Bone morphogenetic protein 7 (BMP7) gene polymorphisms are associated with inverse relationships between vascular calcification and BMD: the Diabetes Heart Study.

Freedman, Barry I,Bowden, Donald W,Ziegler, Julie T,Langefeld, Carl D,Lehtinen, Allison B,Rudock, Megan E,Lenchik, Leon,Hruska, Keith A,Register, Thomas C,Carr, J Jeffrey Mary Ann Liebert, Inc 2009 Journal of bone and mineral research Vol.24 No.10

<P>Inverse relationships have been observed between BMD and vascular calcification (VC), suggesting an underlying metabolic pathway linking these processes. Bone morphogenetic proteins (BMPs) are potential candidate genes that may mediate this relationship. Four single nucleotide polymorphisms (SNPs) in the BMP2 gene, 2 SNPs in BMP4, and 16 SNPs in BMP7 were tested for association with measures of VC using CT (coronary and carotid arteries, abdominal aorta), and BMD was measured using DXA (lumbar spine, hip, and distal radius) and quantitative CT (QCT; thoracic and lumbar spine) in 920 European Americans from 374 Diabetes Heart Study families: 762 with type 2 diabetes. Variance components quantitative trait locus association analysis was computed using SOLAR software, and a bivariate principal component analysis (PCA) assessed for genetic relationships between BMD and VC. Association was observed between several measures of BMD and BMP7 rs17404303 (thoracic spine QCT p = 0.03; lumbar spine QCT p = 0.02; hip DXA p = 0.06, dominant models). In addition, 6 of 16 BMP7 SNPs showed significant and opposing effects on the bivariate PCA for VC and BMD (two-sided exact test, p = 0.0143). Polymorphisms in BMP7 are associated with inverse relationships between bone mineralization and VC in the coronary, carotid, and abdominal aorta in a diabetes-enriched cohort of European Americans.</P>

Decreased <i>SMG7</i> expression associates with lupus-risk variants and elevated antinuclear antibody production

Deng, Yun,Zhao, Jian,Sakurai, Daisuke,Sestak, Andrea L,Osadchiy, Vadim,Langefeld, Carl D,Kaufman, Kenneth M,Kelly, Jennifer A,James, Judith A,Petri, Michelle A,Bae, Sang-Cheol,Alarcó,n-Riquelme, H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.11

<B>Objectives</B><P>Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of <I>NMNAT2</I> at rs2022013, we fine-mapped its 150 kb flanking regions containing <I>NMNAT2</I> and <I>SMG7</I> in a 15 292 case-control multi-ancestry population and tested functions of identified variants.</P><B>Methods</B><P>We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA.</P><B>Results</B><P>We confirmed association at <I>NMNAT2</I> in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at <I>SMG7</I> tagged by rs2702178 in EA only (p=2.4×10<SUP>−8</SUP>, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with <I>SMG7</I> mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased <I>SMG7</I> mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10<SUP>−3</SUP> and 6.8×10<SUP>−8</SUP>, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed <I>SMG7</I> mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=−0.31, p=0.01), and <I>SMG7</I> knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10<SUP>−5</SUP> and 2.0×10<SUP>−4</SUP>, respectively).</P><B>Conclusion</B><P>We confirmed <I>NMNAT2</I> and identified independent <I>SMG7</I> association with SLE. The inverse relationship between levels of the risk allele-associated <I>SMG7</I> mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.</P>

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.

Kaufman, Kenneth M,Zhao, Jian,Kelly, Jennifer A,Hughes, Travis,Adler, Adam,Sanchez, Elena,Ojwang, Joshua O,Langefeld, Carl D,Ziegler, Julie T,Williams, Adrienne H,Comeau, Mary E,Marion, Miranda C,Glen British Medical Association 2013 Annals of the Rheumatic Diseases Vol.72 No.3

<P>The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.</P>

Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility

Zhao, Jian,Wu, Hui,Khosravi, Melanie,Cui, Huijuan,Qian, Xiaoxia,Kelly, Jennifer A.,Kaufman, Kenneth M.,Langefeld, Carl D.,Williams, Adrienne H.,Comeau, Mary E.,Ziegler, Julie T.,Marion, Miranda C.,Adl Public Library of Science 2011 PLoS genetics Vol.7 No.5

<▼1><P>Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the <I>CFH</I>-<I>CFHRs</I> region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic <I>CFH</I> SNP (rs6677604, in intron 11, <I>P</I><SUB>meta</SUB> = 6.6×10<SUP>−8</SUP>, OR = 1.18) and an intergenic SNP between <I>CFHR1</I> and <I>CFHR4</I> (rs16840639, <I>P</I><SUB>meta</SUB> = 2.9×10<SUP>−7</SUP>, OR = 1.17) rather than to previously identified disease-associated <I>CFH</I> exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of <I>CFH</I> to downstream of <I>CFHR1</I>. Within this block, the deletion of <I>CFHR3</I> and <I>CFHR1</I> (<I>CFHR3-1</I>Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of <I>CFHR3-1</I>Δ (<I>P</I><SUB>meta</SUB> = 3.2×10<SUP>−7</SUP>, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (<I>P</I><SUB>meta</SUB> = 3.5×10<SUP>−4</SUP>, OR = 1.14). These results suggested that the <I>CFHR3-1</I>Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of <I>CFH</I>, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing <I>CFH</I> and <I>CFHRs</I> with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of <I>CFHR3</I> and <I>CFHR1</I> genes but not previously identified disease-associated exonic variants of <I>CFH</I>. This study provides the first evidence for consistent association between <I>CFH/CFHRs</I> and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼2>

Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

Guthridge, Joel M.,Lu, R.,Sun, H.,Sun, C.,Wiley, Graham B.,Dominguez, N.,Macwana, Susan R.,Lessard, Christopher J.,Kim-Howard, X.,Cobb, Beth L.,Kaufman, Kenneth M.,Kelly, Jennifer A.,Langefeld, Carl D University of Chicago Press [etc.] 2014 American journal of human genetics Vol.94 No.4

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.