Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese
| Autor: | Dong Wang, Deng-Feng Zhang, Yu-Ye Li, Yong Wu, Xiu-Feng Yu, Rui Bi, Yu Fan, Yong-Gang Yao, Heng Long, Mahadev Malhi, Min Xu |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Population Mutation Missense Genome-wide association study Biology Polymorphism Single Nucleotide Article Cohort Studies Young Adult 03 medical and health sciences Asian People Risk Factors Genetic linkage Leprosy Exome Sequencing Ethnicity Genetics medicine Humans Missense mutation Genetic Predisposition to Disease RNA Messenger Child education Alleles Genetics (clinical) Exome sequencing Aged Genetic association Aged 80 and over education.field_of_study Intracellular Signaling Peptides and Proteins High-Throughput Nucleotide Sequencing Nuclear Proteins Proteins Reproducibility of Results Odds ratio Middle Aged Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Up-Regulation 030104 developmental biology Trans-Activators Female |
| Zdroj: | The American Journal of Human Genetics. 102:794-805 |
| ISSN: | 0002-9297 1421-7945 |
| DOI: | 10.1016/j.ajhg.2018.03.006 |
| Popis: | Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10−9, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10−18, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis. |
| Databáze: | OpenAIRE |
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