Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

**Background:** Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with both microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (cardiovascular) complications. Genetic factors contribute to complication risk, but most studies have focused on European populations, leaving Middle Eastern populations underrepresented. This study aimed to identify susceptibility loci for T2DM complications in the Emirati population using an exome-wide association study (EWAS).

**Methods:** This prospective cross-sectional study recruited 338 T2DM patients from the Dubai Diabetes Center between October 2020 and July 2021. After quality control, 310 individuals (153 men, 157 women; age 14-86 years) and 39,840 SNPs were analyzed. Participants were stratified into four complication groups: retinopathy (n=62), neuropathy (n=47), nephropathy (n=22), and cardiovascular (n=42). DNA was extracted and genotyped using the Illumina Infinium Exome-24 array. Logistic regression assuming additive allelic effects was performed adjusting for age, sex, and BMI. A suggestive association threshold of p<5×10⁻⁴ was used; the Bonferroni-corrected significance threshold was p<1.2×10⁻⁶.

**Key Results:** For retinopathy, significant associations were found with SHANK3 (rs9616915; OR=0.46, p=5.18×10⁻⁴), ZSCAN5A (rs7252603; OR=0.48, p=7.55×10⁻⁴), and DCP1B (rs715146, rs1044950, rs113147414, rs34730825; OR=3.06, p=7.62×10⁻⁴). For neuropathy, associations included ADH4 (rs4148883; OR=2.52, p=1.23×10⁻⁴), SLC11A1 (rs17235409; OR=5.04, p=1.85×10⁻⁴), and MATN4 (rs2072788; OR=2.29, p=2.68×10⁻⁴). For nephropathy, associations included PPP1R3A (rs1799999; OR=3.52, p=1.91×10⁻⁴), ZNF136 (rs140861589; OR=15.82, p=2.80×10⁻⁴), and HSPA12B (rs6076550; OR=14.20, p=2.86×10⁻⁴). For cardiovascular complications, associations included PCNT (rs7279204, rs6518289, rs2839227, rs2839223; ORs 2.70-3.27, p=2.18×10⁻⁴ to 5.22×10⁻⁴), SEPT14 (rs146350220; OR=11.00, p=2.77×10⁻⁴), and WDR73 (rs72750868; OR=5.49, p=4.47×10⁻⁴). Demographic analysis showed that neuropathy and cardiovascular complication patients were significantly older (p<0.001) and had longer diabetes duration (p<0.001). Retinopathy cases had significantly higher median HbA1c (7.75% vs 7.01%, p=0.002).

**Clinical Implications:** This study identifies novel genetic loci associated with T2DM complications in an underrepresented Emirati population. The findings may inform the development of population-specific genetic screening panels for early detection and targeted therapy. However, only 16% of markers from the Euro-centric array passed quality control, indicating that many variants are monomorphic or absent in Arab populations, potentially missing functionally important loci. This highlights the urgent need for inclusive genotyping platforms and larger multi-ethnic studies to ensure equitable benefits from genomic medicine.