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Variants underlying sex bias in Systemic Lupus Erythematosus

Award Number: R21AI160138
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Variants underlying sex bias in Systemic Lupus Erythematosus - ABSTRACT Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that is heavily biased 9:1 towards females. Sex bias in SLE reflects both hormonal and sex chromosome differences between men and women. This proposal focuses on identifying and functionally establishing genetic variants on the X chromosome that contribute to SLE sex bias. Current efforts to understand the genetic architecture of lupus using genome-wide association studies (GWAS) have identified variants at 13 X-linked genes that are associated with SLE. However, causative variants at these loci remain unknown. These GWAS loci may contribute to female bias in SLE if they influence how genes respond to X chromosome inactivation (XCI), the early developmental process that epigenetically silences most X-linked genes in females in order to maintain dosage equivalence with males. Although XCI represses most genes on one X in females, some genes escape XCI and are expressed from both active and inactive Xs. XCI states for >20% of human X genes are variable, and escape XCI from a subset of Xs, but are silenced in other females. Our recent data indicate that heritability at genes that variably escape XCI is enriched in sex-biased disorders including SLE. We hypothesize that causal variants on the X chromosome underlie aberrant inactive X expression in SLE. The objective of this proposal is to identify these causal variants and directly evaluate their response to XCI. To address this hypothesis, we propose in Aim 1 to fine map causal variants on the X chromosome and identify causal genes. Integration of results with eQTL and functional genome annotation will further refine loci and link to causal genes. Association effects will be compared between males and females to further differentiate those likely influenced by X inactivation. In Aim 2 we will functionally evaluate variants mapping to Xq28 for altered gene response to XCI and B cell expression. We will perform multiplex reporter gene assays as an initial screen for functional variants with regulatory potential. We will also establish a novel system to functionally evaluate X chromosome variants by editing stem cells that will be differentiated to B cells and undergo XCI. We expect that results from experiments will be the first to provide a critical functional link between associated variants and X chromosome inactivation, and as such will have a profound impact on understanding mechanisms of SLE and lupus biology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$564 )
2025	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	2	4/16/2025	NON-COMPETING CONTINUATION	-$564
														Subtotal = -$564

Issue Date FY: 2023 ( Subtotal = $201,377 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	2	10/19/2022	NON-COMPETING CONTINUATION	$201,377
														Subtotal = $201,377

Issue Date FY: 2022 ( Subtotal = $240,604 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	1	10/26/2021	NEW	$240,604
														Subtotal = $240,604

Grand Total All Awards = $441,417

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Variants underlying sex bias in Systemic Lupus Erythematosus

Award Number: R21AI160138

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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