Methylenetetrahydrofolate Reductase (MTHFR) and Angiotensin Converting Enzyme (ACE) Gene Polymorphisms among Saudi Population from Qassim Region

Introduction

Hypertension and cardiac diseases are multi-factorial disorders with genetic background determined by multiple gene polymorphisms.

MTHFR plays a central role in folate metabolism. Its involvement in the regulation of homocysteine concentration makes it a risk factor in cardiovascular disorders (CVD) [1]. ACE is a chloride and zinc dependent dipeptidyl carboxypeptidase. As a bioactive component of renin-angiotensin system (RAS) ACE plays a significant role in blood pressure regulation, fluid and electrolyte balancing, cardiovascular system development and vascular remodeling [2].

Objectives

To assess the frequency of MTHFR and ACE gene polymorphisms as potential genetic risk factors for hypertension and cardiovascular disorders among Saudi subjects from Qassim region;

Methods

This work included 273 adult healthy unrelated subjects from Qassim Region. Their DNA was analyzed for genetic polymorphisms of MTHFR (677C/T and 1298 A/C) as well as ACE (I/D) using real-time PCR.

Results

Carriers of the mutant MTHFR; 677 T allele (CT+TT) and that of the 1298 C allele (CC+AC) constituted 33.7% and 48.9% of studied subjects respectively; while carriers of ACE gene mutant D allele (DD+ID) represented 93.3% of subjects. The allele frequencies of MTHFR 677T, 1298C and ACE D alleles were 18.7%, 29.45% and 72.5% respectively. Haplotype analysis of characterized chromosomes revealed that 2.5% were likely to carry the 3 mutant alleles together, 30.91% were likely to carry two of the three mutant alleles and 51.92% were likely to carry one mutant allele (Tables 1 and 2).

Table 1.

Genotype and allele frequencies of studied gene polymorphisms tested by Hardy-Weinberg Law of genetic equilibrium

Genotypes	Number	%	HWE χ2(P)
MTHFR 677C/T (n=270)
CC	179	66.3	0.0016 (p>0.05)
CT	81	30	0.0148 (p>0.05)
TT	10	3.7	0.0311 (p>0.05)
C allele	219.5	81.3
T allele	50.5	18.7
MTHFR 1298A/C (n=269)
AA	138	51.1	0.122 (p>0.05)
AC	105	38.9	0.438 (p>0.05)
CC	27	10	0.499 (p>0.05)
A allele	190.5	70.55
C allele	79.5	29.45
ACE D/I (n=269)
DD	139	51.7	0.041 (p>0.05)
ID	112	41.6	0.200 (p>0.05)
II	18	6.7	0.305 (p>0.05)
D allele	195	72.5
I allele	74	27.5

Table 2.

Haplotype frequencies of studied gene polymorphisms

Haplotypes	Number	Total
Total	524#	100%
Haplotypes with 3 mutant alleles
MTHFR_ 677T/1298C/ACE_D	13 (2.48%)	2.48%
Haplotypes with 2 mutant alleles
MTHFR_ 677C/ 1298C/ACE_D	96 (18.32%)	30.91%
MTHFR_ 677T/ 1298C/ACE_I	5 (0.95%)
MTHFR_ 677T/ 1298A/ACE_D	61 (11.64%)
Haplotypes with one mutant allele
MTHFR_ 677T/ 1298A/ACE_I	20 (3.82%)	51.92%
MTHFR_677C/ 1298C/ACE_I	42 (8.02%)
MTHFR_677C/ 1298A/ACE_D	210 (40.08%)
Haplotypes with normal alleles
MTHFR_677C/ 1298A/ACE_I	77 (14.69%)	14.69%

Discussion

Saudis, particularly in Qassim region, are affected by hypertension and coronary artery diseases [3]. So far, very little information was available about the genetic background of Saudi subjects in terms of their susceptibility to hypertension and CAD. To our knowledge, this is the first report of analysis of three interactive gene polymorphisms that have a probable role in the susceptibility for EHand CAD among Saudi population. This study showed that the mutant allele MTHFR 677T frequency (18.7%) in subjects from Qassim was higher than that reported previously in Riyadh region (14.8%), Bahrain (12.6%) and Jordan (16%) [3].

This study also showed that the mutant allele MTHFR 1298C frequency in studied subjects from Qassim (29.45%), was lower than was reported in several other middle-eastern countries. Regarding the ACE gene polymorphism, this study showed that the ACE DD genotype frequency in Qassim region (51.7%) was higher than reported in other Mediterranean and Asian countries. Analysis of chromosomal haplotypes revealed that the 3 studied mutant alleles were likely to be carried by 2.5% of the characterized chromosomes while 2 mutant alleles were carried by 30.91%.

We conclude that Saudis in Qassim Region are carriers of relatively considerable amount of genetic alleles predisposing them to hypertension and cardiac diseases. This gives a warning to local health authorities for adoption of competent programs for prevention as well as early diagnosis and management.