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(PON1 and PON2) Are Associated with the Risk of Coronary Heart Disease Dharambir K

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(PON1 and PON2) Are Associated with the Risk of Coronary Heart Disease Dharambir K View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 62:36–44, 1998 DNA Polymorphisms in Two Paraoxonase Genes (PON1 and PON2) Are Associated with the Risk of Coronary Heart Disease Dharambir K. Sanghera, Christopher E. Aston, Nilmani Saha, and M. Ilyas Kamboh Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh Summary Introduction A common polymorphism at codon 192 in the human Oxidized LDL is believed to play an important role in paraoxonase (PON) 1 gene has been shown to be as- initiation of atherosclerosis. Numerous studies suggest sociated with increased risk for coronary heart disease the formation of fatty-acid streaks in response to a series (CHD) in Caucasian populations. However, these find- of events, followed by the migration of oxidized LDL- ings have not been reported consistently in all Caucasian loaded monocytes into the subendothelial space of the and non-Caucasian populations, suggesting that this is arteries (Navab et al. 1996). HDL has been shown to not a functional mutation but may mark a functional prevent oxidative modification of LDL in vivo (Klimov mutation present in either PON1 or a nearby gene. Re- et al. 1993) as well as in vitro (Mackness et al. 1993). cently, two other PON-like genes, designated “PON2” Recent studies indicate that two HDL-associated en- and “PON3,” have been identified, and they are linked zymes, PON and platelet-activating–factor acetyl hydro- with the known PON1 gene on chromosome 7. Iden- lase, are responsible for its antioxidative and anti-in- tification of additional polymorphisms in the PON-gene flammatory properties (Stafforini et al. 1993; Watson et cluster may help to locate the functional polymorphism. al. 1995). In vitro studies indicate that PON can signif- In this report, we describe the existence of a common icantly reduce lipid peroxide generation during LDL ox- polymorphism at codon 311 (CysrSer; PON2*S)inthe idation and thus may provide HDL-associated protec- PON2 gene, as well as its association with CHD alone tion against atherosclerosis. Furthermore, serum PON and in combination with the PON1 codon 192 poly- activity has been found to be lower in patients with morphism in Asian Indians. The frequency of the myocardial infarction (MI) (McElveen et al. 1986), di- PON2*S allele was significantly higher in cases than in abetes and familial hypercholesterolemia (Mackness et ϭ controls (.71 vs. .61;P .016 ). The age- and sex-ad- al. 1991), fish-eye disease (Mackness et al. 1987), and justed odds ratio (OR) was 2.5 (95% confidence interval Tangier disease (Mackness et al. 1989). PON tightly ϭ ϭ [95% CI] 1.8–3.1;P .0090 ) for the PON2*S allele binds to HDL subfractions that also contain apolipo- carriers. Further stratification of the PON2*S associa- protein (apo) A-I and apo J (Blatter Garin et al. 1993; tion, on the basis of the presence or absence of the Kelso et al. 1994). PON has largely been studied for its PON1*B allele, showed that the CHD risk associated role in hydrolyzing a large number of organophosphate with the PON2*S allele was confined to PON1*B-allele compounds used in pesticides, insecticides, and nerve carriers. Likewise, the PON1*B-allele risk was present gases (La Du 1992; Davies et al. 1996). Serum PON only among PON2*S carriers. Age- and sex-adjusted levels and activity vary widely among populations of ORs for the PON2*S and PON1*B were 3.6 different ethnic backgrounds (Diepgen et al. 1986; Roy (95% CI ϭ 2.6–4.6 ;P ϭ .011 ) and 2.9 ( 95% CI ϭ et al. 1991). Human serum PON (now called “PON1”) 2.4–3.5;P ϭ .0002 ) among the PON1*B and PON2*S is genetically polymorphic, because of the occurrence of carriers, respectively. Our data indicate that both poly- two common isoforms that differ by substitution of an morphisms synergistically contribute to the CHD risk in amino acid (GlnrArg) at codon 192 (Adkins et al. 1993; this sample and that this genetic risk is independent of Humbert et al. 1993). Individuals homozygous for Gln the conventional plasma lipid profile. (the A allele) have lower PON activity than is seen in individuals homozygous for Arg (the B allele), the latter Received February 28, 1997; accepted for publication October 3, having eight times more activity than has Gln in hydro- 1997; electronically published January 9, 1998. lyzing paraoxon (Davies et al. 1996; La Du 1996). PON Address for correspondence and reprints: Dr. M. I. Kamboh, De- activity is substrate dependent and may be quite opposite partment of Human Genetics, 130 DeSoto Street, University of Pitts- for different substrates (Furlong et al. 1988; La Du et burgh, Pittsburgh, PA 15261. E-mail: [email protected] ᭧ 1998 by The American Society of Human Genetics. All rights reserved. al. 1988; Davies et al. 1996). Notably, compared with 0002-9297/98/6201-0009$02.00 the PON1 A variant, the PON1 B variant is more effi- 36 Sanghera et al.: PON Polymorphisms and the Risk of Heart Disease 37 Table 1 migrants who migrated from the Indian subcontinent to Demographic, Clinical, and Lipid Profile of Asian Indian Controls Singapore during the early 19th century. There is a very and Cases low degree of interracial marriage in Singapore. On the basis of self-reports, no subjects with mixed ancestry VALUES INa were encountered. Controls Cases P Males/Females 144/45 115/14 ) CHD Cases 001. 8. ע 55.20 8. ע Age (Years) 49.6 The study samples comprised 129 unrelated CHD 79. 3. ע 24.85 3. ע BMI (kg/m2) 24.9 Smokers (0/1/2)b 166/0/23 71/26/29c ) cases (115 males and 14 females) with an age range of [ SE ע standard error [ mean ע Nondiabetic/ 169/20 89/40 ) 32–83 years (mean -years). The cases were consecutive CHD pa 0.8 ע diabetic 55.2 d ) Non-MI/MI 189/0 46/69 tients admitted to the Cardiothoracic Surgery Unit at the 0001. 8. ע 27.3 1.0 ע HDL cholesterol 41.3 (mg/dl) Singapore General Hospital, for coronary-artery-bypass graft, between August 1989 and December 1992. Blood 11. 3.9 ע 155.5 4.3 ע LDL cholesterol 165.5 (mg/dl) samples from cases were collected either during preop- erative review or, for those with a history of MI, x3 001. 4.1 ע 216.3 5.3 ע Total cholesterol 241.4 (mg/dl) mo after full recovery. Cases with a positive stress test 84. 6.3 ע 150.7 6.0 ע Triglycerides (mg/ 149.0 dl)e (Bruce method) were evaluated for the presence of CHD by means of coronary angiography. Inclusion criteria 0001. 5.0 ע 98.3 2.0 ע Apo A-I (mg/dl) 141.9 were 150% narrowing of the lumina of at least one of 000. 2.6 ע 105.4 2.7 ע Apo B (mg/dl) 136.0 SE values are for continuous variables. the major coronary arteries. A detailed family history of ע a NOTE.—Mean b The three numerals indicate, respectively, the number of individuals CHD, hypertension, diabetes mellitus, angina, and who have never been smokers, who once were smokers, and who smoking history was obtained from each case by a cer- currently are smokers. c tified physician and cardiologist. MI had occurred in Smoking history was not known for 3 individuals. ∼ d MI information was not available for 15 individuals. 60% of the cases, as judged both by typical electro- e Values are log transformed. cardiogram (ECG) changes (Minnesota code 1.1 or 1.2 in the ECG) and by changes in serum enzymes (aspartate cient in hydrolyzing paraoxon but is less efficient in hy- aminotransferase, lactate dehydrogenase, and creatine drolyzing three additional organophosphates: diazoxon, kinase); and nearly 31% of the cases were diabetic. Cases sarin, and soman (Davies et al. 1996). Recently, the B with less obstruction or with valvular disease were allele of the PON1 codon 192 polymorphism has been excluded. found to be associated with an increased risk of CHD (Ruiz et al. 1995; Serrato and Marian 1995). Our own Controls study, conducted in Asian Indians and Chinese, has in- ϭ 1 dicated that the B allele is a significant risk factor for Unrelated controls (n 189 ) of age 32 years ע ע CHD in Asian Indians but not in Chinese (Sanghera et (mean SE 49.6 0.8 years) were selected from a al. 1997). Two additional studies, in Caucasians, re- larger, population-based control sample of 470 Asian ported a lack of association of the B allele with CHD Indians, to match the age range of cases. The control (Antikainen et al. 1996; Herrman et al. 1996), suggesting samples were collected as part of the Healthy Lifestyle that the B allele may act merely as a marker for an as Promotion Exercise study. All participants completed yet unidentified functional mutation in either PON1 or a nearby gene. In addition to the known human PON1 gene, two additional PON-like genes, designated “PON2” and “PON3,” have been identified, and all three genes have been mapped to chromosome 7q21-q22 (Primo-Parmo et al. 1996a, 1996b). In the present study, we describe the existence of a common polymorphism at codon 311 in the PON 2 gene, as well as its association with CHD risk both alone and in combination with the PON1 co- Figure 1 Restriction patterns of the PCR-amplified 262-bp frag- don 192 polymorphism in Asian Indians.
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