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Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study.

ABSTRACT: Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have largely been performed in lupus patients who are Asian or of European ancestry. This study was undertaken to examine whether some of these same susceptibility loci increase lupus risk in African American individuals.Single-nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1,724 lupus patients and 2,024 healthy controls of African American descent. The loci examined included PTPN22, FCGR2A, TNFSF4, STAT4, CTLA4, PDCD1, PXK, BANK1, MSH5 (HLA region), CFB (HLA region), C8orf13-BLK region, MBL2, KIAA1542, ITGAM, and MECP2/IRAK1.We found the first evidence of genetic association between lupus in African American patients and 5 susceptibility loci (C8orf13-BLK, BANK1, TNFSF4, KIAA1542, and CTLA4; P = 8.0 × 10??, P = 1.9 × 10??, P = 5.7 × 10??, P = 0.00099, and P = 0.0045, respectively). Further, we confirmed the genetic association between lupus and 5 additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P = 7.5 × 10?¹¹, P = 5.2 × 10??, P = 8.7 × 10?? , P = 0.0058, and P = 0.0070, respectively), and provided evidence, for the first time, of genome-wide significance for the association between lupus in African American patients and ITGAM and MSH5 (HLA region).These findings provide evidence of novel genetic susceptibility loci for lupus in African Americans and demonstrate that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicities.

SUBMITTER: Sanchez E

PROVIDER: S-EPMC3205224 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study.

Sánchez Elena E Comeau Mary E ME Freedman Barry I BI Kelly Jennifer A JA Kaufman Kenneth M KM Langefeld Carl D CD Brown Elizabeth E EE Alarcón Graciela S GS Kimberly Robert P RP Edberg Jeffrey C JC Ramsey-Goldman Rosalind R Petri Michelle M Reveille John D JD Vilá Luis M LM Merrill Joan T JT Tsao Betty P BP Kamen Diane L DL Gilkeson Gary S GS James Judith A JA Vyse Timothy J TJ Gaffney Patrick M PM Jacob Chaim O CO Niewold Timothy B TB Richardson Bruce C BC Harley John B JB Alarcón-Riquelme Marta E ME Sawalha Amr H AH

Arthritis and rheumatism 20111101 11

<h4>Objective</h4>Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have largely been performed in lupus patients who are Asian or of European ancestry. This study was undertaken to examine whether some of these same susceptibility loci increase lupus risk in African American individuals.<h4>Methods</h4>Single-nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1 ...[more]

PMID: 21792837

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Project description:BackgroundWe report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations.MethodsOur sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerström Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset.ResultsIn EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10(-10)). Two chromosome 8 regions were associated: p = 4.45 × 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10(-9) at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 × 10(-7)) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs.ConclusionsThe key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.

Dataset Information

Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study.

Publications

Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study.

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