Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy.
One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10(-5)) for association among Vietnamese patients. Next, we enrolled a case-control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10(-8)). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.
McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Andrea
A
Alter
Vinicius Medeiros
VM
Fava
Nguyen Thu
NT
Huong
Meenakshi
M
Singh
Marianna
M
Orlova
Nguyen
N
Van Thuc
Kiran
K
Katoch
Vu Hong
VH
Thai
Nguyen Ngoc
NN
Ba
Laurent
L
Abel
Narinder
N
Mehra
Alexandre
A
Alcaïs
Erwin
E
Schurr
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007194:India; D007438:Introns; D007918:Leprosy / Q000175:diagnosis / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014744:Vietnam; D044465:White People / Q000235:genetics; D055815:Young Adult
D008840:Microfilament Proteins; D018832:Molecular Chaperones; C471711:PACRG protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein