIF6, rs7439293 гена PALLD, rs2298566 гена SNX19, rs3900940 гена MYH15, rs1010 гена VAMP8. Из исследования были исключены однонуклеотидные полиморфизмы, которые, хотя бы в одном исследова-нии, не подтвердили своей ассоциации с ИБС [1,2]. Исследуемые гены показали неоднократную ассоциа-цию с ИБС, инфарктом миокарда и нарушениями липидного обмена в крупных многоцентровых иссле-дованиях -например, ARIC, и нескольких исследова-ниях йцф\случай-контроль [6][7][8].…”

Section: результатыunclassified

“…В 2007г американской корпорацией Celera было проведено крупномасштабное исследование с целью создания генетической шкалы риска ишемической болезни сердца (ИБС) и оценки ее информативности в отношении данной нозологии без учета традицион-ных факторов риска [1]. В исследование было вклю-чено пять однонуклеотидных полиморфизмов (ОНП) rs20455 гена KIF6, rs7439293 гена PALLD, rs2298566 гена SNX19, rs3900940 гена MYH15, rs1010 гена VAMP8.…”

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“…При статистической обработке полученных данных оказа-лось, что высокий генетический риск ассоциирован с ИБС (ОШ=1,64), после учета традиционных факто-ров риска (дислипидемии, артериальная гипертензия и другие), ассоциация сохранилась почти неизмен-ной (ОШ=1,57). В когорте ARIC лица с высоким генетическим риском ИБС составили 4% [1].…”

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Evaluation of the Genetic Riskometer Components Kif6, Palld, Snx19, Myh15, Vamp8 for Ischemic Heart Disease With Sudden Cardiac Death

Максимов¹,

Иванова²,

Орлов³

et al. 2015

Ross. kardiol. ž.

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Цель. Исследование ассоциации однонуклеотидных полиморфизмов rs20455 гена KIF6, rs7439293 гена PALLD, rs2298566 гена SNX19, rs3900940 гена MYH15, rs1010 гена VAMP8, включенных в рискометр ишемической болезни сердца в исследовании корпорации Celera (США), с внезапной сердечной смертью. Материал и методы. В исследование включена группа лиц, умерших внезап-ной сердечной смертью, сформированная по критериям ВОЗ (n=352, средний возраст -53,3±8,9), контрольная группа, подобранная по полу и возрасту из банка ДНК исследований HAPIEE, MONICA (n=381, средний возраст -53,1±8,3), группа подростков (n=296, средний возраст -15,6±0,9). ДНК выде-лена методом фенол-хлороформной экстракции из миокарда лиц, умерших внезапной сердечной смертью, и венозной крови лиц, включенных в контроль-ные группы. Генотипирование выполнено методом Real-time PCR с использо-ванием технологии TaqMan-зондов (Applied Biosystems). Результаты. По частотам генотипов и аллелей полиморфизмов rs7439293 гена PALLD, rs2298566 гена SNX19, rs3900940 гена MYH15 не было найдено статистически значимых различий между группами. В группе лиц старше 50 лет, умерших внезапной сердечной смертью, выявлено статистически значи-мое уменьшение доли носителей генотипа GG полиморфизма rs20455 гена KIF6 (9,0%) по сравнению с контрольной группой (17,8%) (р=0,009, ОШ=0,456, 95% ДИ 0,256-0,810). В группе мужчин старше 50 лет, умерших внезапной сердечной смертью, найдено значимое уменьшение доли носителей генотипа СС (8,0%) (р=0,002, ОШ=0,328, 95% ДИ 0,159-0,678) и увеличение доли носи-телей генотипа СТ (49,6%) (р=0,025, ОШ=1,729, 95% ДИ 1,084-2,758) поли-морфизма rs1010 гена VAMP8 по сравнению с контрольной группой (21,0%, 36,3%, соответственно). Заключение. Полиморфизмы rs20455 гена KIF6 и rs1010 гена VAMP8 ассоци-ированы с внезапной сердечной смертью. Aim. The study of mononucleotide polymorphisms associations rs20455 gene KIF6, rs7439293 gene PALLD, rs2298566 gene SNX19, rs3900940 gene MYH15, rs1010 gene VAMP8, included into the Riskometer of ischemic heart disease of the Celera Corporation (USA), in sudden cardiac death. Material and methods. To the study the group of persons included, died from sudden cardiac death, according to the WHO criteria (n=352, mean age -53,3±8,9 y.), control group from matched by age and gender from DNA bank of HAPIEE, MONICA studies (n=381, mean age -53,1±8,3 y.), adolescents group (n=296, mean age -15,6±0,9 y.). DNA extracted via the phenol-chloroform extraction from myocardium of the dyed due to sudden cardiac death, and from venous blood of controls. Genotyping performed with Real-time PCR method using the Taq-Mancatheters technology (Applied Biosystems). РоссийскийResults.

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“…22 The hazard ratios of coronary heart disease in humans with the CC and CT MYH15 alleles were 1.47 (P < 0.001) and 1.09 (P ¼ 0.18), respectively, relative to TT homozygous individuals. 23 The T allele was also associated with a decreased risk of myocardial infarction, 23 hypertrophic cardiomyopathy, 23 noncardioembolic stroke, 24 and ischemic stroke. 24 A link between other cardiac myosin heavy chain polymorphisms and hypertrophic cardiomyopathy has also been implicated in increased risk of sudden infant death syndrome in humans, 25 the prevalence of which increases in association with environmental hypoxia.…”

Section: Myh15mentioning

confidence: 99%

Myosin Heavy Chain 15 is Associated with Bovine Pulmonary Arterial Pressure

Neary

Lund

et al. 2014

Pulm. circ.

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Bovine pulmonary hypertension, brisket disease, causes significant morbidity and mortality at elevations above 2,000 m. Mean pulmonary arterial pressure (mPAP) is moderately heritable, with inheritance estimated to lie within a few major genes. Invasive mPAP measurement is currently the only tool available to identify cattle at risk of hypoxia-induced pulmonary hypertension. A genetic test could allow selection of cattle suitable for high altitude without the need for invasive testing. In this study we evaluated three candidate genes (myosin heavy chain 15 [MYH15], NADH dehydrogenase flavoprotein 2, and FK binding protein 1A) for association with mPAP in 166 yearling Angus bulls grazing at 2,182 m. The T allele (rs29016420) of MYH15 was linked to lower mPAP in a dominant manner (CC 47.2 AE 1.6 mmHg [mean AE standard error of the mean]; CT/TT 42.8 AE 0.7 mmHg; P ¼ 0.02). The proportions of cattle with MYH15 CC, CT, and TT genotypes were 55%, 41%, and 4%, respectively. Given the high frequency of the deleterious allele, it is likely that the relative contribution of MYH15 polymorphisms to pulmonary hypertension is small, supporting previous predictions that the disease is polygenic. We evaluated allelic frequency of MYH15 in the Himalayan yak (Bos grunniens), a closely related species adapted to high altitude, and found 100% prevalence of T allele homozygosity. In summary, we identified a polymorphism in MYH15 significantly associated with mPAP. This finding may aid selection of cattle suitable for high altitude and contribute to understanding human hypoxia-induced pulmonary hypertension.

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Five common gene variants identify elevated genetic risk for coronary heart disease

Cited by 90 publications

References 36 publications

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Evaluation of the Genetic Riskometer Components Kif6, Palld, Snx19, Myh15, Vamp8 for Ischemic Heart Disease With Sudden Cardiac Death

Myosin Heavy Chain 15 is Associated with Bovine Pulmonary Arterial Pressure

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