مختصر البحث:
Background: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder involving impaired β-cell
function and insulin resistance. Zinc transporter 8 (ZnT8), encoded by SLC30A8, contributes to zinc transport
into insulin secretory granu…
Background: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder involving impaired β-cell
function and insulin resistance. Zinc transporter 8 (ZnT8), encoded by SLC30A8, contributes to zinc transport
into insulin secretory granules and is involved in insulin crystallization and regulated insulin secretion. Therefore,
genetic variation in SLC30A8 may influence susceptibility to T2DM.
Objective: This study evaluated the association of SLC30A8 polymorphisms rs11558471 and rs35859536 with
T2DM risk and selected metabolic phenotypes in Iraqi adults.
Methods: This case-control study included 296 unrelated Iraqi adults, comprising 150 patients with T2DM and
146 non-diabetic controls. Genotyping was performed using allele-specific polymerase chain reaction. Genetic
associations were tested under codominant, dominant, recessive, overdominant, and log-additive inheritance
models. Model fit was assessed using the Akaike Information Criterion and Bayesian Information Criterion.
Logistic regression models were adjusted for age, sex, and BMI. Additive regression, multivariate analysis of
covariance, and haplotype analysis were also performed. Secondary genotype–phenotype analyses were
considered exploratory.
Results: rs11558471 was significantly associated with T2DM across multiple inheritance models. After adjustment
for age, sex, and BMI, A/G and A/A genotypes were associated with increased odds of T2DM compared
with the G/G genotype [adjusted odds ratio = 3.24, 95% confidence interval: 1.68–6.25; and adjusted odds ratio
= 16.27, 95% confidence interval: 5.34–49.57, respectively]. The log-additive model showed the lowest Akaike
Information Criterion and Bayesian Information Criterion values, supporting an allele-dose association [adjusted
odds ratio per A allele = 3.72, 95% confidence interval: 2.34–5.90]. rs11558471 was also associated with HbA1c,
fasting blood glucose, insulin, LDL cholesterol, and total cholesterol. rs35859536 showed a possible protective
association mainly under the recessive model [adjusted odds ratio = 0.09, 95% confidence interval: 0.01–0.88],
which also had the lowest Akaike Information Criterion and Bayesian Information Criterion values. Haplotype
analysis showed a significant global association, with the C–G haplotype associated with higher estimated odds
of T2DM.
Conclusion: SLC30A8 regulatory variation, particularly rs11558471, was associated with T2DM susceptibility
among Iraqi adults. The best-fitting log-additive model supports an allele-dose relationship for rs11558471,
while rs35859536 showed a possible recessive protective association. These findings support further investigation
of SLC30A8/ZnT8-related β-cell pathways in T2DM susceptibility; however, replication in larger independent
cohorts and functional validation are required before clinical or predictive application.
