Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese

Abstract

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, 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, 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.

Advances in the Immunology and Genetics of Leprosy

“…This finding suggested a role for synapsin-2 in the progression of infection from mycobacteria to the nerves (117). Unexpectedly, two oxidative stress-related genes, SOD2 and HIF1A, were also found to be associated with leprosy, which may be explained by the possibility that oxidative stress is a means of defense used by M. leprae-infected cells (158,159). Early in 2004, a genome-wide linkage scan study reported the association between the 5 ′ regulatory region of PARK2/PACRG and Vietnamese leprosy, which was confirmed in Brazilian leprosy patients (160).…”

Genetic association of the cytochrome c oxidase-related genes with Alzheimer’s disease in Han Chinese

“…In addition, we took advantage of the exome sequencing data of 107 genetically unrelated AD patients (authors' unpublished data) that were selected using an extreme phenotype sampling strategy [51], to identify potential disease-causal/rare/functional variants in the exonic regions of the COX-related genes by comparing to 368 control subjects (including 160 in-house nondementia controls [52], Han Chinese in Beijing (CHB, N = 103) and Southern Han Chinese (CHS, N = 105) from the 1000 Genomes Project phase 3 [53,54]). These genetically unrelated AD patients (46.7% females, age 64.6 ± 10.29 years, 37.4% were APOE ε4 carriers) either had an early onset age <= 55 years old and/ or a positive family history (presence of disease in one or more first-degree family members).…”

“…For sequencing the exon and flanking regions of the COX-related genes, we used the next generation sequencing technologies as described in our previous studies [47,52,60]. In brief, the paired-end reads were generated on the HiSeq 4000 sequencer (Illumina).…”

“…Exons sequencing of the COX-related genes identified variants associated with AD risk In order to further explore whether there are potential mutations or undetected rare variants in the COX-related genes to be associated with AD, the coding and flanking regions of the COXrelated genes were sequenced in 107 AD cases with extreme phenotypes (onset age <= 55 years old and/or with family history of AD), and were compared with a combined control population containing 368 individuals [52][53][54]. The genotyping data from 4327 East Asians from the ExAC (http://exac.broadinstitute.org) [65] was used as another control.…”

Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches

“…Finally, LRRK2 is a negative regulator of inflammasome activation ( 56 , 57 ) and an inducer of ROS production ( 54 , 57 ), two known mechanisms of immune defense against bacterial infections also modified by variants of LACC1 , a gene consistently associated with leprosy ( 20 , 25 , 34 , 35 ). Recently, the LACC1 contribution to leprosy risk has been reinforced: a GWAS-based analysis focusing on functional variants detected association between leprosy and a LACC1 missense variant (rs3764147, c.760A > G, p.Ile254Val) ( 22 ).…”