Spanish Caucasians Research Articles

Killer cell immunoglobulin-like receptors (KIR) genes can be an adequate tool in forensic anthropological studies: evaluation in a wide Caucasian Spanish population

ABSTRACT Most immune system polymorphisms have undergone molecular evolution largely due to natural selection driven primarily by host-pathogen interactions, showing significant human geographic expansion signs. Killer cell immunoglobulin-like receptors (KIRs) show great genetic and allelic variation among different populations. The aim of this study was to analyse the frequency of KIR genes in a large cohort of healthy Spanish Caucasians (SC) to be able to compare them with other world populations. A total of 609 healthy SC unrelated individuals were analysed and compared with 16 worldwide populations. KIR genotyping was analysed by PCR-SSO technique. Our results showed that all KIR genes were present in the Spanish population. iKIR2D genes of the Spanish population were similar in different European populations like Danish, Finland, Irish and Italian populations, Czech and Turkish populations but very different to Australian, Bornean, Chinese, Indian, Venezuelan, and Russian populations. KIR3DL1 gene frequency in the Australian population was significantly lower than the Spanish population. aKIR genes frequencies of the Spanish population were similar to European populations, but slight differences were found in English, Finnish, Irish and Macedonian populations. In conclusion, our results enrich the Caucasian genetic information resources of the KIR gene pool for genetic susceptibility diseases and forensic anthropological studies.

Characterization of three new HLA Class I Alleles in Spanish Caucasians, HLA-A*02:620, HLA-B*27:150 and HLA-B*07:05:01:02

Three new HLA class I alleles, HLA-A*02:620, HLA-B*27:150 and HLA-B*07:05:01:02, were described in the Spanish Caucasoid population.

Clinic-Based Study on Meibomian Gland Dysfunction in Japan.

To estimate the prevalence of meibomian gland dysfunction (MGD) in the Japanese population. We undertook a clinical study on the prevalence of MGD in Japan using the same diagnostic criteria as a previous population-based study conducted in Spanish Caucasians. The participants were consecutive patients scheduled for cataract surgery at Inouye Eye Hospital. All participants were aged 50 years or older. Patients completed a symptoms questionnaire and underwent a comprehensive slit-lamp examination. Meibomian gland dysfunction was diagnosed when one or more of the following was present in at least in one eye: absent, viscous, or waxy white secretion upon digital expression; presence of two or more lid margin telangiectases; and/or plugging of two or more gland orifices. The study included 510 patients (205 men and 305 women). Mean participant age was 71.1 ± 8.5 years (range, 50-93 years). The prevalences of symptomatic and total MGD (symptomatic MGD + asymptomatic MGD) were 11.2% and 74.5%, respectively. The prevalence of total MGD increased significantly as participant age increased (P < 0.0001). The ratio of males to females and the prevalence of any systemic disease did not differ between patients who were positive or negative for MGD. For the total MGD group, all slit-lamp findings were more frequent, fluorescein score was higher, tear film breakup time was shorter, and meibo-score was larger, compared to non-MGD patients. Based on the present diagnostic criteria, prevalence of MGD is higher in Tokyo, compared to the Spanish population.

Association of the MYH9 Gene Polymorphisms with Chronic Renal Disease Secondary to Hypertensive Nephrosclerosis, in a Caucasian Population

Background: Hypertensive nephrosclerosis (HN) is a chronic kidney disease (CKD) associated to essential hypertension, but their causal relationship is controversial. New evidence suggests that MYH9 gene alterations are associated with HN in African Americans. The aim of this study is to investigate the role of this gene in Spanish Caucasians. Methods: We compare high-risk MYH9 variants of patients with HN recruited according to standard clinical criteria (CKD stages 3-5), with essential hypertensives without renal disease (estimated glomerular filtration rate (eGFR) > 60 ml/min/1,73m2 and albuminuria < 300 mg/g creatinine), and also CKD patients with HN and progressive impairment of renal function with those who were stable. Diabetics were excluded. Results: A blood sample was obtained for genetic study of 238 patients with HN-CKD and 233 hypertensive controls. The rs3752462-T and rs4821480-T (risk alleles for CKD) were more frequent in the CKD group, but without significant difference. We found no differences for these SPNs with blood pressure, creatinine, albuminuria or renal disease progression. Conclusions: The effect of two common MYH9 single nucleotide polymorphisms (SPNs) on the development of CKD secondary to HN in our Spanish Caucasian population is low or zero; in any case less than that found in other, mainly African Americans.

Effect of the FTO rs9930506 Polymorphism on the Main Comorbidities of the Cardiorenal Metabolic Syndrome in an Elderly Spanish Cohort

Background/Aim: Fat mass and obesity-associated (FTO) gene polymorphisms have been linked to the risk of obesity and diabetes, two well-recognized risk factors for renal disease. Our aim was to determine whether a common FTO polymorphism was associated with a reduced estimated glomerular filtration rate (eGFR) independently of body mass index (BMI) and type 2 diabetes mellitus (T2DM) in a cohort of elderly individuals from the region of Asturias (Northern Spain; RENASTUR cohort). Methods: A total of 544 Spanish Caucasians aged 55-85 years were genotyped for the FTO rs9930506 single-nucleotide polymorphism (SNP). Individuals with a previous diagnosis of renal disease were not eligible for the study. The eGFR was calculated with the Modification of Diet in Renal Disease formula, and individuals with an eGFR of <60 ml/min/1.73 m² (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on BMI, hypertension, diabetes, eGFR and blood lipid values was statistically determined. Results: The rs9930506 GG genotype was significantly more common in the group with a BMI of >25 (p = 0.03; odds ratio = 2.43; 95% CI: 1.09-5.43). Age and T2DM were significant risk factors for a reduced eGFR, but neither obesity nor the FTO genotypes were associated with a reduced eGFR. Conclusion: The common FTO rs9930506 polymorphism was a risk factor for overweight and obesity in the RENASTUR cohort. However, this SNP was not associated with other comorbidities of the cardiorenal metabolic syndrome in this population.

Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia

Genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism may be important predictors of antipsychotic drug-induced weight gain (AIWG). We tested whether two functional MTHFR polymorphisms are related to AIWG. Weight gain was studied in two cohorts of first-episode, initially drug-naive schizophrenia patients; Chinese Han (n = 182) and Spanish Caucasians (n = 72) receiving antipsychotics for 10 wk and 3 months respectively. Blood DNA was genotyped for 677C/T and 1298A/C MTHFR polymorphisms. Patients with the 677 CC genotype had a significantly greater increase in BMI compared to T-allele carriers in both Chinese (p = 0.012) and Spanish (p = 0.017) samples. The 677C/T MTHFR polymorphism showed an additive effect, but no significant interaction, with the -759C/T HTR2C polymorphism previously associated with AIWG. These results suggest that the 677C/T MTHFR polymorphism might, along with the -759C/T HTR2C polymorphism and other genetic factors, provide a useful marker for the important and limiting side effect of AIWG.

Association between a MYH9 polymorphism (rs3752462) and renal function in the Spanish RENASTUR cohort

The MYH9 gene encodes a protein that is expressed in the kidney glomerular podocytes. MYH9 single nucleotide polymorphisms (SNPs) have been linked to the risk for chronic kidney disease (CKD) and end stage renal disease. Our aim was to determine whether MYH9 SNPs were associated with renal disease in Spanish Caucasians. The RENASTUR cohort consisted of 592 Spanish Caucasians, aged 55–85years. They were genotyped for SNPs rs3752462 and rs4821480, which tagged haplotype E. The main values between individuals with a glomerular filtration rate (eGFR) <60 and ≥60ml/min/1.73m2 were statistically compared. The next variables were significantly associated with the eGFR in the univariate analysis: age, gender, type 2 diabetes, total cholesterol, total LDL-cholesterol, and the MYH9 rs3752462 (TC+TT genotypes; p=0.003). This SNP remained significantly associated with the eGFR in the multivariate analysis.In conclusion, SNP rs3752462 was an independent predictor of reduced eGFR in the Spanish RENASTUR population. The genotyping of this MYH9 SNP could help to identify individuals at risk of developing CKD.

A Common APOE Polymorphism Is an Independent Risk Factor for Reduced Glomerular Filtration Rate in the Spanish RENASTUR Cohort

Objective:APOE gene variants may contribute to the risk of chronic kidney disease. Our aim was to determine whether the common APOE-ε2/ε3/ε4 polymorphism is associated with a reduced estimated glomerular filtration rate (eGFR) in the RENASTUR population, a cohort of elderly individuals from the region Asturias (northern Spain). Methods: A total of 743 Spanish Caucasians aged 55-85 years were genotyped for the APOE-ε2/ε3/ε4 polymorphism. Individuals with a previous diagnosis of renal disease were not eligible for the study. Participants with a documented history of type 2 diabetes mellitus (T2DM) or hypertension or who were receiving antidiabetic or antihypertensive drugs were classified as diabetics and hypertensives. The eGFR was calculated using the Modification of Diet in Renal Disease formula, and those with an eGFR <60 ml/min/1.73 m² (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on clinical (hypertension, T2DM) and analytical findings was statistically determined. Results: In addition to age and T2DM, APOE-ε2 was significantly associated with an eGFR <60 ml/min/1.73 m² (p = 0.002; OR = 2.30). This association remained statistically significant after correction for multiple variables. Although the effect of the APOE-ε2 allele on the eGFR was observed both among diabetics and nondiabetics, the significance was stronger in the T2DM group. Conclusion: The APOE-ε2 allele is a genetic risk factor for impaired renal function among healthy elderly Spanish individuals.

Independent Replication of an Association of CNVR7113.6 with Crohnʼs Disease in Caucasians

A recent genome-wide association study (GWAS) of copy number variants (CNVs) in Crohn's disease (CD) confirmed association of three CNVs. The GWAS also provided evidence that a fourth CNV, CNVR7113.6, on chromosome 17 may alter susceptibility to CD (P = 0.0018). The aim of our study was to confirm the CNVR7113.6 association by genotyping two independent inflammatory bowel disease (IBD) cohorts and by conducting a subsequent meta-analysis. In all, 1369 New Zealand Caucasians (489 CD patients, 463 ulcerative colitis [UC] patients, and 417 controls) and 2737 Spanish Caucasians (711 CD patients, 549 UC patients, and 1477 controls) were genotyped for a single nucleotide polymorphism (SNP), rs413778, in high linkage disequilibrium (r(2) = >0.99) with CNVR7113.6. Chi-square analysis was conducted to test for association of rs413778 with overall CD, UC, IBD, and with disease phenotype. New Zealand and Spanish genotypes were then combined with imputed rs413778 genotypes from the Wellcome Trust Case Control Consortium (WTCCC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) CD datasets to conduct a meta-analysis. The minor allele of rs413778 conferred protection against CD in the Spanish cohort (CD: P = 0.004, odds ratio [OR] = 0.82, 95% confidence interval [CI]: 0.71-0.94). A similar, albeit nonsignificant protective effect was observed in New Zealand CD patients (P = 0.098, OR = 0.83, 95% CI: 0.66-1.04). No association with UC or disease phenotypes was detected in either cohort. Meta-analysis found significant cumulative evidence for a protective effect of rs413778 in Caucasian CD (P = 1.19E-05, OR = 0.86, 95% CI: 0.80-0.92). This study provides the first independent replication of the association of CNVR7113.6 with CD.

Beta2-glycoprotein I gene polymorphisms Val247Leu and Trp316Ser in Spanish patients with primary antiphospholipid syndrome

The significance of beta2-glycoprotein I (β2GPI) polymorphisms in the production of anti-β2GPI and other antiphospholipid autoantibodies (aPL) and in the pathogenesis of primary antiphospholipid syndrome (PAPS) is not well understood. We performed a study comparing the distribution of polymorphisms at codons 247 (Val247Leu) and 316 (Trp316Ser) of the β2GPI gene in a Caucasian Spanish population of PAPS patients and healthy controls, and then making correlations with the development of anti-β2GPI antibodies and other aPL and associated clinical manifestations. A total of 57 PAPS patients and 100 control subjects were included. In the analysis of Val247Leu polymorphism, alleles (V and L) and genotypes (V/V, V/L, L/L) were similarly distributed in PAPS patients and controls (P = 0.66 and P = 0.22, respectively). Regarding Trp316Ser polymorphism, we found a higher percentage of patients with respect to controls expressing S allele (11.4 vs. 5%, P = 0.02) and T/S genotype (22.8 vs. 10%, P = 0.02). However, when we compared T/T and T/S genotypes in PAPS patients, we found no differences regarding generation of anti-β2GPI, other aPL and clinical manifestations favoring any genotype. Our findings suggest that among Spanish Caucasians, polymorphisms at codon 247 (Val247Leu) do not seem to influence PAPS pathogenesis. On the contrary, polymorphisms at codon 316 (Trp316Ser), by means of an increased S allele and T/S genotype presence in Spanish Caucasian patients, might play a role in the pathogenic development of PAPS, although mechanism would not involve an increased production of anti-β2GPI and other aPL.

Interactions between functional serotonergic polymorphisms and demographic factors influence personality traits in healthy Spanish Caucasians

Data from epidemiological genetic studies suggest that variability in personality traits is explained, at least partly, by genetic factors. Recently, a growing number of molecular genetic studies have suggested the involvement of the serotonin system in specific traits. To investigate the association between three serotonergic polymorphisms [A-1438G (rs6311) of the HTR2A gene, and STin2 VNTR and 5-HTTLPR of the SLC6A4 gene] and personality traits assessed with the Temperament and Character Inventory. Four hundred and four unrelated healthy volunteers [50% males, mean age (standard deviation)=40.5 (11.3)] from Asturias (northern Spain) were genotyped using standard methods. Cloninger's Temperament and Character Inventory was used for investigation of temperament and character traits. The genetic variants were in Hardy-Weinberg equilibrium and genotypic frequencies were similar in both the sexes. 5-HTTLPR was associated with a direct effect on self directedness (F=6.20, P=0.002), and interacting with educational level (F=3.10, P=0.016) and A-1438G (F=3.34, P=0.011) with respect to novelty seeking. STin2 VNTR interacted with age in relation to reward dependence (F=2.74, P=0.013) and with sex in relation to cooperation (F=5.10, P=0.007). In addition, SLC6A4 haplotypes had significant effects on harm avoidance (lower in volunteers with L12), self directedness (higher in volunteers with L12), and self transcendence (higher in volunteers with S10). Our findings suggest a strong genetic component in personality traits manifested primarily through interaction effects that occur between genetic factors alone and between genetic and demographic factors.

Polymorphisms of the IL‐1 Gene Complex Are Associated With Alcohol Dependence in Spanish Caucasians: Data From an Association Study

There is growing evidence for involvement of pro-inflammatory cytokines in alcohol dependence. The aim of this study was to investigate whether 4 functionally relevant polymorphisms of the interleukin-1 (IL-1) and tumor necrosis factor-alpha genes were associated with alcohol dependence and with measures of clinical severity and treatment outcome. Two hundred alcohol-dependent (AD) patients and 420 healthy controls from the same Spanish Caucasian population were genotyped using standard methods. Baseline and 6-month assessments included alcohol intake, addiction severity, and biomarkers of alcohol intake. Alcohol-dependent patients showed an excess of IL-1alpha-889 C/T [50.8% vs. 39.3%, chi(2) (df) = 7.30 (2), uncorrected p = 0.026, corrected p = 0.104] and IL-1RA (86 bp)(n) A1/A1 genotypes [64.8% vs. 50.8%, chi(2) (df) = 12.65 (3), corrected p = 0.020]. The A1/A1 excess was associated with alcohol dependence only in men [69.9% vs. 49.5%, chi(2) (df) = 15.72 (2), corrected p < 0.001]. Six-month clinical and hematological outcome measures did not vary by genotype of the 4 polymorphisms. Haplotype analysis revealed an excess of the IL-1alpha-889 C/IL-1beta +3953 C/IL-1RA A2 haplotype in the control group compared with AD patients [20.0% vs. 14.1%, chi(2) (df) = 7.25 (1), p = 0.007; odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.46-0.89] and in the abstainers after 6 months of treatment compared with nonabstinent patients [14.7% vs. 6.2%, chi(2) (df) = 5.65 (1), p = 0.017; OR = 2.56, 95% CI = 1.15-5.62]. Our findings provide further tentative evidence of the role of IL-1 in alcohol dependence as well as evidence that the nature of the associations may be direct, gender-specific, or involve haplotype effects. However, findings from single association studies constitute tentative knowledge and must be interpreted carefully and precise replication is required.

Is there an optimum endurance polygenic profile?

We analysed seven genetic polymorphisms that are candidates to explain individual variations in human endurance phenotypic traits, at least in Caucasian people (ACE Ins/Del, ACTN3 Arg577Ter, AMPD1 Gln12Ter, CKMM 1170 bp/985 + 185 bp, HFE His63Asp, GDF-8 Lys153Arg and PPARGC1A Gly482Ser) in 46 world-class endurance athletes and 123 controls (all Spanish Caucasians). Using the model developed by Williams & Folland we determined (1) the 'total genotype score' (TGS, from the accumulated combination of the seven polymorphisms, with a maximum value of '100' for the theoretically optimal polygenic score) in the non-athlete (control) group, in the athlete group and in the total Spanish population, and (2) the probability for the occurrence of Spanish individuals with the 'perfect' polygenic endurance profile (i.e. TGS = 100). The probability of a Spanish individual possessing a theoretically optimal polygenic profile for up to the seven candidate genetic polymorphisms we studied was very small, i.e. approximately 0.07% (or 1 in 1351 Spanish individuals). The mean TGS was higher in athletes (70.22 +/- 15.58) than in controls (62.43 +/- 11.45) and also higher than predicted for the total Spanish population (60.80 +/- 12.1), suggesting an overall more 'favourable' polygenic profile in the athlete group. However, only three of the best Spanish endurance athletes (who are also amongst the best in the world) had the best possible score for up to six genes and none of them had the optimal profile. Other polymorphisms yet undiscovered as well as several factors independent of genetic endowment may explain why some individuals reach the upper end of the endurance performance continuum.

Variability of fingerprint ridge density in a sample of Spanish Caucasians and its application to sex determination

Despite the fact that the differences in epidermal ridge density between men and women have been accepted for some time, they have only been thoroughly demonstrated in a small number of populations. The aim of this study is to determine whether such differences exist in a sample of the Spanish population by counting epidermal ridges within three well-defined fingerprint areas. If significant gender differences do exist, then the likelihood of inferring gender from given ridge densities will be explored. The data used in this study was obtained from all 10 fingerprints of 200 individuals of the Spanish Caucasian population (100 males and 100 females) between the ages of 20 and 30. Results show that women tend to have a significantly higher ridge density than men in the distal region of all 10 fingers (radial and ulnar count areas), but not in the proximal region (lower count area). The application of Bayes’ theorem, assuming that prior probabilities known for each sex, indicate a threshold for discrimination of sexes.

Identification of CYP2D6 null variants among long‐stay, chronic psychiatric inpatients: Is it strictly necessary?

We identified the null variants *3,*4,*5,*6,*7 and *8 of the CYP2D6 gene [encoding for cytochrome P450 (debrisoquine hydroxylase)] in a group of 84 chronic-stay psychiatric inpatients with severe schizophrenia or related disorders and receiving treatment with one or more CYP2D6 substrates for years. We also studied a group of 100 healthy controls of similar ethnic origin (Spanish Caucasians). Three patients were poor metabolizers (PMs) for antipsychotic drugs according to their CYP2D6 genotype (i.e. homozygous for the *4 allele) but they exhibited no adverse drug reaction over the years despite chronic treatment with CYP2D6 substrates. We suggest that CYP2D6 genetic screening is more useful in other type of psychiatric patients, particularly in younger ones starting treatment protocols.

Association between obsessive–compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene

Background Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive–compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. Methods The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. Results Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. Conclusions Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.

Association between the T102C polymorphism of the serotonin-2A receptor gene and schizophrenia

Studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. We conducted a case-control study of the T102C polymorphism in Spanish Caucasians. We compared T102C polymorphism genotypes and allele frequencies in 188 schizophrenia patients and 440 healthy controls. There were significant differences in the distribution of the three genotypes (TT, TC and CC) and in the allele frequencies in controls and schizophrenics. The C allele was more frequent in schizophrenia patients than in healthy controls. The Cochrane-Armitage test for trend indicated a significant dosage effect for schizophrenia of the risk allele (C).

Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians

A recent genetic association study has identified a microsatellite in the coding sequence of the asporin gene as a susceptibility factor for osteoarthritis (OA). Alleles of this microsatellite determine the variable number of aspartic acid residues in the amino-terminal end of the asporin protein. Asporin binds directly to the growth factor transforming growth factor beta and inhibits its anabolic effects in cartilage, which include stimulation of collagen and aggrecan synthesis. The OA-associated allele, with 14 aspartic acid residues, inhibits the anabolic effects of transforming growth factor beta more strongly than other asporin alleles, leading to increased OA liability. We have explored whether the association found in several cohorts of Japanese hip OA and knee OA patients was also present in Spanish Caucasians. We studied patients that had undergone total joint replacement for primary OA in the hip (n = 303) or the knee (n = 188) and patients with hand OA (n = 233), and we compared their results with controls (n = 294) lacking overt OA clinical symptoms. No significant differences were observed in any of the multiple comparisons performed, which included global tests of allele frequency distributions and specific comparisons as well as stratification by affected joint and by sex. Our results, together with reports from the United Kingdom and Greece, indicate that the stretch of aspartic acid residues in asporin is not an important factor in OA susceptibility among European Caucasians. It remains possible that lifestyle, environmental or genetic differences allow for an important effect of asporin variants in other ethnic groups as has been reported in the Japanese, but this should be supported by additional studies.

CYP2D6 genotype and phenotype determination in a Mexican Mestizo population

Although CYP2D6 genetic polymorphism plays an important role in interindividual and interethnic variability in drug response, very few pharmacogenetic data are available from Hispanic populations, including Mexicans. For this purpose, this study was undertaken to determine CYP2D6 genotype and phenotype in a healthy Mexican Mestizo population. Genotyping of five CYP2D6 mutant alleles by PCR-RFLP, and CYP2D6*5 and duplicated CYP2D6 alleles by long-PCR was performed in two hundred and forty three Mexican Mestizos. Of these, one hundred subjects were also phenotyped using dextromethorphan as the probe drug. The frequency of CYP2D6*2, *3, *4, *5, *10, *17 was 19.34%, 1.44%, 11.21%, 2.67%, 12.45%, and 1.65%, respectively, while duplicated CYP2D6 alleles were found in 12.76% of the 243 genotyped subjects. Among the 100 phenotyped subjects, we identified ten (10%, 95% confidence interval of 4.12-15.9) individuals as poor metabolizers by using the published antimode for Caucasians. The mean log10 dextromethorphan/dextrorphan ratio of the total sample was -2.05. The mean (SD) of the log10 MR in the CYP2D6 subgroups was UM = -2.6 (0.86); EM = -2.09 (0.98); IM = -1.71 (1.06); and PM = 0.42 (0.625). These data show a trend toward a smaller mean log MR (higher enzyme activity) as the number of active alleles increases. The PM frequency of CYP2D6 in the population studied was 10%, which is very similar to Spanish Caucasians. The observed frequency of the CYP2D6 alleles tested was unique for the Mexican Mestizo sample analyzed, and in accordance to the Caucasian, Asian and African admixture in this population.

Variation in the eNOS Gene Modifies the Association Between Total Energy Expenditure and Glucose Intolerance

Endothelium-derived nitric oxide (NO) facilitates skeletal muscle glucose uptake. Energy expenditure induces the endothelial NO synthase (eNOS) gene, providing a mechanism for insulin-independent glucose disposal. The object was to test 1) the association of genetic variation in eNOS, as assessed by haplotype-tagging single nucleotide polymorphisms (htSNPs) with type 2 diabetes, and 2) the interaction between eNOS haplotypes and total energy expenditure on glucose intolerance. Using multivariate models, we tested associations between eNOS htSNPs and diabetes (n = 461 and 474 case and control subjects, respectively) and glucose intolerance (two cohorts of n = 706 and 738 U.K. and Spanish Caucasians, respectively), and we tested eNOS x total energy expenditure interactions on glucose intolerance. An overall association between eNOS haplotype and diabetes was observed (P = 0.004). Relative to the most common haplotype (111), two haplotypes (121 and 212) tended to increase diabetes risk (OR 1.22, 95% CI 0.96-1.55), and one (122) was associated with decreased risk (0.58, 0.39-0.86). In the cohort studies, no association was observed between haplotypes and 2-h glucose (P > 0.10). However, we observed a significant total energy expenditure-haplotype interaction (P = 0.007). Genetic variation at the eNOS locus is associated with diabetes, which may be attributable to an enhanced effect of total energy expenditure on glucose disposal in individuals with specific eNOS haplotypes. Gene-environment interactions such as this may help explain why replication of genetic association frequently fails.