Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

Mahmoud Khalifa; Asma Noureen; Kathrin Ertelthalner; Ahmad Reza Bandegi; Rhena Delport; Wance J J Firdaus; Finney S Geethanjali; Kalpana Luthra; Orawan Makemaharn; Richard W C Pang; Abdel-Halim Salem; Jun Sasaki; Wulf Schiefenhoevel; Arno Lingenhel; Florian Kronenberg; Gerd Utermann; Konrad Schmidt

doi:10.1016/j.atherosclerosis.2015.07.015

Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

Atherosclerosis. 2015 Oct;242(2):521-8. doi: 10.1016/j.atherosclerosis.2015.07.015. Epub 2015 Jul 15.

Authors

Mahmoud Khalifa¹, Asma Noureen¹, Kathrin Ertelthalner², Ahmad Reza Bandegi³, Rhena Delport⁴, Wance J J Firdaus³, Finney S Geethanjali⁵, Kalpana Luthra⁶, Orawan Makemaharn⁷, Richard W C Pang⁸, Abdel-Halim Salem³, Jun Sasaki⁹, Wulf Schiefenhoevel¹⁰, Arno Lingenhel¹, Florian Kronenberg², Gerd Utermann³, Konrad Schmidt¹¹

Affiliations

¹ Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
² Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
³ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
⁴ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
⁵ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Department of Clinical Biochemistry, Christian Medical College Vellore, Tamil Nadu, India.
⁶ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
⁷ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Department of Obstetrics and Gynaecology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁸ Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
⁹ Graduate School of Pharmaceutical Medicine, International University of Health and Welfare, Fukuoka, Japan.
¹⁰ Max-Planck-Institute for Ornithology, Andechs, Germany.
¹¹ Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital, Lambaréné, Gabon; Department for Tropical Medicine, Eberhard-Karls-University Tuebingen, Tuebingen, Germany. Electronic address: konrad.schmidt@i-med.ac.at.

PMID: 26302166
DOI: 10.1016/j.atherosclerosis.2015.07.015

Abstract

Objective: The variant allele of rs3798220 in the apolipoprotein(a) gene (LPA) is used to assess the risk for coronary artery disease (CAD) in Europeans, where it is associated with short alleles of the Kringle IV-2 (KIV-2) copy number variation (CNV) and high lipoprotein(a) (Lp(a)) concentrations. No association of rs3798220 with CAD was detected in a GWAS of East Asians. Our study investigated the association of rs3798220 with Lp(a) concentrations and KIV-2 CNV size in non-European populations to explain the missing association of the variant with CAD in Asians.

Methods: We screened three populations from Africa and seven from Asia by TaqMan Assay for rs3798220 and determined KIV-2 CNV sizes of LPA alleles by pulsed-field gel electrophoresis (PFGE). Additionally, CAD cases from India were analysed. To investigate the phylogenetic origin of rs3798220, 40 LPA alleles from Chinese individuals were separated by PFGE and haplotyped for further SNPs.

Results: The variant was not found in Africans. Allele frequencies in East and Southeast Asians ranged from 2.9% to 11.6%, and were very low (0.15%) in CAD cases and controls from India. The variant was neither associated with short KIV-2 CNV alleles nor elevated Lp(a) concentrations in Asians.

Conclusion: Our study shows that rs3798220 is no marker for short KIV-2 CNV alleles and high Lp(a) in East and Southeast Asians, although the haplotype background is shared with Europeans. It appears unlikely that this SNP confers atherogenic potential on its own. Furthermore, this SNP does not explain Lp(a) attributed risk for CAD in Asian Indians.

Keywords: Copy number variation; Coronary artery disease; Genetic variation; Lipoprotein(a); Population genetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Africa
Alleles
Apolipoproteins A / genetics*
Asia
Asian People
China
Coronary Artery Disease / ethnology
Coronary Artery Disease / genetics
DNA Copy Number Variations*
Electrophoresis, Gel, Pulsed-Field
Gene Frequency
Genetic Markers
Genetic Variation
Genome-Wide Association Study
Genotype
Haplotypes
Humans
India
Phylogeny
Polymorphism, Single Nucleotide*
Protein Isoforms / genetics

Substances

Apolipoproteins A
Genetic Markers
Protein Isoforms