Insulin resistance phenotypes and coronary artery disease in a native Pakistani cohort.

OBJECTIVE: To determine the relationship between insulin resistance (IR) and atheroma burden in Pakistanis. METHODS: A prospective case-control study of 400 patients selected for the presence/absence of angiographic disease. Coronary atheroma burden was quantified and IR and cardiovascular risk factors were measured. RESULTS: The patients were divided into two groups by QuickI score. Waist circumference (90 +/- 10 vs. 90 +/- 9 cm; p = 0.7) was similar but the groups differed in body mass index (26.5 +/- 3.7 vs. 24.2 +/- 3.5 kg/m(2); p < 0.001) and waist:hip ratio (0.94 +/- 0.09 vs. 0.90 +/- 0.06; p < 0.001). Lipid parameters showed similar high-density lipoprotein cholesterol (HDL-C) (0.77 +/- 0.23 vs. 0.82 +/- 0.22 mmol/l; p = 0.1) differences in triglycerides [1.32 (0.08-3.98) vs. 1.12 (0.37-3.61) mmol/l; p = 0.01], but no difference in low-density lipoprotein cholesterol (LDL-C) (2.75 +/- 1.00 vs. 2.90 +/- 0.94 mmol/l; p = 0.14). In insulin-resistant patients C-reactive protein (CRP) [6.8 (0.3-175.1) vs. 3.9 (0.2-57.9) mg/l: p < 0.001], sialic acid (82 +/- 14 vs. 77 +/- 15 mg/l; p < 0.001) aspartate transaminase [24 (7-171) vs. 21 (7-83) IU/l; p < 0.001] and gamma-glutamyl transferase [27 (8-482) vs. 21 (7-168) IU/l; p = 0.005] levels were increased. In insulin-resistant patients (n = 187), coronary artery disease (CAD) burden correlated (r = 0.55) with age (beta = 1.62; p < 0.001), HDL-C (beta = -53.2; p < 0.001), lipoprotein (a) (beta = 11.4; p = 0.007), smoking (beta = 7.98; p = 0.004), CRP (beta = 6.06; p = 0.03) and QuickI index (beta = -146; p = 0.04). In contrast in insulin-sensitive patients (n = 178) CAD burden (r = 0.46) correlated with LDL-C (beta = 10.0; p = 0.02), CRP (beta = 7.13; p = 0.03), HDL-C (beta = -38.1; p = 0.03), and weakly with age (beta = 0.73; p = 0.07) and smoking (beta = 5.52; p = 0.09). CONCLUSIONS: Indian Asians show a dichotomous insulin-resistance phenotype. Atheroma is associated with low HDL-C and inflammation associated in all but LDL-C is a factor in the insulin sensitive in contrast to age and extent of IR in the insulin resistant.

Metabolic syndrome and risk of coronary heart disease in a Pakistani cohort.

OBJECTIVE: To assess the relation of the metabolic insulin resistance syndrome (M-IRS) with coronary heart disease (CHD) in Pakistani patients. SUBJECTS: 200 patients with angiographic disease (CHD(+)) matched with 200 patients with chest pain without occlusive disease (CHD(-)). DESIGN: Prospective case-control study. SETTING: Tertiary referral cardiology unit in Pakistan. RESULTS: M-IRS was present in 37% of CHD(+) versus 27% of CHD(-) patients by criteria for white patients or 47% versus 42%, respectively, by Asian criteria (p < 0.001). After adjustment for other risk factors, M-IRS was not a significant predictor for CHD or angiographic disease. Age (p = 0.03), smoking (p < 0.001), diabetes-years (p = 0.003), sialic acid (p = 0.01), and creatinine (p = 0.008) accounted for the excess risk of CHD. Similarly, age (p = 0.005), creatinine (p < 0.001), cigarette pack-years (p = 0.02), diabetes-years (p = 0.003), and sialic acid (p = 0.08) were predictors of greater angiographic disease. M-IRS differed between Pakistani and white patients, as waist circumference correlated weakly (r = -0.03-0.08, p = 0.45-0.52) with triglycerides, high density lipoprotein cholesterol, systolic blood pressure, or glucose. Sialic acid was the only inflammatory marker associated with M-IRS. CONCLUSIONS: Despite strong associations between individual risk factors associated with M-IRS and a univariate association between M-IRS and CHD in native Pakistanis, the principal discriminant risk factors in this group are age, smoking, inflammation, diabetes-years, and impaired renal function. The poor sensitivity of M-IRS for CHD reflects the high underlying prevalence of M-IRS, thus reducing sensitivity, confounding by other urban lifestyle traits, or a lack of association of waist circumference with M-IRS risk factors. The definition of M-IRS may have to be revised to increase its power as a discriminant risk factor for CHD in Pakistani populations.

Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia.

The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I-converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72; P=0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24; P=0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97; P=0.02), plasma glucose (OR=3.31; 95% CI, 3. 10 to 3.52; P=0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72; P=0.06) and increased to 3.10 (95% CI, 1.20 to 7.52; P=0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.

Effects of lipids in patients with familial hypercholesterolaemia on the kinetics of the sodium-lithium countertransporter.

Sodium-lithium countertransport kinetics were measured in 87 patients (50 male; 37 female) with heterozygous familial hypercholesterolaemia (FH) and a group of 38 age range and sex-distribution matched controls. Basic clinical data including basic anthropometry, blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose and insulin measurement. Patients with FH had elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol and apolipoprotein B concentrations compared to controls. The activity and log transformed maximal velocity (Vmax) of the sodium-lithium countertransporter unlike the affinity (Km) were reduced in patients with FH compared to controls (geometric means 0.172 vs 0.217 mmol Li+/L.RBC.hr; P = 0.02; 0.237 vs. 0.317 mmol Li+/L.RBC.hr; P = 0.009 respectively). In multiple regression analysis, log normalised SLC activity correlated weakly with log triglyceride (beta = 0.225; P = 0.06) and cholesterol (beta = -0.112 P = 0.06). Log Vmax correlated with log triglyceride (beta = 0.307; P = 0.02), and high-density lipoprotein (HDL) (beta = 0.74; P = 0.03) whilst Km correlated with HDL (beta = 1.73; P<0.001) and apoAI (beta = -1.76; P = 0.0048), LDL (beta = -0.14; P = 0.05), and creatine kinase (beta = 0.003; P = 0.01). Cholesterol and triglyceride concentrations rather than insulin resistance seem to be the key features affecting the environmental alteration of sodium lithium countertransporter Vmax in patients with familial hypercholesterolaemia.

Identification of genetic heterogeneity in Refsum's disease.

Refsum's disease (MIM 266500) is a recessive disorder characterised by defective peroxisomal alpha-oxidation of phytanic acid. A Refsum's disease gene, phytanoyl-CoA hydroxylase (PAHX), has been localised to chromosome 10p13 between the markers D10S226-D10S223. This study investigated whether all cases of Refsum's disease were linked with chromosome 10p13. Eight genetically informative families comprising 92 individuals including 17 living patients with a Refsum's disease phenotype and initial plasma phytanic acid > 200 micromol/L were recruited. Linkage to the 10pter-10p11.2 region was investigated using a panel of eight dinucleotide repeat markers. Linkage analysis of this phenotypically identical cohort suggested that Refsum's disease was genetically heterogeneous (Zmax = 5.28, alpha = 0.45). Two subgroups were identified. One group of four families with eight affected individuals had a maximum multipoint lod score for linkage of 3.89 in the region D10S547 to D10S191, whilst in another three families with nine affected individuals linkage to this region was definitely excluded. Our results show that Refsum's disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. This suggests that Refsum's disease, in common with other peroxisomal 'diseases', may be more accurately described as a heterogeneous syndrome.

Differing relationships of methylene tetrahydrofolate reductase genotypes with cardiovascular risk in familial and polygenic hypercholesterolaemia.

BACKGROUND: Plasma homocysteine and the methylene tetrahydrofolate reductase C677T polymorphism have been suggested as being risk factors for cardiovascular disease. OBJECTIVE: To determine whether plasma homocysteine and the methylene tetrahydrofolate reductase C677T polymorphism are risk factors for coronary heart disease in patients with heterozygous familial hypercholesterolaemia as compared with those with polygenic hyperlipidaemia. METHODS: Plasma homocysteine and the methylene tetrahydrofolate reductase polymorphism were assessed with other risk factors in 112 patients with familial hypercholesterolaemia and 72 patients with polygenic hyperlipidaemia, of whom 29 (25.8%) and 30 (41%) respectively had established cardiovascular disease and in 100 healthy normal subjects. RESULTS: Plasma homocysteine was not significantly elevated in patients with and without coronary heart disease with familial hypercholesterolaemia or polygenic hyperlipidaemia compared with controls. The allele frequencies for C677T were significantly different in patients with coronary heart disease and with polygenic hyperlipidaemia (0.35 versus 0.29) (P = 0.02) as opposed to those with coronary heart disease and familial hypercholesterolaemia (0.25 versus 0.30) (P = 0.63). Methylene tetrahydrofolate reductase genotype but not homocysteine had a weak association with coronary heart disease in logistic regression analysis in patients with polygenic hyperlipidaemia (P = 0.05) but neither methylene tetrahydrofolate reductase genotype or plasma homocysteine was a risk factor in patients with familial hypercholesterolaemia. CONCLUSION: Whilst methylene tetrahydrofolate reductase genotype may be a weak risk factor for coronary heart disease in polygenic hyperlipidaemia as opposed to familial hypercholesterolaemia, homocysteine does not seem to be an important risk factor for coronary heart disease in patients in southern UK.