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Association of VDR Gene Variant (rs1544410) with Type 2 Diabetes in a Pakistani Cohort.

ABSTRACT: The present study was designed to measure the mean values of body mass index (BMI), random blood sugar/ fast ing blood sugar (RBS/FBS) tests, and Hb A_1c and to investigate the role of a genetic variant rs1544410 in the VDR gene in a Pakistani cohort. For this purpose, a total of 917 samples including 469 diabetes mellitus type 2 (T2DM), 145 DM type 1 (T1DM), and 303 healthy control were collected. Out of the total sample set, 500 individuals (250 T2DM cases and 250 controls) were genotyped for rs1544410. It was found that 65 (26.0%) cases and 32 (12.8%) controls had homozygous AA, while 69 (27.6%) cases and 139 (55.6%) controls had heterozygous AG, and 116 (46.4%) cases and 79 (31.6%) controls had homozygous GG (χ² = 41.81, p = 0.0001). In addition, a similar distribution of allele frequency was determined in cases and controls [p value = 0.866; odds ratio (OR) = 0.967; relative risk (RR) = 1.034]. A significant difference was observed in homozygous dominant [OR = 2.394 (1.501-3.816); RR = 1.46 (1.225-1.740); p = 0.003] and homozygous recessive models [OR = 2.970 (2.086-4.227); RR = 1.798 (1.501-2.154); p = <0.0001] analysis of rs1544410 in the VDR gene. These findings suggest that the VDR gene is associated with T2DM and genotype GG of genetic variant rs1544410 is the susceptible genotype in our Pakistani cohort.

SUBMITTER: Khan A

PROVIDER: S-EPMC6956633 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND AIMS:Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM). MATERIALS AND METHODS:We have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1-2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum. RESULTS:After adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567-6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = -5.478, 95% CI: -8.315 to -2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = -6.319, 95% CI: -9.466 to -3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes. CONCLUSIONS:This study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results.

Project description:BACKGROUND: Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown. METHODS: From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04). CONCLUSIONS: Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome.

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Association of VDR Gene Variant (rs1544410) with Type 2 Diabetes in a Pakistani Cohort.

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