Genealogical analysis as a new approach for the investigation of drug intolerance heritability

Abstract

Genealogical analysis has proven a useful method to understand the origins and frequencies of hereditary diseases in many populations. However, this type of analysis has not yet been used for the investigation of drug intolerance among patients suffering from inherited disorders. This study aims to do so, using data from familial hypercholesterolemia (FH) patients receiving high doses of statins. The objective is to measure and compare various genealogical parameters that could shed light on the origins and heritability of muscular intolerance to statins using FH as a model. Analysis was performed on 224 genealogies from 112 FH subjects carrying either the low-density lipoprotein receptor (LDLR) prom_e1 deletion>15 kb (n=28) or c.259T>G (p.Trp87Gly) (n=84) mutations and 112 non-FH controls. Number of ancestors, geographical origins and genetic contribution of founders, inbreeding and kinship coefficients were calculated using the S-Plus-based GENLIB software package. For both mutations, repeated occurrences of the same ancestors are more frequent among the carriers' genealogies than among the controls', but no difference was observed between tolerant and intolerant subjects. Founders who may have introduced both mutations in the population appear with approximately the same frequencies in all genealogies. Kinship coefficients are higher among carriers, with no difference according to statins tolerance. Inbreeding coefficients are slightly lower among >15-kb deletion carriers than among c.259 T>G carriers, but the differences between tolerants and intolerants are not significant. These findings suggest that although muscular intolerance to statins shows a family aggregation, it is not transmitted through the same Mendelian pattern as LDLR mutations.

Figure 1

Location of the Saguenay-Lac-Saint-Jean region.

Figure 2

Distribution of immigrant and regional founders according to their presence in the genealogies of statin-tolerant and statin-intolerant carriers of >15-kb deletion and c.259 T>G mutation. (a) Immigrant founders. (b) Regional founders.

Figure 3

Genetic contributions of immigrant founders to statin-tolerant and statin-intolerant carriers of >15-kb deletion and c.259 T>G mutation. (a) >15-kb deletion. (b) 259 T>G.

Figure 4

Kinship coefficients among statin-tolerant and statin-intolerant carriers and non-carriers (controls) of >15-kb deletion and c.259T>G mutation.

Figure 5

Inbreeding coefficients among statin-tolerant and statin-intolerant carriers of >15-kb deletion and c.259 T>G mutation per generation.