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GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION

Award Number: R01HL047619
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/1992
PERIOD OF PERFORMANCE END DATE: 11/30/2005

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GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION - DESCRIPTION: Plasma levels of lipoprotein(a) [Lp(a)] are 2-3 times higher in individuals of African descent than in Caucasians. Differences in the plasma levels of Lp(a) among African-Americans are due predominantly to sequence variations linked to the apo(a) gene, but the mechanism responsible for Blacks having elevated plasma levels of Lp(a) relative to other populations is not known. The goal of this proposal is to elucidate the genetic and metabolic mechanisms responsible for the markedly higher plasma levels of Lp(a) in African-Americans and Black Africans (collectively referred to as Blacks) compared to Caucasians. First, the levels of plasma apo(a) isoforms will be compared in parents and offspring of a unique cohort of inter-ethnic families to determine if the differences in plasma levels of Lp(a) are due to sequence variants in the apo(a) gene or to the effect of other genes. Next, the metabolism of Lp(a) in Blacks and Caucasians will be compared to determine if the higher plasma levels of Lp(a) in Blacks are due to an increase in the rate of Lp(a) synthesis or to a decrease in its rate of catabolism. Based on the results of these studies, we will examine at a molecular level either the synthetic or catabolic pathway(s) of Lp(a). We propose that the higher plasma levels of Lp(a) in Blacks are due to differences in the molecular machinery responsible for the synthesis and transport of apo(a) out of liver cells. This hypothesis will be tested by examining the secretion of recombinant apo(a) isoforms of various sizes from cultured fibroblasts of Blacks and Caucasians. Alternatively, the levels of Lp(a) may be higher in Blacks due to a difference in the manner in which Lp(a) is removed from the circulation. Since little is known about catabolic pathways of Lp(a), we first will examine the role of two putative Lp(a) receptors - the VLDL receptor and the LDL receptor related protein using genetically altered mice that express human Lp(a). If either receptor is shown to participate in Lp(a) clearance from plasma, its sequences in humans will be screened and the relationship between any newly identified sequence variants and plasma levels of Lp(a) will be examined in families and populations. These studies will provide a better understanding of the genetic and metabolic mechanisms responsible for the higher plasma levels of Lp(a) in Blacks, and may provide new insights into the paradoxical finding that Blacks do not have a greater incidence of coronary atherosclerosis despite having much higher plasma levels of Lp(a).


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: 2004 ( Subtotal = $351,000 )
2004	2004	UNIV OF TX ALLERGY & INFECTIOUS DISEASES TRNG GRANT CMT	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	12	11/20/2003	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2003 ( Subtotal = $351,000 )
2003	2003	UNIV OF TX ALLERGY & INFECTIOUS DISEASES TRNG GRANT CMT	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	11		NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2002 ( Subtotal = $351,000 )
2002	2002	UNIV OF TX ALLERGY & INFECTIOUS DISEASES TRNG GRANT CMT	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	10	11/17/2001	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2001 ( Subtotal = $351,000 )
2001	2001	UNIV OF TX ALLERGY & INFECTIOUS DISEASES TRNG GRANT CMT	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	9	12/18/2000	COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 1999 ( Subtotal = $334,729 )
1999	1999	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	8	5/7/1999	NON-COMPETING CONTINUATION	$334,729
														Subtotal = $334,729

Issue Date FY: 1998 ( Subtotal = $322,062 )
1998	1998	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Cardiovascular Diseases Research	000	7	5/30/1998	NON-COMPETING CONTINUATION	$322,062
														Subtotal = $322,062

Grand Total All Awards = $2,060,791

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GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION

Award Number: R01HL047619

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/1992

PERIOD OF PERFORMANCE END DATE: 11/30/2005

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