<Emphasis Type="Italic">SUMO4</Emphasis> 163 G&gt;A variation is associated with kidney disease in Indian subjects with type 2 diabetes

Genetic susceptibility probably plays a role in the development and/or progression of diabetic kidney disease. Small ubiquitin-related modifier 4 (SUMO4) mRNA is expressed in human kidney. Substitution of methionine with valine at codon 55 (M55V) of SUMO4 gene induces higher nuclear factor-kB activity, which is known to mediate the development of kidney disease in individuals with diabetes. We investigated the association between the SUMO4 M55V (rs237025, c.163 G>A) and kidney disease in north Indian subjects with diabetes. A case–control analysis was performed using genomic DNA samples from 216 diabetic patients without nephropathy (DM) and 201 diabetic with nephropathy (DN). The SUMO4 c.163 G>A polymorphism was genotyped using polymerase chain reaction amplification followed by restriction digestion. The duration of diabetes was significantly greater in DN. The genotypic and allelic frequencies were different in DM and DN groups: GG genotype was significantly more frequent in DN as compared to DM (p = 0.018, OR 1.72, 95 % CI 1.1–2.7). Similarly the G allele was more frequent in DN compared to DM (p = 0.017, OR 1.4, 95 % CI 1.1–1.8). This study suggests that SUMO4 c.163 G>A polymorphism is associated with the susceptibility to diabetic nephropathy in north Indian subjects with type 2 diabetes.     

Lack of association between the G-660C polymorphism in the dopamine transporter gene (SLC6A3) and schizophrenia in the Iranian population

BACKGROUND:

Dopaminergenic system plays an essential role in the plasticity of the human brain. The dopamine transporter gene (SLC6A3) mediates active reuptake of dopamine from synapsis, terminates dopamine signals, and therefore, is implicated in a number of dopamine-related disorders like psychosis. Variations in the form of single nucleotide polymorphisms in the core promoter of the SLC6A3 gene are reported to be involved in the pathogenesis of schizophrenia. In this study, we also attempted to establish the possible role of the polymorphism G-660C in the SLC6A3 gene promoter in schizophrenia in a case-control study.

MATERIALS AND METHODS:

The allele and genotype frequency were analyzed in an Iranian cohort of 200 unrelated patients and 200 controls using polymerase chain reaction and restriction fragment length polymorphism.

RESULTS:

The genotype frequency for case and control groups was GG 100%, GC 0%, CC 0%, and GG 100%, GC 0%, CC 0%, respectively. The C allele was failed in both groups.

CONCLUSION:

Our data suggest clearly that there is no association between the -660G/C polymorphism and outcome of schizophrenia in the Iranian population.     

Angiotensin II type 1 receptor A1166C gene polymorphism and essential hypertension in Calabar and Uyo cities,Nigeria

OBJECTIVES:

The angiotensin II protein is a vasoconstrictor that exerts most of its influence through the angiotensin II type 1 receptor (AT₁R). Inconsistent association between the A1166C polymorphism of the AT₁R gene and hypertension has been reported among various populations but not among the peoples of Calabar and Uyo. This study was designed to determine the frequency of the A1166C polymorphism of the AT₁R gene and its association with hypertension in a sample population of Calabar and Uyo.

MATERIALS AND METHODS:

A population-based case control design consisting of total of 1224 participants, 612 each of patients and controls were randomly recruited from hypertension clinics and the general population. Genotyping of the A1166C allele of the AT₁R gene to identify variants was performed using polymerase chain reaction and restriction enzyme digestion. Multiple regressions were applied to test whether the A1166 genotypes were predictors of hypertension.

RESULTS:

99% of the study population had the wild type AA genotype, and 1% was AC heterozygous carriers of the A1166C polymorphism.

CONCLUSION:

The A1166C polymorphism was not a predictor of hypertension in the sample population of Calabar and Uyo.     

Frequency of fokI and taqI polymorphism of vitamin D receptor gene in Indian population and its association with 25-hydroxyvitamin D levels

BACKGROUND:

The VDR protein is at the centre of the vitamin D endocrine system, a complex physiological system with substantial feedback regulatory mechanisms involved in maintaining serum calcium and 1, 25 dihydroxy vitamin D3. Variations in VDR gene are shown to have implications in several diseases and have also been implicated as an important genetic factor affecting bone mass.

AIM:

To determine the frequency of Fok I and Taq I variants in healthy Indian individuals and its association with 25-OH-Vitamin D levels.

SETTINGS AND DESIGN:

Blood samples were collected from 143 unrelated normal individuals (Male-84 and Female-59) and their genotypes determined.

MATERIALS AND METHODS:

After amplification by polymerase chain reaction, each polymorphism was genotyped by restriction fragment length polymorphism. For 100 normal healthy individuals 25-hydroxyvitamin D estimation was done using DiaSorin kit method.

STATISTICAL ANALYSIS:

Graph pad software was used to calculate the P values from the Chi-square.

RESULTS:

Out of 143 samples analyzed for FokI and TaqI polymorphisms the following genotypic frequency was obtained FF 59%, Ff 36%, ff 5% and TT 49%, Tt 43%, tt 8% respectively.

CONCLUSIONS:

Results indicate that the distribution of the polymorphic loci Fok I and Taq I vary considerably not only in different populations, but also within India. Furthermore, when the genotypes were analyzed with respect to 25-OH-Vitamin D levels, a significant association was seen for the Taq 1 SNP but not with the Fok I.     

Absence of mutations in GJB2 (Connexin-26) gene in an ethnic group of southwest Iran

BACKGROUND:

The common GJB2 gene mutation (35delG) has been previously reported from Iranian patients that were affected with nonsyndromic autosomal recessive deafness. We, therefore, for the first time, investigated the prevalence and frequency of the GJB2 gene mutation in the Iranian deaf population with Arabian origins.

MATERIALS AND METHODs:

We amplified and sequenced the entire coding sequence of the GJB2 gene from 61 deaf patients and 26 control subjects.

RESULT:

None of the analyzed samples revealed deafness-associated mutation.

CONCLUSION:

This finding differs from several reports from Iran as we have focused on the GJB2 gene that possesses various mutations as the cause of congenital recessive deafness.     

Protein tyrosine phosphatase non-receptor type 22 gene polymorphism C1858T is not associated with leprosy in Azerbaijan,Northwest Iran

BACKGROUND:

Leprosy (Hansen''s disease) is a human chronic granulomatous infectious disease caused by Mycobacterium leprae. Several types of study support a role for host genetics in susceptibility to leprosy. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an intracellular lymphoid protein tyrosine phosphatase that has been shown to play a negative regulatory role in T-cell activation.

AIMS:

The aim of the present study was to find out associating the PTPN22 C1858T (R620W) polymorphism and leprosy in the Azeri population from Northwest Iran.

MATERIALS AND METHODS:

A total of 153 treated leprosy patients and 197 healthy and ethnic matched controls entered this study. We used restriction fragment length polymorphism method to type PTPN22 C1858T polymorphism.

RESULTS:

There was no significant difference in distribution of genotype and allele frequencies of PTPN22 C1858T polymorphism between leprosy patients and controls (P = 0.641 and 0.645; respectively). Moreover, there was no significant association between different clinical findings (karnofsky performance status score, clinical forms and manifestations of leprosy) and PTPN22 C1858T polymorphism. Data showed a low frequency of the minor (T) allele by 2.3% in leprosy and 1.5% in healthy individuals.

CONCLUSIONS:

The PTPN22 C1858T (R620W) is not relevant in susceptibility to leprosy in the Azeri population of Northwest Iran.     

Prion Protein Expression and Processing in Human Mononuclear Cells: The Impact of the Codon 129 Prion Gene Polymorphism

Background

So far, all clinical cases of new variant Creutzfeldt-Jakob disease (vCJD), thought to result from the Bovine Spongiform Encephalopathy (BSE) prion agent, have shown Methionine–Methionine (M/M) homozygosity at the M129V polymorphism of the PRNP gene. Although established, this relationship is still not understood. In both vCJD and experimental BSE models prion agents do reach the bloodstream, raising concerns regarding disease transmission through blood transfusion.

Methodology/Principal Findings

We investigated the impact of the M129V polymorphism on the expression and processing of the prion protein in human peripheral blood mononuclear cells (PBMCs) from three blood donor populations with Methionine-Methionine (M/M), Valine-Valine (V/V) and M/V genotypes. Using real-time PCR, ELISA and immunoblot assays we were unable to find differences in prion protein expression and processing relating to the M129V polymorphism.

Conclusions/Significance

These results suggest that in PBMCs, the M129V PrP polymorphism has no significant impact on PrP expression, processing and the apparent glycoform distribution. Prion propagation should be investigated further in other cell types or tissues.     

Risk conferred by FokI polymorphism of vitamin D receptor (VDR) gene for essential hypertension

BACKGROUND:

The vitamin D receptor (VDR) gene serves as a good candidate gene for susceptibility to several diseases. The gene has a critical role in regulating the renin-angiotensin system (RAS) influencing the regulation of blood pressure. Hence determining the association of VDR polymorphisms with essential hypertension is expected to help in the evaluation of risk for the condition.

AIM:

The aim of this study was to evaluate association between VDRFok I polymorphism and genetic susceptibility to essential hypertension.

MATERIALS AND METHODS:

Two hundred and eighty clinically diagnosed hypertensive patients and 200 normotensive healthy controls were analyzed for Fok I (T/C) [rs2228570] polymorphism by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Genotype distribution and allele frequencies in patients and controls, and odds ratios (ORs) were calculated to predict the risk for developing hypertension by the individuals of different genotypes.

RESULTS:

The genotype distribution and allele frequencies of Fok I (T/C) [rs2228570] VDR polymorphism differed significantly between patients and controls (χ² of 18.0; 2 degrees of freedom; P = 0.000). FF genotype and allele F were at significantly greater risk for developing hypertension and the risk was elevated for both the sexes, cases with positive family history and habit of smoking.

CONCLUSIONS:

Our data suggest that VDR gene Fok I polymorphism is associated with the risk of developing essential hypertension     

Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population

Background

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+ 408 C > A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes.

Objective

To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population.

Methods

We conducted a case–control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory.

Results

No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P > 0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P < 0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P < 0.05).

Conclusion

The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance.     

Relation of type 2 diabetes mellitus with gender,education, and marital status in an Iranian urban population

Background:

Type 2 diabetes mellitus is one of the most important cardiovascular risk factors. Objectives: This study was performed to assess the relationship of diabetes with gender, education, and marital status in an Iranian urban population.

Methods:

A total of 892 men and women aged 30-85 were recruited using a cluster-stratified sampling method from an urban population. Using a questionnaire, demographical data including gender, education, and marital status were collected. A blood sample after fasting for at least eight hours was collected from each subject. Associations of type 2 diabetes mellitus and studied variables were tested for significance.

Results:

The prevalence of diabetes mellitus was 11.6%; 11.1% in men and 12.1% in women with no significant difference between them. Diabetes mellitus was most prevalent in the oldest age (age more than 60 years, 22.9%) and low education groups (17.9%, P < 0.001). Marital status was not significantly related to diabetes mellitus (P= 0.37).

Conclusion:

The prevalence of diabetes mellitus is related to education within the Iranian population. Thus preventive strategies should be based on the affective factors. Key Words: Diabetes mellitus, Education, Marital status, Gender     

Association study of the ABCC8 gene variants with type 2 diabetes in south Indians

BACKGROUND:

The ABCC8 gene which encodes the sulfonylurea receptor plays a major role in insulin secretion and is a potential candidate for type 2 diabetes. The -3c → t (rs1799854) and Thr759Thr (C → T, rs1801261) single nucleotide polymorphisms (SNPs) of the ABCC8 gene have been associated with type 2 diabetes in many populations. The present study was designed to investigate the association of these two SNPs in an Asian Indian population from south India.

MATERIALS AND METHODS:

A total of 1,300 subjects, 663 normal glucose tolerant (NGT) and 637 type 2 diabetic subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES). The -3c → t and Thr759Thr were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a few variants were confirmed by direct sequencing.

RESULTS:

The frequency of the ‘t’ allele of the -3c → t SNP was found to be 0.27 in NGT and 0.29 in type 2 diabetic subjects (P = 0.44). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetic group (P = 0.18). Neither the genotypic frequency nor the allele frequency of the Thr759Thr polymorphism was found to differ significantly between the NGT and type 2 diabetic groups.

CONCLUSION:

The -3c → t and the Thr759Thr polymorphisms of the ABCC8 gene were not associated with type 2 diabetes in this study. However, an effect of these genetic variants on specific unidentified sub groups of type 2 diabetes cannot be excluded.     

Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children

INTRODUCTION:

The relationship between chromosomal non-disjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the polymorphism in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677 C-T in women having Down syndrome (DS) children.

MATERIALS AND METHODS:

The prevalence of these variant genotypes (MTHFR 677 C-T polymorphism) in women having DS children (case mothers) (n = 110) was compared with controls (n = 111) from Punjab. Genotyping was done using the polymerase chain reaction method followed by restriction fragment length polymorphism.

RESULTS:

In the present study, 1.8% of case mothers had TT genotype while none of the control mothers showed this genotype. T allele frequency among cases was 0.13 and 0.11 in controls. The Chi-square value showed a non-significant difference between cases and controls.

CONCLUSION:

No association has been observed between 677 C-T polymorphism and risk of non-disjunction in case mothers. Detection of polymorphisms in more genes of folate pathway is required to find out the exact cause of non-disjunction.     

CD14 C-159T polymorphism and its association with chronic lung diseases: A pilot study on isocyanate exposed population of Central India

CONTEXT:

CD14 functions as a multifunctional receptor for bacterial cell wall components including endotoxin and lipopolysaccharide and is likely to influence the cytokine profile and subsequent immunoglobulin E production in response to antigen/allergen contact in allergic phenotypes.

AIMS:

The present study was to investigate genetic polymorphism in CD14 gene - 159C/T, which may be one of the risk factor for increased prevalence of Chronic Lung Diseases in the Central India.

SETTINGS AND DESIGN:

Survivors of Methyl isocyanates toxicity in Bhopal still suffering from various respiratory ailments were examined.

MATERIALS AND METHODS:

Polymerase chain reaction-restriction fragment length polymorphism was performed to determine the polymorphism of C-159T.

RESULTS:

The genotype and allelic frequencies were in Hardy-Weinberg’s equilibrium. Prevalence of CC, CT, and TT were 5.5%, 22.2% and 9.25% respectively in asthmatics; 16.6%, 20.3% and 5.5% respectively in chronic obstructive pulmonary disease (COPD) patients and 5.5%, 14.8% and 1.85 respectively among interstitial lung disorder (ILD) patients; whereas the control cohort with no methyl isocyanate exposure displayed (CC, CT, and TT) cytosine, thymine as 2%, 1.6% and 2% respectively. Increased risk of Asthma among those carrying TT genotype and T allele (odds ratio [OR] =2.61 and 2.02 respectively).

CONCLUSION:

COPD risk significantly found among those with CC genotype and C allele (OR = 2.81 and 1.50 respectively), whereas ILD risk found significantly among CT genotype and C allele (OR = 1.75 and 1.40 respectively). Therefore, single nucleotide polymorphism (SNP) C-159T polymorphism in CD14 gene might be a risk factor for development of CLD in this population.     

Cytogenetic abnormalities in 222 infertile men with azoospermia and oligospermia in Iran: Report and review

BACKGROUND:

Infertility affects approximately 10%-15% of couples in reproductive age. In half of the couples, causes are male-related, associated with impaired spermatogenesis. There is a complex correlation between genetics and infertility. Several factors affect on gametogenesis, from which factors that lead to chromosomal abnormalities are one of the best known. The aim of this study was to determine type and rate of chromosomal abnormalities in infertile azoospermic and oligospermic males in Iranian population.

MATERIALS AND METHODS:

The records of a total of 222 participants were evaluated retrospectively.

RESULTS:

As a whole we observed 13.96% chromosomal abnormality, from which 12.15% showed numerical and 1.8% showed structural abnormalities.

CONCLUSION:

Comparison of our results with the review of the literature shows a higher incidence (4- fold) of gonosomal, in particular, numerical gonosomal, chromosomal anomalies. Cytogenetic analysis is strongly suggested for infertile men, particularly in those who suffer from azoospermia.     

Glycated Haemoglobin Is Inversely Related to Serum Vitamin D Levels in Type 2 Diabetic Patients

Objective

A correlation between glucose control and 25(OH)D metabolism has been suggested by previous studies. However, this correlation has not yet been evaluated considering the impact of chronic complications of type 2 diabetes, especially the presence of nephropathy. Thus, the aim of this study was to determine the correlation between A1C and 25(OH)D in a well characterized cohort of type 2 diabetic patients.

Research Design and Methods

We cross-sectionally examined the association between A1C and serum 25(OH) D in 715 type 2 diabetic patients attending our clinic during the years 2011–2012. The average age was 68±12 years (range 26–94 years). The relation between A1C and serum 25(OH)D levels was modelled by multiple linear regression analyses.

Results

Serum 25(OH)D levels were inversely associated with A1C levels (r = −0.116, p = .003). This relation maintains its independence in the multivariate analysis after adjusting for age, sex, A1C, BMI, treatment and duration of diabetes and nephropathy.

Conclusions

In type 2 diabetic patients, high A1C levels are associated with low concentrations of serum 25(OH)D independently of duration of diabetes, diabetic treatment and nephropathy. Future studies are needed to clarify the biological relation between glucose control and vitamin D metabolism in type 2 diabetes.     

Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy

Objective

To investigate the association of Mannose-binding lectin (MBL) and the MBL2 gene with type 2 diabetes and diabetic nephropathy and the influence of MBL2 polymorphisms on serum MBL levels.

Methods

The study population included 675 type 2 diabetic patients with or without nephropathy and 855 normoglycemic controls. The single nucleotide polymorphisms (SNPs) of rs1800450, rs1800451, and rs11003125 of the MBL2 gene were determined by the Multiplex Snapshot method. Serum MBL levels were measured by enzyme-linked immune sorbent assay.

Results

Rs1800450 and rs11003125 SNPs demonstrated strong linkage disequilibrium in the study population (r² = 0.97). The haplotypes constructed from the G allele of rs1800450 and the C allele of rs11003125 increased the risk for type 2 diabetes (OR = 1.2, 95% CI = 1.1–1.4, P = 0.01). For rs1800450, GG and GA genotypes were associated with type 2 diabetes (P = 0.02, 0.01, respectively). For rs11003125, the GC genotype frequency was significantly different between patients and controls (18.1% vs. 24.9%, P = 0.001). Analyses of genotypes and allele frequency distributions among patients with normal UAE, microalbuminuria, and macroalbuminuria showed that there was no obvious evidence of association between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels.

Conclusions

The rs1800450 and rs11003125 SNPs of the MBL2 gene have strong linkage disequilibrium and are associated with type 2 diabetes in the North Chinese Han population. No association was observed between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels. An association between elevated serum MBL and diabetic nephropathy was also observed.     

Phenotype-genotype updates from familial Mediterranean fever database registry of Mansoura University Children’ Hospital,Mansoura, Egypt

BACKGROUND:

Familial Mediterranean fever (FMF) is autosomal recessive disease that affects people from Mediterranean region, Europe and Japan. Its gene (Mediterranean fever [MEFV]) has more than 100 mostly non-sense mutations.

OBJECTIVES:

The objective of the following study is to provide some phenotype-genotype correlates in FMF by categorizing the Egyptian FMF cases from Delta governorates after analysis of the four most common mutations of MEFV gene (M680I, M694I, M694V, V726A).

SUBJECTS AND METHODS:

Clinically, suspected FMF cases using Tel-Hashomer criteria were enrolled in the study. Cases were referred to Mansoura University Children''s Hospital that serves most of the most middle Delta governorates, in the period from 2006 to 2011. Subjects included 282 males and 144 females, mean age of onset 9.3 ± 2.2 years. All cases were analyzed for these mutations using amplification refractory mutation system based on the polymerase chain reaction technique. Five FMF patients agreed to undergo renal biopsy to check for development of amyloidosis. Analysis of data was carried out using SPSS (SPSS, Inc., Chicago, IL, USA).

RESULTS:

Mutation was found in 521 out of 852 studies alleles, the most frequent is M694V (35.4%) followed by M694I, V726A and M680I. 11 cases were homozygous; 7 M694V, 3 M680I and only one M694I case. Severe abdominal pain occurred in 31 (7.28%) but severe arthritis in 103 cases (24.2%). Strong association was found between arthritis and homozygous mutant compared with single and double heterozygous (72.7% vs. 33.3% and 20.24%, P < 0.001). Four amyloid cases were M694V positive.

CONCLUSION:

M694V allele is the most common among Egyptian FMF especially those with amyloidosis. We recommend routine check for amyloidosis in FMF cases to statistically validate this link.     

Deoxyribonucleic acid repair gene X-ray repair cross-complementing group 1 polymorphisms and non-carcinogenic disease risk in different populations: A meta-analysis

PURPOSE:

This study aims to assess a meta-analysis of the association of X-ray repair cross-complementing group 1 (XRCC1) polymorphisms with the risk of various non-carcinogenic diseases in different population.

MATERIALS AND METHODS:

This meta-analysis was performed by critically reviewing reveals 38 studies involving 10043 cases and 11037 controls. Among all the eligible studies, 14 focused on Arg194Trp polymorphism, 33 described the Arg399Gln and three articles investigated on Arg280His. Populations were divided into three different ethnic subgroups include Caucasians, Asians and other (Turkish and Iranian).

RESULTS:

Pooled results showed no correlation between Arg194Trp and non-carcinogenic disease. There was only weak relation in the recessive (odds ratio [OR] =1.11, 95% confidence interval [CI]: 0.86-1.44) model in Asian population and dominant (OR = 1.04, 95% CI: 0.66-1.63) model of other populations. In Arg399Gln polymorphism, there was no relation with diseases of interest generally. In the pooled analysis, there were weak relation in the dominant (OR = 1.08, 95% CI: 0.86-1.35) model of Asian population and quite well-correlation with recessive (OR = 1.49, 95% CI: 1.19-1.88), dominant (OR = 1.23, 95% CI: 0.94-1.62), and additive (OR = 1.23, 95% CI: 0.94-1.62) models of other subgroup. For Arg280His, there was a weak relation only in the dominant model (OR = 1.06, 95% CI: 0.74-1.51).

CONCLUSION:

The present meta-analysis correspondingly shows that Arg399Gln variant to be associated with increased non-carcinogenic diseases risk through dominant and recessive modes among Iranian and Turkish population. It also suggests a trend of dominant and recessive effect of Arg280His variant in all population and its possible protective effect on non-carcinogenic diseases.