@article{8c4a978daac842688c60722b9be2949b,
title = "Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans",
abstract = "Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A—C—B—DRB1—DQA—DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA– B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA–C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.",
author = "Hanscombe, {Ken B.} and Morris, {David L.} and Noble, {Janelle A.} and Dilthey, {Alexander T.} and Philip Tombleson and Kaufman, {Kenneth M.} and Mary Comeau and Langefeld, {Carl D.} and Alarcon-Riquelme, {Marta E.} and Gaffney, {Patrick M.} and Jacob, {Chaim O.} and Sivils, {Kathy L.} and Tsao, {Betty P.} and Alarcon, {Graciela S.} and Brown, {Elizabeth E.} and Jennifer Croker and Jeff Edberg and Gary Gilkeson and James, {Judith A.} and Kamen, {Diane L.} and Kelly, {Jennifer A.} and Joseph McCune and Merrill, {Joan T.} and Michelle Petri and Rosalind Ramsey-Goldman and Reveille, {John D.} and Salmon, {Jane E.} and Hal Scofield and Tammy Utset and Wallace, {Daniel J.} and Weisman, {Michael H.} and Kimberly, {Robert P.} and Harley, {John B.} and Lewis, {Cathryn M.} and Criswell, {Lindsey A.} and Vyse, {Timothy J.}",
note = "Funding Information: We would like to thank the original study participants and their families for their contributions to this research, along with clinical colleagues who facilitated data collection. NIH (R01 AI024717, U01 HG008666, P30 AR070549, P01 AI08394 and R01 AR042460 to J.B.H., P01 AR49084 and R01 AR064820 to R.P.K. and E.E.B., P01 AR049084, K24 AR 00218, P60AR 064464 (formerly P60 AR30692), UL1TR001422 (formerly ULRR025741) to R.R.-G., R01 AR056360, AR063124, P30 GM110766 and U19 AI082714 to P.M.G., U19AI082714, U01AI101934, P30GM103510, U54GM104938, P30AR053483 to J.A.J.); the US Department of Veterans Affairs (I01 BX001834 to J.B.H.); US Department of Defense (PR094002 to J.B.H). National Institute for Health Research Biomedical Research Centre (NIHR BRC) at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation and King{\textquoteright}s College London and by the NIHR BRC at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. Funding Information: NIH (R01 AI024717, U01 HG008666, P30 AR070549, P01 AI08394 and R01 AR042460 to J.B.H., P01 AR49084 and R01 AR064820 to R.P.K. and E.E.B., P01 AR049084, K24 AR 00218, P60AR 064464 (formerly P60 AR30692), UL1TR001422 (formerly ULRR025741) to R.R.-G., R01 AR056360, AR063124, P30 GM110766 and U19 AI082714 to P.M.G., U19AI082714, U01AI101934, P30GM103510, U54GM104938, P30AR053483 to J.A.J.); the US Department of Veterans Affairs (I01 BX001834 to J.B.H.); US Department of Defense (PR094002 to J.B.H). National Institute for Health Research Biomedical Research Centre (NIHR BRC) at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation and King{\textquoteright}s College London and by the NIHR BRC at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press.",
year = "2018",
month = nov,
day = "1",
doi = "10.1093/hmg/ddy280",
language = "English (US)",
volume = "27",
pages = "3813--3824",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",
}