@article {48488,
	title = {Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.},
	journal = {Human Molecular Genetics},
	volume = {26},
	year = {2017},
	month = {2017 Mar 15},
	pages = {1205-1216},
	abstract = {<p>We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 {\texttimes} 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 {\texttimes} 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 {\texttimes} 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 {\texttimes} 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 {\texttimes} 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56\%) of the correlated (r2 \&gt; 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 {\texttimes} 10-198 \&lt; P \&lt; 5 {\texttimes} 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P \&lt; 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.</p>
},
	keywords = {Adaptor Proteins, Signal Transducing, Asian Continental Ancestry Group, Autophagy-Related Proteins, Chemokine CCL22, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Lupus Erythematosus, Systemic, Polymorphism, Single Nucleotide, Ribonuclease H},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddx026},
	author = {Molineros, Julio E and Yang, Wanling and Zhou, Xu-Jie and Sun, Celi and Okada, Yukinori and Zhang, Huoru and Heng Chua, Kek and Lau, Yu-Lung and Kochi, Yuta and Suzuki, Akari and Yamamoto, Kazuhiko and Ma, Jianyang and Bang, So-Young and Lee, Hye-Soon and Kim, Kwangwoo and Bae, Sang-Cheol and Zhang, Hong and Shen, Nan and Looger, Loren L and Nath, Swapan K}
}
@article {45181,
	title = {Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM.},
	journal = {Human Molecular Genetics},
	volume = {23},
	year = {2014},
	month = {2014 Aug 1},
	pages = {4161-76},
	abstract = {<p>Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 {\texttimes} 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ({\textquoteright}A{\textquoteright}) relative to the non-risk allele ({\textquoteright}G{\textquoteright}), in a dose-dependent fashion: ({\textquoteright}AA{\textquoteright} \&lt; {\textquoteright}AG{\textquoteright} \&lt; {\textquoteright}GG{\textquoteright}). CD11b protein levels in patients{\textquoteright} monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the {\textquoteright}A{\textquoteright} transcript than {\textquoteright}G{\textquoteright} transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.</p>
},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddu106},
	author = {Maiti, Amit K and Kim-Howard, Xana and Motghare, Prasenjeet and Pradhan, Vandana and Chua, Kek Heng and Sun, Celi and Arango-Guerrero, Mar{\'\i}a Teresa and Ghosh, Kanjaksha and Niewold, Timothy B and Harley, John B and Anaya, Juan-Manual and Looger, Loren L and Nath, Swapan K}
}
