Table 3. Association of rare LIPG regulatory variants with HDL-C phenotypic extremes.

Discovery cohort	Variants identified	Individualswith variantb	Association with discovery cohort (P value)c	Functional variants (effect direction)d	Individuals with variant decreasing promoter activity	Association for variants decreasing promoter activity (P value)e	Individuals with variant increasing promoter activity	Association for variants increasing promoter activity (P value)f	Individuals with exclusive variant decreasing promoter activityg	Association for exclusive variants decreasing promoter activity (P value)h	Individuals with exclusive variant increasing promoter activityg	Association for exclusive variants increasing promoter activityi
HHDL Sequencing Cohort	−1487 A>G	16	0.2142	−1487 A>G (↓)	6	0.0301	1	0.0364	6	0.0301	0	0.0297
	−1324 C>T			−1080 G>T (↓)
	−1234 C>T			−537 T>C (↓)
	−1080 G>T			−410 C>G (↓)
	−612 C>A
	−537 T>C			−303 A>G (↑)a
	−410 C>G
	−403 C>G
	−274 C>T
	−19 A>G
	−324 A>Ga
	−303 A>Ga
LHDL Sequencing Cohort	−1666 G>C	9		−1666 G>C (↑)	0		7		0		5
	−1223 A>G			−1223 A>G (↑)
	−1052 C>A			−1052 C>A (↑)
	−175 G>A			−175 G>A (↑)
	44 T>C
	−324 A>Ga			−303 A>G (↑)a
	−303 A>Ga

^aRare variants found in individuals from both HHDL and LHDL Sequencing Cohorts.

^bIndividuals were included if they harbored at least 1 rare LIPG regulatory variant of those identified. Three individuals from the HHDL Sequencing Cohort had two rare regulatory mutations each: one with −1487 A>G and −1080 G>T, one with −1234 C>T and −324 A>G, and one with −1487 A>G and −303 A>G. All three individuals were included once each in the total counts.

^cThe number of individuals with a rare variant was compared between the 2 cohorts with a 2-tailed Fisher's exact test. All rare variants were considered, regardless of functional impact on LIPG expression and including variants found in both sequencing cohorts.

^dFunctional variants were found to alter LIPG promoter activity relative to WT in vitro by luciferase reporter assays (Figure 2).

^eVariants decreasing promoter activity were tested for association with the HHDL Sequencing Cohort with a 2-tailed Fisher's exact test. All functional variants decreasing promoter activity were tested, including variants found in both sequencing cohorts.

^fVariants increasing promoter activity were tested for association with the LHDL Sequencing Cohort with a 2-tailed Fisher's exact test. All functional variants increasing promoter activity were tested, including variants found in both sequencing cohorts.

^gExclusive variants are defined as variants occurring in individuals in either of the 2 sequencing cohorts.

^hNumber of individuals with a rare exclusive variant decreasing promoter activity was compared between the 2 cohorts via 2-tailed Fisher's exact test.

ⁱNumber of individuals with a rare exclusive variant increasing promoter activity was compared between the 2 cohorts via 2-tailed Fisher's exact test.