Genetic Studies of Cardiovascular Diseases

Abstract

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the underdeveloped countries like Pakistan, leading to socioeconomic destabilization of the community. Among the different factors that play a role in the onset and progression of disease, raised plasma cholesterol levels is considered to be a major factor in the development of atherosclerosis, a typical character for the development of CVDs. Candidate gene screening of hypercholesterolemia families and sporadic individuals revealed two mutations in LDL-C binding domain (La) of LDLR (c.264G>C, p.R88S and c.887_889GCA>AGC, p.296*), four missense mutations in EGF like domain (c. 1019_1020delinsTG, p.C340L; c.1211C>T, p.T404I; c.1214 A>C, p.N405T; c.1634G>A, p.G545E and c.1916T>G, p.V639) and one premature terminating mutation (c.2416_2417 Ins G, p.V806GfsX11) in the transmembrane domain of LDLR. The La domain mutation has been shown to lead to inefficient binding of LDL-C with the receptor, while mutations in EGF like domain were found to cause decreased recycling of LDLR to the hepatocytes surface, which resulted in raised cholesterol levels in the patients. Two variants in PCSK9 i.e., c.314G>A, p.R105Q and c.464C>T, p.P155L, were also found in two different families with a history of CABG. The variant c.314G>A, p.R105Q resulted in 19% decrease in LDL-C levels in heterozygote carriers compared to homozygote normal individuals predicting it to be a “loss of function mutation”, while the second variant c.464C>T, p.P155L was located in the autocatalytic site of PCSK9 which may impact on LDL-C, but its exact effect could not be determined due to the small family size. In case control studies on MI cases in Pakistani population, the screening of selected panel of single nucleotide polymorphisms (SNPs) within five different genes was conducted. It was found that rs1333049 (ANRIL) was significantly associated with the onset of disease (p<0.001), while rs10920501 (FAM5C), rs1042579 (THBD), rs4646994 (ACE) and Intron 4 VNTR (eNOS) were not associated with the onset of MI (p>0.05). The stratification of data based on coronary artery disease (CAD) family history revealed significant association of the risk allele in ACE and eNOS polymorphisms with OR 1.83(95% CI=1.06-3.14) and 1.82(95% CI=1.03-3.22), respectively. This also indicates that the clustering of genetic factors within the ixfamilies are responsible for the onset of MI in Pakistani families. The relationship of rs1333049 risk allele “C” with phenotype impact on the lipid profile also showed a marked decrease in total cholesterol in individual homozygous for risk allele, which was observed in an independent cohort of hypercholesterolemia patients from the affected families as compared to their normolipidemic individuals. From this study, it is revealed that the Pakistani population has genetic heterogeneity, which predisposes the individuals to an increased risk of MI.