Multivariate analysis of genome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA

Jia, Xiaocan; Yang, Yongli; Chen, YuanCheng; Xia, Zhenhua; Zhang, Weiping; Feng, Yu; Li, Yifan; Tan, Jiebing; Xu, Chao; Zhou, Qiang; Deng, Hong‐Wen; Shi, Xiaoguang

doi:10.1016/j.ijcard.2018.10.102

Cited by 21 publications

(12 citation statements)

References 42 publications

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“…Among adults, a small male predominance of HPI-related outcomes has been found in a meta-analysis based on 169 studies (OR 1.12, 95% CI: 1.09, 1.15) [ 407 ]. Shared genetic basis underlying OP and a variety of HPI-related chronic extra-gastroduodenal diseases (CAD, DM, dyslipidemia) has been reported [ 408 , 409 , 410 , 411 , 412 , 413 , 414 , 415 , 416 , 417 , 418 , 419 ]. The shared biology and bi-(multi-)directional links between OP and HPI-associated chronic diseases apply particularly to CVD, CKD, CLD, DM and neurodegenerative diseases; these disorders are interrelated and often accompanied by OP/OF [ 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 , 428 , 429 , 430 ], and the risk of OP/OF increases when two or more HPI-associated chronic diseases are present.…”

Section: Hpi-associated Chronic Extra-gastroduodenal Diseases Medmentioning

confidence: 99%

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

Fisher

Smith

2020

JCM

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Osteoporosis (OP) and osteoporotic fractures (OFs) are common multifactorial and heterogenic disorders of increasing incidence. Helicobacter pylori (H.p.) colonizes the stomach approximately in half of the world’s population, causes gastroduodenal diseases and is prevalent in numerous extra-digestive diseases known to be associated with OP/OF. The studies regarding relationship between H.p. infection (HPI) and OP/OFs are inconsistent. The current review summarizes the relevant literature on the potential role of HPI in OP, falls and OFs and highlights the reasons for controversies in the publications. In the first section, after a brief overview of HPI biological features, we analyze the studies evaluating the association of HPI and bone status. The second part includes data on the prevalence of OP/OFs in HPI-induced gastroduodenal diseases (peptic ulcer, chronic/atrophic gastritis and cancer) and the effects of acid-suppressive drugs. In the next section, we discuss the possible contribution of HPI-associated extra-digestive diseases and medications to OP/OF, focusing on conditions affecting both bone homeostasis and predisposing to falls. In the last section, we describe clinical implications of accumulated data on HPI as a co-factor of OP/OF and present a feasible five-step algorithm for OP/OF risk assessment and management in regard to HPI, emphasizing the importance of an integrative (but differentiated) holistic approach. Increased awareness about the consequences of HPI linked to OP/OF can aid early detection and management. Further research on the HPI–OP/OF relationship is needed to close current knowledge gaps and improve clinical management of both OP/OF and HPI-related disorders.

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Section: Hpi-associated Chronic Extra-gastroduodenal Diseases Medmentioning

confidence: 99%

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

Fisher

Smith

2020

JCM

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“…Cichonska et al (19) recently employed meta-analysis using canonical correlation analysis (metaCCA) to allow multivariate representation of both genotypic and phenotypic variables based on the published univariate GWAS summary statistics. This new approach has been applied to identify potential pleiotropic genes associated with lipid-related measures, psychiatric disorders, and chronic diseases (19)(20)(21)(22). In this study, the genetic pleiotropyinformed metaCCA method was used to identify shared variants and pleiotropic effects in seven autoimmune/autoinflammatory diseases: celiac disease (CEL), inflammatory bowel disease (IBD), which includes Crohn's disease (CRO) and ulcerative colitis (UC), multiple sclerosis (MS), primary biliary cirrhosis (PBC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D).…”

Section: Introductionmentioning

confidence: 99%

Identification of 67 Pleiotropic Genes Associated With Seven Autoimmune/Autoinflammatory Diseases Using Multivariate Statistical Analysis

et al. 2020

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Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery, this univariate approach has limitations in detecting complex genotype-phenotype correlations. Multivariate analysis is essential to identify shared genetic risk factors acting through common biological mechanisms of autoimmune/autoinflammatory diseases. In this study, GWAS summary statistics, including 41,274 single nucleotide polymorphisms (SNPs) located in 11,516 gene regions, were analyzed to identify shared variants of seven autoimmune/autoinflammatory diseases using the metaCCA method. Gene-based association analysis was used to refine the pleiotropic genes. In addition, GO term enrichment analysis and protein-protein interaction network analysis were applied to explore the potential biological functions of the identified genes. A total of 4,962 SNPs (P < 1.21 × 10 −6) and 1,044 pleotropic genes (P < 4.34 × 10 −6) were identified by metaCCA analysis. By screening the results of gene-based P-values, we identified the existence of 27 confirmed pleiotropic genes and highlighted 40 novel pleiotropic genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one autoimmune/autoinflammatory in the VEGAS2 analysis. Using the metaCCA method, we identified novel variants associated with complex diseases incorporating different GWAS datasets. Our analysis may provide insights for the development of common therapeutic approaches for autoimmune/autoinflammatory diseases based on the pleiotropic genes and common mechanisms identified.

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“…Numerous studies revealed that genetic mutations of functional genes, especially those located in the regulatory and coding regions, may affect the gene structure and expression level, finally contributing to the diabetic pathogenesis and susceptibility [13,14]. Haplotype blocks (multiple SNPs) are emerging to be more effective and precise in their application of disease diagnosis and therapy due to linkage disequilibrium of the SNPs in chromosomes compared to a single SNP [15].…”

Section: Introductionmentioning

confidence: 99%

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility

Zheng

Sheng

et al. 2020

Genes

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Genetic variability is an important causative factor for susceptibility and pathogenesis of type 2 diabetes (T2D). Histone deacetylase, sirtuin 2 (SIRT2), plays regulatory roles in glucose metabolism and insulin sensitivity. However, whether the SIRT2 variants or haplotypes contribute to T2D risk remain to be elucidated. In this study, we first detected three novel polymorphisms (P-MU1, P-MU2, and P-MU3) in the promoter of SIRT2 in the Chinese population. All pairwise sets of the three loci were strongly in linkage disequilibrium. Next, we constructed the haplotype block structure, and found H1-GGC and H2-CCA accounted for the most (total 91.8%) in T2D. The haplotype combination H1-H1-GGGGCC displayed a high risk for T2D (OR = 2.03, 95% CI = 1.12–3.72). By association analysis, we found the individuals carrying H1-H1-GGGGCC had significantly higher fasting plasma glucose and glycated hemoglobin. The haplotype H1-GGC presented a 6.74-fold higher promoter activity than H2-CCA, which was consistent with the correlation results. Furthermore, we clarified the mechanism whereby the C allele of both the P-MU1 and P-MU2 loci disrupted the signal transducer and activator of transcription 1 (STAT1) binding sites, leading to the attenuation of the SIRT2 transcription. Together, these data suggest that the linked haplotype GGC could be considered as a promising marker for T2D diagnosis and therapy assessment.

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Multivariate analysis of genome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA

Cited by 21 publications

References 42 publications

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

Identification of 67 Pleiotropic Genes Associated With Seven Autoimmune/Autoinflammatory Diseases Using Multivariate Statistical Analysis

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility

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