RELATIONSHIP OF RAS GENE POLYMORPHISM TO TYPE-II DIABETES AND SYNDROME-X

Metabolic syndrome, syndrome X, which is reaching epidemic proportions in
population, is a cluster of insulin resistance and/or type-II diabetes mellitus with two
or more of hypertension, dyslipidemia, central obesity and albuminuria in an
individual patient. Genetic predisposition for metabolic syndrome was, to large
extent, believed to be an important aspect in its pathogenesis. The renin-angiotensin
system (RAS) genes are proposed as important genetic factors for diabetic
complications. Therefore, the angiotensin converting enzyme (ACE) gene
polymorphisms (II, ID or DD), which is an important component of RAS genes, might
be included in the pathogenesis of metabolic syndrome and is a candidate gene for
investigation in metabolic syndrome. We aimed to study the possible ACE genotypingplasma
ACE activity-metabolic syndrome relationship, and to assess the possible role
of ACE genotyping in the pathogenesis of variable components of metabolic
syndrome. This study is also a trial to take the distribution of ACE-I/D genotype
among subjects as a possible risk marker for metabolic syndrome. ACE genotypes
were determined by PCR amplification, and plasma ACE activity was measured by
colorimetric method in 100 subjects (40 metabolic syndrome patients diagnosed
according to WHO criteria, 30 type-II diabetic patients without any other criteria of
metabolic syndrome, and 30 healthy controls). Insulin resistance was judged by
homeostasis model assessment (HOMA) index after estimation of fasting blood
glucose and plasma insulin. Moreover, HbA1c, plasma lipids including total
cholesterol, LDL-c, HDL-c, triglycerides and APO-A were assessed.
Microalbuminuria was determined by dipstick method. The indices body mass index
(BMI) and waist:hip ratio (WHR) were used to differentiate obese from non-obese
subjects. ACE-DD genotype and D-allele were found more frequent among metabolic
syndrome patients (Odds ratios were1.25 and 1.16 respectively) and among type-II
diabetics (Odds ratios were1.25 and 1.10 respectively) than among healthy controls;
and more frequent among metabolic syndrome patients than among type-II diabetic
patients (Odds ratios were 1.10 and 1.32 respectively). The plasma ACE activity was
found significantly higher in patient's groups compared to healthy subjects and in
metabolic patients compared to diabetics. Also, it was significantly and positively
correlated to HOMA index in both metabolic syndrome and diabetic patients. The
plasma ACE also in overall studied subjects had direct significant correlation with
FBG, HbA1c, plasma insulin, HOMA index, TC, LDL-c, and TG; and indirect 
significant correlation with HDL-c and APO-A. Moreover, in the three studied groups
DD genotype subgroups had a statistically significant increase in plasma ACE
activity, FBG, HbA1c, plasma insulin, HOMA, total cholesterol, LDL-c, and
triglycerides and a significant decrease in HDL-c and APO-A compared to II
genotype subjects. Lastly, the ACE-DD genotype was associated with hypertension
and with microalbuminuria than any of II genotype (Odds ratios were 3.50 and 6
respectively) and ID genotype (Odds ratios were 2.33 and 1.29 respectively); but not
associated with obesity.
In conclusion, ACE Deletion Polymorphism; DD genotype was associated with
metabolic syndrome and type-II diabetes mellitus as well as with obvious increase in
plasma ACE activity. All components of metabolic syndrome, except obesity were
more aggressive when the ACE genotype was DD. Therefore, ACE may be a strong
genetic risk factor that is involved in the pathogenesis of metabolic syndrome with
type-II diabetes. Moreover, by detection of DD genotype, we can predict the higher
possibility of occurrence of metabolic complications in type-II diabetics in the future
and suggest early interventions to delay or prevent these complications.