Cleft Palate Craniofac J. 2022 Sep 18:10556656221125392. doi: 10.1177/10556656221125392. Online ahead of print.
OBJECTIVE: The role of MMP16 in lip development is unclear. This study aimed to identify nonsyndromic cleft lip with or without palate (NSCL ± P) susceptible loci of MMP16 in western Han Chinese.
DESIGN: We performed targeted sequencing around MMP16 combined with a 2-phase association analysis on common variants. Phase 2 association analysis was performed with NSCL ± P specific subphenotypes (NSCL and NSCLP). Then we used rare variants burden analysis and genotyping, accompanied by motif analysis.
SETTING: This study was completed in a tertiary medical center.
PATIENTS, PARTICIPANTS: Phase 1 targeted sequencing included 159 patients with NSCL ± P and 542 normal controls; phase 2 included 1626 patients with NSCL ± P (1047 NSCL and 579 NSCLP) and 2255 normal controls.
INTERVENTIONS: Venous blood samples were collected from patients and used to extract DNA.
MAIN OUTCOME MEASURES: After Bonferroni correction, phase 1 significant threshold of p-value was 4.28 × 10-5 (0.05/1167 single nucleotide polymorphisms [SNPs]), and phase 2 was .00025 (0.05/200 SNPs). Burden analysis significant threshold p-value was .05.
RESULTS: Common variants phase 1 association analysis identified 11 statistically significant SNPs (lowest p = 1.90 × 10-9, odds ratio (OR) = 0.27, 95% CI: 0.17-0.44), phase 2 replication identified 16 SNPs in NSCL ± P (lowest p = 6.26 × 10-6, OR = 0.77, 95% CI: 0.69-0.86) and 9 in NSCL (lowest p = 8.44 × 10-5, OR = 0.76, 95% CI: 0.66-0.87). Rare variants burden analysis showed no significant results, genotyping results showed they were maternally inherited.
CONCLUSIONS: Our study identified MMP16 susceptible SNPs in NSCL ± P and NSCL, emphasizing its potential role in lip development. Our study also highlighted the importance to perform association analysis with subphenotypes divided.