Causal relationship between blood metabolites and risk of five infections: a Mendelian randomization study.

OBJECTIVE: Infectious diseases continue to pose a significant threat in the field of global public health, and our understanding of their metabolic pathogenesis remains limited. However, the advent of genome-wide association studies (GWAS) offers an unprecedented opportunity to unravel the relationship between metabolites and infections. METHODS: Univariable and multivariable Mendelian randomization (MR) was commandeered to elucidate the causal relationship between blood metabolism and five high-frequency infection phenotypes: sepsis, pneumonia, upper respiratory tract infections (URTI), urinary tract infections (UTI), and skin and subcutaneous tissue infection (SSTI). GWAS data for infections were derived from UK Biobank and the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted method on the UK Biobank data, along with a series of sensitivity analyses. Subsequently, replication and meta-analysis were performed on the FinnGen consortium data. RESULTS: After primary analysis and a series of sensitivity analyses, 17 metabolites were identified from UK Biobank that have a causal relationship with five infections. Upon joint analysis with the FinGen cohort, 7 of these metabolites demonstrated consistent associations. Subsequently, we conducted a multivariable Mendelian randomization analysis to confirm the independent effects of these metabolites. Among known metabolites, genetically predicted 1-stearoylglycerol (1-SG) (odds ratio [OR] = 0.561, 95% confidence interval [CI]: 0.403-0.780, P < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (OR = 0.780, 95%CI: 0.689-0.883, P < 0.001) was causatively associated with a lower risk of sepsis, and genetically predicted phenylacetate (PA) (OR = 1.426, 95%CI: 1.152-1.765, P = 0.001) and cysteine (OR = 1.522, 95%CI: 1.170-1.980, P = 0.002) were associated with an increased risk of UTI. Ursodeoxycholate (UDCA) (OR = 0.906, 95%CI: 0.829-0.990, P = 0.029) is a protective factor against pneumonia. Two unknown metabolites, X-12407 (OR = 1.294, 95%CI: 1.131-1.481, P < 0.001), and X-12847 (OR = 1.344, 95%CI: 1.152-1.568, P < 0.001), were also identified as independent risk factors for sepsis. CONCLUSIONS: In this MR study, we demonstrated a causal relationship between blood metabolites and the risk of developing sepsis, pneumonia, and UTI. However, there was no evidence of a causal connection between blood metabolites and the risk of URTI or SSTI, indicating a need for larger-scale studies to further investigate susceptibility to certain infection phenotypes.

Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population.

Tuberculosis (TB) remains a global public health problem worldwide. The objective of the current study is to investigate the possible association of ACE I/D polymorphism with pulmonary TB (PTB) for Chinese in Sichuan province. Three hundred eighty-six PTB patients and 398 healthy controls were genotyped to analyze the I/D polymorphism using PCR method. The results showed that the I/D polymorphism was not associated with susceptibility to PTB for Chinese (D vs. I: OR 1.03, 95% CI 0.84-1.26, and P=0.77; DD vs. II+DI: OR 1.09, 95% CI 0.73-1.63, and P=0.68; DD+DI vs. II: OR 1.00, 95% CI 0.74-1.33, and P=0.98). The I/D polymorphism in the ACE gene may not a risk factor for PTB in Chinese.

The D/I polymorphism in the angiotensin-converting enzyme gene and chronic obstructive pulmonary disease risk: a meta-analysis.

BACKGROUND: The deletion/insertion (D/I) polymorphism in the angiotensin-converting enzyme (ACE) gene has been implicated in susceptibility of chronic obstruction pulmonary disease (COPD), but a number of studies have reported inconclusive results. The aim of this study is to investigate the relationship between the D/I polymorphism in the ACE gene and COPD risk by meta-analysis. METHOD: We searched Pubmed database, Embase database, CNKI database and Wanfang database, covering all studies until October 10, 2011. Statistical analysis was performed by using the software Revman4.2 and STATA 10.0. RESULTS: A total of 710 COPD cases and 862 controls in 10 case-control studies were included in this study. The results suggested that the DD homozygote carriers did not have an increased or decreased risk of COPD when compared with the heterozygote DI and II homozygote carriers. However, in the subgroup analysis by race, significant increased risks were found in Asian DD homozygote carriers (OR = 2.6 and 95% CI = 1.47-4.57 for DD vs. DI+II) but not in Caucasian DD homozygote carriers (OR = 0.91, 95%CI = 0.69-1.22, P = 0.54 for DD vs. DI+II). CONCLUSIONS: This meta-analysis suggested that the ACE gene is a COPD susceptible gene in Asian populations. Future studies are needed to validate our conclusions..

Polymorphisms in the CTLA-4 gene and rheumatoid arthritis susceptibility: a meta-analysis.

INTRODUCTION: The +49A/G polymorphism and CT60 polymorphism in the CTLA-4 gene have been extensively examined for the association with rheumatoid arthritis (RA); however, results of different studies have been inconclusive. The aim of this study is to comprehensively evaluate the genetic risks of +49A/G and CT60 polymorphisms in the CTLA-4 gene for RA. METHODS: A meta-analysis was carried out to analyze the association of +49A/G and CT60 polymorphisms with RA risk. RESULTS: A total of 30 case-control studies in 20 articles were included in this meta-analysis. The results indicated that the variant G allele carriers (GG + GA) of +49A/G polymorphism had an 18% increased risk of RA when compared with the homozygote AA (odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.04-1.34 for GG + AG vs. AA). In addition, the variant CT60 A allele carriers of CT60 polymorphism had a 14% decreased risk of RA when compared with the homozygote GG (OR = 0.86, 95%CI = 0.78-0.95 for AA + AG vs. GG). In the subgroup analysis by ethnicity, significant elevated RA risks were associated with +49G allele carriers in Asians, but not in Europeans. However, for CT60 polymorphism, significant decreased RA risks were associated with CT60 A allele carriers in Europeans, but not in Asians. CONCLUSIONS: This meta-analysis suggested that the +49A/G and CT60 polymorphisms in the CTLA-4 gene may be risk factors for RA.