Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels.
Lipoprotein Lp(a) levels are highly heritable and are associated with cardiovascular risk. We performed a genome-wide linkage analysis to delineate the genomic regions that influence the concentration of Lp(a) in families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Lp(a) levels were measured in 387 individuals belonging to 21 extended Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1 cM genetic map. The variance component linkage method was used to evaluate linkage and to detect quantitative trait loci (QTLs). The main QTL that showed strong evidence of linkage with Lp(a) levels was located at the structural gene for apo(a) on chromosome 6 (LOD score=13.8). Interestingly, another QTL influencing Lp(a) concentration was located on chromosome 2 with an LOD score of 2.01. This region contains several candidate genes. One of them is the tissue factor pathway inhibitor (TFPI), which has antithrombotic action and also has the ability to bind lipoproteins. However, quantitative trait association analyses performed with 12 SNPs in TFPI gene revealed no association with Lp(a) levels. Our study confirms previous results on the genetic basis of Lp(a) levels. In addition, we report a new QTL on chromosome 2 involved in the quantitative variation of Lp(a). These data should serve as the basis for further detection of candidate genes and to elucidate the relationship between the concentration of Lp(a) and cardiovascular risk.
López
Sonia
S
Department of Hematology, Haemostasis and Thrombosis Unit, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Maria Claret 167, Barcelona, Spain.
Buil
Alfonso
A
Ordoñez
Jordi
J
Souto
Juan Carlos
JC
Almasy
Laura
L
Lathrop
Mark
M
Blangero
John
J
Blanco-Vaca
Francisco
F
Fontcuberta
Jordi
J
Soria
José Manuel
JM
D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D013030:Spain; D019851:Thrombophilia / Q000097:blood / Q000235:genetics*; D055815:Young Adult
D017270:Lipoprotein(a); D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor